A synthetic eicosanoid LX-mimetic unravels host-donor interactions in allogeneic BMT-induced GvHD to reveal an early protective role for host neutrophils.

PubMed

Devchand, Pallavi R; Schmidt, Birgitta A; Primo, Valeria C; Zhang, Qing-yin; Arnaout, M Amin; Serhan, Charles N; Nikolic, Boris

2005-02-01

Lipoxin A(4) (LXA(4)) and aspirin-triggered 15-epi-LXA(4) are potent endogenous lipid mediators thought to define the inflammatory set-point. We used single prophylactic administrations of a synthetic aspirin-triggered lipoxin A(4) signal mimetic, ATLa, to probe dynamics of early host-donor interactions in a mouse model for the inflammation-associated multifactorial disease of allogeneic bone marrow transplant (BMT) -induced graft-vs.-host disease (GvHD). We first demonstrated that both host and donor are responsive to the ATLa signals. The simple and restricted regimen of a single prophylactic administration of ATLa [100 ng/mL to donor cells or 1 microg (approximately 50 microg/kg) i.v. to host] was sufficient to delay death. Clinical indicators of weight, skin lesions, diarrhea and eye inflammation were monitored. Histological analyses on day 45 post-BMT showed that the degree of cellular trafficking, particularly neutrophil infiltrate, and protection of end-organ target pathology are different, depending on whether the host or donor was treated with ATLa. Taken together, these results chart some ATLa protective effects on GvHD cellular dynamics over time and identify a previously unrecognized effect of host neutrophils in the early phase post-BMT as important determinants in the dynamics of GvHD onset and progression.-Devchand, P. R., Schmidt, B. A., Primo, V. C., Zhang, Q.-y., Arnaout, M. A., Serhan, C. N., Nikolic, B. A synthetic eicosanoid LX-mimetic unravels host-donor interactions in allogeneic BMT-induced GvHD to reveal an early protective role for host neutrophils.

Adoptively transferred TRAIL+ T cells suppress GVHD and augment antitumor activity

PubMed Central

Ghosh, Arnab; Dogan, Yildirim; Moroz, Maxim; Holland, Amanda M.; Yim, Nury L.; Rao, Uttam K.; Young, Lauren F.; Tannenbaum, Daniel; Masih, Durva; Velardi, Enrico; Tsai, Jennifer J.; Jenq, Robert R.; Penack, Olaf; Hanash, Alan M.; Smith, Odette M.; Piersanti, Kelly; Lezcano, Cecilia; Murphy, George F.; Liu, Chen; Palomba, M. Lia; Sauer, Martin G.; Sadelain, Michel; Ponomarev, Vladimir; van den Brink, Marcel R.M.

2013-01-01

Current strategies to suppress graft-versus-host disease (GVHD) also compromise graft-versus-tumor (GVT) responses. Furthermore, most experimental strategies to separate GVHD and GVT responses merely spare GVT function without actually enhancing it. We have previously shown that endogenously expressed TNF-related apoptosis-inducing ligand (TRAIL) is required for optimal GVT activity against certain malignancies in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In order to model a donor-derived cellular therapy, we genetically engineered T cells to overexpress TRAIL and adoptively transferred donor-type unsorted TRAIL+ T cells into mouse models of allo-HSCT. We found that murine TRAIL+ T cells induced apoptosis of alloreactive T cells, thereby reducing GVHD in a DR5-dependent manner. Furthermore, murine TRAIL+ T cells mediated enhanced in vitro and in vivo antilymphoma GVT response. Moreover, human TRAIL+ T cells mediated enhanced in vitro cytotoxicity against both human leukemia cell lines and against freshly isolated chronic lymphocytic leukemia (CLL) cells. Finally, as a model of off-the-shelf, donor-unrestricted antitumor cellular therapy, in vitro–generated TRAIL+ precursor T cells from third-party donors also mediated enhanced GVT response in the absence of GVHD. These data indicate that TRAIL-overexpressing donor T cells could potentially enhance the curative potential of allo-HSCT by increasing GVT response and suppressing GVHD. PMID:23676461

[Differential regulation of CCR5 expression on T lymphocytes in healthy donors after mobilization with rhG-CSF and its correlation with aGVHD].

PubMed

Wang, Meng; Ma, Xiang-Juan; Dong, Yu-Jun; Qiu, Zhi-Xiang; Liu, Wei; Li, Yuan; Wang, Mang-Ju; Sun, Yu-Hua; Ren, Han-Yun

2013-08-01

This study was to investigate the differential regulation of CCR5 expression on T cells in healthy donors after mobilization with recombinant human granulocyte colony-stimulating factor (rhG-CSF) and analyze its correlation with acute graft-versus-host disease (aGVHD) so as to understand the possible mechanisms underlying rhG-CSF-induced immune tolerance. Sixty-eight related healthy donor and their corresponding recipient for allogeneic hematopoietic stem cell transplantation (allo-HSCT) were enrolled in this study. The expression of CCR5 on CD4(+) and CD8(+) T cells in the peripheral blood (PB) before and after mobilization were detected by using flow cytometry (FCM) respectively. According to the changes of CCR5 expression on CD4(+) and CD8(+) T cells, the Sixty-two evaluable donors were divided into the downregulated and unchanged/upregulated (non-downregulated) groups, and the incidence of grades II to IV aGVHD in two groups were compared. The results showed that the mean value of CCR5 expression on CD4(+) and CD8(+) T cells in PB was not different significantly after mobilization (P > 0.05). Apparent inconsistency was showed among different individuals. Thirty-four (50%) donors displayed downregulation of CCR5 expression, while 34 (50%) donors manifested unchanged or upregulated CCR5 expression on CD4(+) T cells. CCR5 expression on CD8(+) T cells was downregulated in 42 (61.8%), unchanged or upregulated in 26 (38.3%) donors. The cumulative incidence of grades II to IV aGVHD in the downregulated and non-downregulated groups for CD4(+) T cells were 16.1% and 41.9% (P = 0.032), and recipients with CCR5 downregulation on CD8(+) T cells showed an increased tendency of developing aGVHD (37.8% vs 16.0%, P = 0.065). In conclusion, rhG-CSF mobilization could lead to differential regulation of CCR5 expression on T cells, which might influence the migration of T cells in vivo, decrease T cell trafficking towards GVHD target organs, and thus reduce the incidence of aGVHD

Origin of Langerhans cells in normal skin and chronic GVHD after hematopoietic stem-cell transplantation.

PubMed

Andani, Rafiq; Robertson, Ivan; Macdonald, Kelli P A; Durrant, Simon; Hill, Geoffrey R; Khosrotehrani, Kiarash

2014-01-01

Chronic graft-versus-host disease (cGVHD) is a common complication following allogeneic stem-cell transplantation (SCT). Past studies have implicated the persistence of host antigen-presenting cells (APCs) in GVHD. Our objective was to determine the frequency of host Langerhans cells (LCs) in normal skin post-SCT and ask if their persistence could predict cGVHD. Biopsies of normal skin from 124 sex-mismatched T-cell-replete allogenic SCT recipients were taken 100 days post-transplant. Patients with acute GVHD and those with <9 months of follow-up were excluded and prospective follow-up information was collected from remaining 22 patients. CD1a staining and X and Y chromosome in-situ hybridization were performed to label LCs and to identify their host or donor origin. At 3 months, 59 ± 5% of LCs were host derived. The density of LCs and the proportion of host-derived LCs were similar between patients that did or did not develop cGVHD. Most LCs in the skin remained of host origin 3 months after SCT regardless of cGVHD status. This finding is in line with the redundant role of LCs in acute GVHD initiation uncovered in recent experimental models. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Uptake and use of recommendations for the diagnosis, severity scoring and management of chronic GVHD: an international survey of the EBMT-NCI Chronic GVHD Task Force.

PubMed

Duarte, R F; Greinix, H; Rabin, B; Mitchell, S A; Basak, G; Wolff, D; Madrigal, J A; Pavletic, S Z; Lee, S J

2014-01-01

In 2005, the National Institutes of Health (NIH) consensus conference published a series of papers recommending methods to improve the conduct of clinical trials in chronic GVHD. Although the NIH recommendations were primarily aimed at strengthening research, several papers addressed issues relevant for clinical practice, particularly diagnosis, severity scoring, and ancillary and supportive care practices. We conducted an international survey to assess the uptake of these recommendations, identify barriers to greater use and document the use and perceived effectiveness of available treatments. The response rate for the American survey of 1387 practitioners was 21.8%, and it was 24.6% for 407 centers surveyed in Europe, Asia, Australia and Africa. Most respondents were familiar with the NIH consensus recommendations (94-96%) and used them in practice. Multiple barriers to greater use were reported. Besides lack of time (55-62%), unfamiliarity with the recommendations, scarcity of evidence supporting the impact of recommendations on outcomes, insufficient training/experience in chronic GVHD management and inaccessibility of subspecialists were also endorsed. Systemic corticosteroids were reported to be the most effective treatment for chronic GVHD, but many others were perceived to have moderate or great success. Therapeutic management of steroid-refractory chronic GVHD was identified as the highest priority for research.

Pirfenidone ameliorates murine chronic GVHD through inhibition of macrophage infiltration and TGF-β production

PubMed Central

Du, Jing; Paz, Katelyn; Flynn, Ryan; Vulic, Ante; Robinson, Tara M.; Lineburg, Katie E.; Alexander, Kylie A.; Meng, Jingjing; Roy, Sabita; Panoskaltsis-Mortari, Angela; Loschi, Michael; Hill, Geoffrey R.; Serody, Jonathan S.; Maillard, Ivan; Miklos, David; Koreth, John; Cutler, Corey S.; Antin, Joseph H.; Ritz, Jerome; MacDonald, Kelli P.; Schacker, Timothy W.; Luznik, Leo

2017-01-01

Allogeneic hematopoietic stem cell transplantation is hampered by chronic graft-versus-host disease (cGVHD), resulting in multiorgan fibrosis and diminished function. Fibrosis in lung and skin leads to progressive bronchiolitis obliterans (BO) and scleroderma, respectively, for which new treatments are needed. We evaluated pirfenidone, a Food and Drug Administration (FDA)-approved drug for idiopathic pulmonary fibrosis, for its therapeutic effect in cGVHD mouse models with distinct pathophysiology. In a full major histocompatibility complex (MHC)-mismatched, multiorgan system model with BO, donor T-cell responses that support pathogenic antibody production are required for cGVHD development. Pirfenidone treatment beginning one month post-transplant restored pulmonary function and reversed lung fibrosis, which was associated with reduced macrophage infiltration and transforming growth factor-β production. Pirfenidone dampened splenic germinal center B-cell and T-follicular helper cell frequencies that collaborate to produce antibody. In both a minor histocompatibility antigen–mismatched as well as a MHC-haploidentical model of sclerodermatous cGVHD, pirfenidone significantly reduced macrophages in the skin, although clinical improvement of scleroderma was only seen in one model. In vitro chemotaxis assays demonstrated that pirfenidone impaired macrophage migration to monocyte chemoattractant protein-1 (MCP-1) as well as IL-17A, which has been linked to cGVHD generation. Taken together, our data suggest that pirfenidone is a potential therapeutic agent to ameliorate fibrosis in cGVHD. PMID:28254742

The predictive value of selected serum microRNAs for acute GVHD by TaqMan MicroRNA arrays.

PubMed

Zhang, Chunyan; Bai, Nan; Huang, Wenrong; Zhang, Pengjun; Luo, Yuan; Men, Shasha; Wen, Ting; Tong, Hongli; Wang, Shuhong; Tian, Ya-Ping

2016-10-01

Currently, the diagnosis of acute graft-versus-host disease (aGVHD) is mainly based on clinical symptoms and biopsy results. This study was designed to further explore new no noninvasive biomarkers for aGVHD prediction/diagnosis. We profiled miRNAs in serum pools from patients with aGVHD (grades II-IV) (n = 9) and non-aGVHD controls (n = 9) by real-time qPCR-based TaqMan MicroRNA arrays. Then, predictive models were established using related miRNAs (n = 38) and verified by a double-blind trial (n = 54). We found that miR-411 was significantly down regulated when aGVHD developed and recovered when aGVHD was controlled, which demonstrated that miR-411 has potential as an indicator for aGVHD monitoring. We developed and validated a predictive model and a diagnostic model for aGVHD. The predictive model included two miRNAs (miR-26b and miR-374a), which could predict an increased risk for aGVHD 1 or 2 weeks in advance, with an AUC, Positive Predictive Value (PPV), and Negative Predictive Value (NPV) of 0.722, 76.19 %, and 69.70 %, respectively. The diagnostic model included three miRNAs (miR-28-5p, miR-489, and miR-671-3p) with an AUC, PPV, and NPV of 0.841, 85.71 % and 83.33 %, respectively. Our results show that circulating miRNAs (miR-26b and miR-374a, miR-28-5p, miR-489 and miR-671-3p) may serve as biomarkers for the prediction and diagnosis of grades II-IV aGVHD.

Assessment of dry eye in a GVHD murine model: Approximation through tear osmolarity measurement.

PubMed

Martínez-Carrasco, Rafael; Sánchez-Abarca, Luis Ignacio; Nieto-Gómez, Cristina; García, Elisabet Martín; Ramos, Teresa L; Velasco, Almudena; Sánchez-Guijo, Fermín; Aijón, José; Hernández-Galilea, Emiliano

2017-01-01

Dry eye disease is one of the most frequent pathological events that take place in the course of the graft versus host disease (GVHD), and is the main cause of deterioration in quality of life for patients. Thus, demonstration of dry eye signs in murine models of oGVHD is crucial for the validation of these models for the study of the disease. Given the increasing evidence that tear osmolarity is an important player of dry eye disease, our purpose in this study was to validate the use of a reliable method to assess tear osmolarity in mice: the electrical impedance method. Then, we wanted to test its utility with an oGVHD model. Tear volume assessment was also performed, using the phenol red thread test. We found differences in tear osmolarity in mice that received a transplant with cells from bone marrow and spleen (the GVHD group) when compared with mice that only received bone marrow cells (the BM group) at day 7 (362 ± 8 mOsm/l and 345 ± 9 mOsm/l respectively; P < 0.01) and day 21 (348 ± 19 mOsm/l vs. 326 ± 15 mOsm/l; P < 0.05). We found also differences in tear volume at day 14 (2.30 ± 0.61 mm in oGVHD group and 2.89 ± 0.62 mm in BM group; P = 0.06) and at day 21 (2.10 ± 0.30 mm in oGVHD group and 2.89 ± 0.32 mm in BM group; P < 0.01). Besides this, we observed reduction in epithelial thickness between the GVHD and BM groups (37.0 ± 6.2 μm and 43.6 ± 3.3 μm respectively; P < 0.05). These data show the usefulness of the electrical impedance method to measure tear osmolarity in mice. We can also conclude that this oGVHD model mimics the tear film alterations found in human dry eye disease, what contributes to give relevance to this model for the study of GVHD. Copyright © 2016 Elsevier Ltd. All rights reserved.

Pirfenidone ameliorates murine chronic GVHD through inhibition of macrophage infiltration and TGF-β production.

PubMed

Du, Jing; Paz, Katelyn; Flynn, Ryan; Vulic, Ante; Robinson, Tara M; Lineburg, Katie E; Alexander, Kylie A; Meng, Jingjing; Roy, Sabita; Panoskaltsis-Mortari, Angela; Loschi, Michael; Hill, Geoffrey R; Serody, Jonathan S; Maillard, Ivan; Miklos, David; Koreth, John; Cutler, Corey S; Antin, Joseph H; Ritz, Jerome; MacDonald, Kelli P; Schacker, Timothy W; Luznik, Leo; Blazar, Bruce R

2017-05-04

Allogeneic hematopoietic stem cell transplantation is hampered by chronic graft-versus-host disease (cGVHD), resulting in multiorgan fibrosis and diminished function. Fibrosis in lung and skin leads to progressive bronchiolitis obliterans (BO) and scleroderma, respectively, for which new treatments are needed. We evaluated pirfenidone, a Food and Drug Administration (FDA)-approved drug for idiopathic pulmonary fibrosis, for its therapeutic effect in cGVHD mouse models with distinct pathophysiology. In a full major histocompatibility complex (MHC)-mismatched, multiorgan system model with BO, donor T-cell responses that support pathogenic antibody production are required for cGVHD development. Pirfenidone treatment beginning one month post-transplant restored pulmonary function and reversed lung fibrosis, which was associated with reduced macrophage infiltration and transforming growth factor-β production. Pirfenidone dampened splenic germinal center B-cell and T-follicular helper cell frequencies that collaborate to produce antibody. In both a minor histocompatibility antigen-mismatched as well as a MHC-haploidentical model of sclerodermatous cGVHD, pirfenidone significantly reduced macrophages in the skin, although clinical improvement of scleroderma was only seen in one model. In vitro chemotaxis assays demonstrated that pirfenidone impaired macrophage migration to monocyte chemoattractant protein-1 (MCP-1) as well as IL-17A, which has been linked to cGVHD generation. Taken together, our data suggest that pirfenidone is a potential therapeutic agent to ameliorate fibrosis in cGVHD. © 2017 by The American Society of Hematology.

Defining Genetic Risk for GVHD and Mortality Following Allogeneic Hematopoietic Stem Cell Transplantation

PubMed Central

Hansen, John A; Chien, Jason W; Warren, Edus H; Zhao, Lue Ping; Martin, Paul J

2011-01-01

Purpose of review To explore what is known about the genetics of hematopoietic stem cell transplantation (HCT) and how genetic polymorphism affects risk of graft-versus-host disease (GVHD) and mortality. Recent findings Genetic variation found across the human genome can impact HCT outcome by 1) causing genetic disparity between patient and donor, and 2) modifying gene function. Single nucleotide polymorphisms (SNP) and structural variation can result in mismatching for cellular peptides known as histocompatibility antigens (HA). At least 25 to 30 polymorphic genes are known to encode functional HA in mismatched individuals, but their individual contribution to clinical GVHD is unclear. HCT outcome may also be affected by polymorphism in donor or recipient. Association studies have implicated several genes with GVHD and mortality, however results have been inconsistent most likely due to limited sample size, and differences in racial diversity and clinical covariates. New technologies using DNA arrays genotyping for a million or more SNPs promise genome-wide discovery of HCT associated genes, however adequate statistical power requires study populations of several thousand patient-donor pairs. Summary Available data offers strong preliminary support for the impact that genetic variation has on risk of GVHD and mortality following HCT. Definitive results however await future genome-wide studies of large multi-center HCT cohorts. PMID:20827186

Translation, Cross Cultural Adaptation and Validation of the Lee Chronic Graft-versus-Host Disease (GVHD) Symptom Scale in a Brazilian Population

PubMed Central

de Souza, Clarissa Vasconcellos; Vigorito, Afonso Celso; Miranda, Eliana C M; Garcia, Celso; Colturato, Vergílio Antonio Rensi; Mauad, Marcos Augusto; Moreira, Maria Cláudia Rodrigues; da Silva Bouzas, Luis Fernando; Lermontov, Simone; Hamerschlak, Nelson; Rodrigues, Morgani; de Almeida Barros, Jose Carlos; Chiattone, Ricardo; Lee, Stephanie J; Flowers, Mary ED

2017-01-01

The Lee chronic graft-versus-disease (cGVHD) Symptom Scale is a patient-reported instrument developed and validated in English to measure symptoms and functional impact of cGVHD. This tool has not been validated in a Latin America population. The Brazil-Seattle Chronic GVHD Consortium conducted a multicenter study at five Brazilian institutions to validate the Lee cGVHD Symptom Scale in adults with chronic GVHD. Study objectives included the translation and validation of the instrument in Brazilian Portuguese and evaluation of the correlation with other quality of life (QoL) tools (i.e., Medical Outcomes Study Short Form 36 [SF-36] and the Functional Assessment of Chronic Illness Therapy with Bone Marrow Transplant subscale [FACT-BMT]). Translation and validation were according to the American Association of Orthopedic Surgeons Outcome Committee guideline. Spearman’s correlation coefficient was used to measure construct validity. Reliability was assessed using Cronbach’s alpha and intraclass correlation coefficients. Between April 2011 and August 2012, 47 patients with cGVHD by the 2005 NIH criteria were enrolled in this study. Cohort median age was 48 (23–69) years and 29 (62%) were male. Lee cGVHD Symptom Scale reliability was adequate (Cronbach’s alpha 0.62–0.83). The correlations between similar domains of the Lee cGVHD Symptom Scale, SF-36 and FACT-BMT were moderate to high. The Brazilian Portuguese version of the Lee cGVHD Symptom Scale is valid and reliable and can be used in clinical trials of cGVHD in Brazil. PMID:27058616

Development, preliminary usability and accuracy testing of the EBMT 'eGVHD App' to support GvHD assessment according to NIH criteria-a proof of concept.

PubMed

Schoemans, H; Goris, K; Durm, R V; Vanhoof, J; Wolff, D; Greinix, H; Pavletic, S; Lee, S J; Maertens, J; Geest, S D; Dobbels, F; Duarte, R F

2016-08-01

The EBMT Complications and Quality of Life Working Party has developed a computer-based algorithm, the 'eGVHD App', using a user-centered design process. Accuracy was tested using a quasi-experimental crossover design with four expert-reviewed case vignettes in a convenience sample of 28 clinical professionals. Perceived usefulness was evaluated by the technology acceptance model (TAM) and User satisfaction by the Post-Study System Usability Questionnaire (PSSUQ). User experience was positive, with a median of 6 TAM points (interquartile range: 1) and beneficial median total, and subscale PSSUQ scores. The initial standard practice assessment of the vignettes yielded 65% correct results for diagnosis and 45% for scoring. The 'eGVHD App' significantly increased diagnostic and scoring accuracy to 93% (+28%) and 88% (+43%), respectively (both P<0.05). The same trend was observed in the repeated analysis of case 2: accuracy improved by using the App (+31% for diagnosis and +39% for scoring), whereas performance tended to decrease once the App was taken away. The 'eGVHD App' could dramatically improve the quality of care and research as it increased the performance of the whole user group by about 30% at the first assessment and showed a trend for improvement of individual performance on repeated case evaluation.

Costimulatory molecule-targeted immunotherapy of cutaneous graft-versus-host disease.

PubMed

Kim, Juyang; Kim, Hye J; Park, Keunhee; Kim, Jiyoung; Choi, Hye-Jeong; Yagita, Hideo; Nam, Seok H; Cho, Hong R; Kwon, Byungsuk

2007-07-15

Chronic graft-versus-host disease (cGVHD) is an increasingly frequent complication of allogeneic stem cell transplantation. Current therapies for cGVHD reduce symptoms but are not cures. The B10.D2-->Balb/c (H-2(d)) minor histocompatibility antigen-mismatched model, which reflects clinical and pathological symptoms of human cGVHD, was used in this study. We demonstrated that a single injection of an agonistic monoclonal antibody (mAb) against CD137, a member of the tumor necrosis factor receptor superfamily, reverses skin fibrosis, ulceration, and alopecia, a dominant feature of cGVHD (cutaneous GVHD), ultimately improving general health conditions. The reversal is associated with markedly reduced CD4(+) T-cell cytokines and increased apoptosis of donor CD4(+) T cells. The Fas pathway is required for ameliorating cutaneous GVHD by anti-CD137 mAb. Taken together, these data indicate that the anti-CD137 mAb has a therapeutic effect on cutaneous GVHD by removing donor CD4(+) T cells that cause cutaneous GVHD. Thus, our study demonstrates an agonistic mAb, specific for a costimulatory molecule, as a possible target for therapeutic intervention in cutaneous GVHD.

Higher CD3(+) and CD34(+) cell doses in the graft increase the incidence of acute GVHD in children receiving BMT for thalassemia.

PubMed

Gaziev, J; Isgrò, A; Marziali, M; Daniele, N; Gallucci, C; Sodani, P; Simone, M D; Adorno, G; Paciaroni, K; Andreani, M; Lanti, A; Del Proposto, G; Testi, M; De Angelis, G; Roveda, A; Alfieri, C; Saltarelli, F; Lucarelli, G

2012-01-01

We evaluated the incidence of GVHD, risk factors and the impact of graft composition on acute GVHD (aGVHD) in 92 children who underwent BMT for thalassemia following busulfan/cyclophosphamide (BUCY)-based conditioning regimens and GVHD prophylaxis with CSA/short-MTX and methylprednisolone. The incidence of grade 2-4 and 3-4 aGVHD was 35% (95% confidence interval (CI) 25-44) and 9% (95% CI 4-16), respectively. We found that CD3(+) and CD34(+) cell doses above the median were associated with high incidence of grade 2-4 aGVHD (49 vs 20%, P=0.005 and 46 vs 23%, P=0.021, respectively). In multivariate analysis, high CD3(+) (hazard ratio (HR) 4.6; 95% CI 1.4-14.7; P=0.010) and CD34(+) (HR 4.3; 95% CI 1.4-12.7; P=0.011) cell doses were associated with grade 2-4 aGVHD. We further examined the effect of CD3(+) and CD34(+) cell doses on aGVHD using quartile cutoff points and found a minimum threshold for CD3(+) (38 × 10(6)/kg) and CD34(+) (4 × 10(6)/kg) cells above which the incidence of grade 2-4 aGVHD is significantly increased. This study shows for the first time a positive correlation between the number of CD3(+) and CD34(+) cells and aGVHD in children receiving sibling BMT, and indicates that using tailored and more intensive post transplant immunosuppression may permit to better control aGVHD.

Improved outcome of children transplanted for high-risk leukemia by using a new strategy of cyclosporine-based GVHD prophylaxis.

PubMed

Bleyzac, N; Cuzzubbo, D; Rénard, C; Garnier, N; Dubois, V; Domenech, C; Goutagny, M-P; Plesa, A; Grardel, N; Goutelle, S; Janoly-Duménil, A; Bertrand, Y

2016-05-01

There is currently a major concern regarding the optimal immunosuppression therapy to be administered after hematopoietic stem cell transplantation (HSCT) to reduce both the toxicity of GvHD and the rate of relapse. We report the outcome of high-risk leukemia children transplanted with a new way of managing cyclosporine (CsA)-based GvHD prophylaxis. A total of 110 HSCT in 109 ALL or AML children who received CsA without mycophenolate or methotrexate in matched related as well as in matched or mismatched unrelated stem cell transplantation were included. CsA dosage regimens were individualized to obtain specific trough blood concentrations values. The incidences of grade I-II and III-IV acute GvHD were 69.1% and 1.8%, respectively, and 8.4% for chronic GvHD. GvHD was neither more frequent nor severe in unrelated than in related HSCT. GvHD occurred in 87% of patients with a mean CsA trough concentration ⩽120 ng/mL versus 43% with concentration >120 ng/mL (P<0.0001). Five-year disease-free survival (DFS) and overall survival were 78% and 83.6%, respectively. DFS was 76.9% for ALL and 80.4% for AML patients. There was no difference in DFS between matched siblings and matched unrelated or mismatched unrelated HSCT. DFS in patients with minimal residual disease (MRD) ⩾10(-3) and in those with MRD <10(-3) before SCT was comparable. Our results indicate that a GvHD prophylaxis regimen based on CsA without mycophenolate or methotrexate is safe and effective whatever the donor compatibility is. These results suggest that GvL effect may be enhanced by this strategy of GvHD prophylaxis.

Donor CD4+ Foxp3+ regulatory T cells are necessary for posttransplantation cyclophosphamide-mediated protection against GVHD in mice

PubMed Central

Ganguly, Sudipto; Ross, Duncan B.; Panoskaltsis-Mortari, Angela; Kanakry, Christopher G.; Blazar, Bruce R.; Levy, Robert B.

2014-01-01

Posttransplantation cyclophosphamide (PTCy) is an effective prophylaxis against graft-versus-host disease (GVHD). However, it is unknown whether PTCy works singularly by eliminating alloreactive T cells via DNA alkylation or also by restoring the conventional (Tcon)/regulatory (Treg) T-cell balance. We studied the role of Tregs in PTCy-mediated GVHD prophylaxis in murine models of allogeneic blood or marrow transplantation (alloBMT). In 2 distinct MHC-matched alloBMT models, infusing Treg-depleted allografts abrogated the GVHD-prophylactic activity of PTCy. Using allografts in which Foxp3+ Tregs could be selectively depleted in vivo, either pre- or post-PTCy ablation of donor thymus–derived Tregs (tTregs) abolished PTCy protection against GVHD. PTCy treatment was associated with relative preservation of donor Tregs. Experiments using combinations of Foxp3– Tcons and Foxp3+ Tregs sorted from different Foxp3 reporter mice indicated that donor Treg persistence after PTCy treatment was predominantly caused by survival of functional tTregs that retained Treg-specific demethylation and also induction of peripherally derived Tregs. Finally, adoptive transfer of tTregs retrieved from PTCy-treated chimeras rescued PTCy-treated, Treg-depleted recipients from lethal GVHD. Our findings indicate that PTCy-mediated protection against GVHD is not singularly dependent on depletion of donor alloreactive T cells but also requires rapidly recovering donor Tregs to initiate and maintain alloimmune regulation. PMID:25139358

Mismatch for the minor histocompatibility antigen HA-2 and GVHD occurrence in HLA-A*0201-positive Tunisian recipients of HSCs.

PubMed

Sellami, Mohamed Hichem; Torjemane, Lamia; Espadas de Arias, Alejandro; Kaabi, Houda; Ladeb, Saloua; Ben Othman, Tarek; Poli, Francesca; Hmida, Slama

2010-01-01

Graft-versus-Host disease (GVHD) has been widely linked to immunogenetic causes such as disparity between the recipient and its HLA geno-identical donor for some Non-HLA antigens called minor histocompatibility antigens (MiHAgs). HA-2 is one of potential human MiHAgs but its effect on the GVHD occurrence remains not clear. In order to examine such association in the Tunisian cohort of HSCs recipients, we performed a retrospective study on patients who received an HLA-identical HSCT between 2000 and 2009. The study was performed on 60 HLA-A2-positive patients who had received a haematopoietic stem cell transplant from an HLA-identical sibling. All patients received cyclosporine A and/or methotrexate for GVHD prophylaxis. HA-2 genotyping assay was performed with SSP-PCR method and HLA-A*0201 positive samples were identified mainly with Luminex HLA-Typing method. Luminex HLA-Typing assay showed that only 53 cases were positives for the HLA-A*0201 allele. Among these cases, only 3 pairs were mismatched for the MiHAg HA-2. Acute GVHD occurred in 01 HA-2-mismatched pair while chronic GVHD was detected in 02 disparate couples. Univariate and multivariate analyses showed that MiHAg HA-2 disparity does not have any significant effect on the occurrence of either acute or chronic GVHD. This last one appeared to be correlated only with the age of patient (adulthood) (p: 0.011, OR: 22.092). Our findings support the previously reported data denying the influence of the HA-2 disparity on the GVHD occurrence after HSCT.

Third-party CD4+ invariant natural killer T cells protect from murine GVHD lethality

PubMed Central

Schneidawind, Dominik; Baker, Jeanette; Pierini, Antonio; Buechele, Corina; Luong, Richard H.; Meyer, Everett H.

2015-01-01

Graft-versus-host disease (GVHD) is driven by extensive activation and proliferation of alloreactive donor T cells causing significant morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Invariant natural killer T (iNKT) cells are a potent immunoregulatory T-cell subset in both humans and mice. Here, we explored the role of adoptively transferred third-party CD4+ iNKT cells for protection from lethal GVHD in a murine model of allogeneic HCT across major histocompatibility barriers. We found that low numbers of CD4+ iNKT cells from third-party mice resulted in a significant survival benefit with retained graft-versus-tumor effects. In vivo expansion of alloreactive T cells was diminished while displaying a T helper cell 2-biased phenotype. Notably, CD4+ iNKT cells from third-party mice were as protective as CD4+ iNKT cells from donor mice although third-party CD4+ iNKT cells were rejected early after allogeneic HCT. Adoptive transfer of third-party CD4+ iNKT cells resulted in a robust expansion of donor CD4+CD25+FoxP3+ regulatory T cells (Tregs) that were required for protection from lethal GVHD. However, in vivo depletion of myeloid-derived suppressor cells abrogated both Treg expansion and protection from lethal GVHD. Despite the fact that iNKT cells are a rare cell population, the almost unlimited third-party availability and feasibility of in vitro expansion provide the basis for clinical translation. PMID:25795920

Stem cell mobilization with G-CSF analogs: a rational approach to separate GVHD and GVL?

PubMed

Morris, Edward S; MacDonald, Kelli P A; Hill, Geoffrey R

2006-05-01

The separation of graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) remains the "holy grail" of allogeneic stem cell transplantation, and improvements are urgently needed to allow more effective therapy of malignant disease. The use of G-CSF-mobilized peripheral blood as a clinical stem cell source is associated with enhanced GVL effects without amplification of significant acute GVHD. Preclinical studies have demonstrated that G-CSF modulates donor T cell function before transplantation, promoting T(H)2 differentiation and regulatory T cell function. In addition, the expansion of immature antigen-presenting cells (APCs) and plasmacytoid dendritic cells (DCs) favors the maintenance of this pattern of T cell differentiation after transplantation. Although these patterns of T cell differentiation attenuate acute GVHD, they do not have an impact on the cytolytic pathways of the CD8(+) T cells that are critical for effective GVL. Recently, it has been demonstrated that modification of G-CSF, either by pegylation of the native cytokine or conjugation to Flt-3L, results in the expansion and activation of donor iNKT cells, which significantly augment CD8(+) T cell-mediated cytotoxicity and GVL effects after transplantation. Given that these cytokines also enhance the expansion of regulatory T cells and APCs, they further separate GVHD and GVL, offering potential clinical advantages for the transplant recipient.

The search for drug-targetable diagnostic, prognostic and predictive biomarkers in chronic graft-versus-host disease.

PubMed

Ren, Hong-Gang; Adom, Djamilatou; Paczesny, Sophie

2018-05-01

Chronic graft-versus-host disease (cGVHD) continues to be the leading cause of late morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is an increasingly applied curative method for both benign and malignant hematologic disorders. Biomarker identification is crucial for the development of noninvasive and cost-effective cGVHD diagnostic, prognostic, and predictive test for use in clinic. Furthermore, biomarkers may help to gain a better insight on ongoing pathophysiological processes. The recent widespread application of omics technologies including genomics, transcriptomics, proteomics and cytomics provided opportunities to discover novel biomarkers. Areas covered: This review focuses on biomarkers identified through omics that play a critical role in target identification for drug development, and that were verified in at least two independent cohorts. It also summarizes the current status on omics tools used to identify these useful cGVHD targets. We briefly list the biomarkers identified and verified so far. We further address challenges associated to their exploitation and application in the management of cGVHD patients. Finally, insights on biomarkers that are drug targetable and represent potential therapeutic targets are discussed. Expert commentary: We focus on biomarkers that play an essential role in target identification.

In vivo kinetics and nonradioactive imaging of rapidly proliferating cells in graft-versus-host disease

PubMed Central

Buxbaum, Nataliya P.; Farthing, Donald E.; Maglakelidze, Natella; Lizak, Martin; Merkle, Hellmut; Carpenter, Andrea C.; Oliver, Brittany U.; Kapoor, Veena; Castro, Ehydel; Swan, Gregory A.; dos Santos, Liliane M.; Bouladoux, Nicolas J.; Bare, Catherine V.; Flomerfelt, Francis A.; Eckhaus, Michael A.; Telford, William G.; Belkaid, Yasmine; Bosselut, Remy J.; Gress, Ronald E.

2017-01-01

Hematopoietic stem cell transplantation (HSCT) offers a cure for cancers that are refractory to chemotherapy and radiation. Most HSCT recipients develop chronic graft-versus-host disease (cGVHD), a systemic alloimmune attack on host organs. Diagnosis is based on clinical signs and symptoms, as biopsies are risky. T cells are central to the biology of cGVHD. We found that a low Treg/CD4+ T effector memory (Tem) ratio in circulation, lymphoid, and target organs identified early and established mouse cGVHD. Using deuterated water labeling to measure multicompartment in vivo kinetics of these subsets, we show robust Tem and Treg proliferation in lymphoid and target organs, while Tregs undergo apoptosis in target organs. Since deuterium enrichment into DNA serves as a proxy for cell proliferation, we developed a whole-body clinically relevant deuterium MRI approach to nonradioactively detect cGVHD and potentially allow imaging of other diseases characterized by rapidly proliferating cells. PMID:28614804

Evaluation of CMV/human herpes virus-6 positivity in bronchoalveolar lavage fluids as early detection of acute GVHD following BMT: evidence of a significant relationship.

PubMed

Takemoto, Y; Takatsuka, H; Wada, H; Mori, A; Saheki, K; Okada, M; Tamura, S; Fujimori, Y; Okamoto, T; Kakishita, E; Kanamaru, A

2000-07-01

We evaluated the relationship between CMV and human herpes virus-6 (HHV-6) reactivation and the incidence of grades 2 to 4 acute GVHD post BMT. Bronchoalveolar lavage fluid (BALF) samples extracted from 54 BMT recipients on post-BMT day 35 were analyzed by PCR for detection of CMV DNA, HHV-6 DNA and CMV plus HHV-6 DNA. CMV DNA was detected in 26 patients and 13 (50%) developed grades 2 to 4 acute GVHD. Of the 28 who were CMV negative, only six (21.4%) developed grades 2 to 4 acute GVHD. HHV-6 was detected in 18 patients, and 11 (61.1%) developed grades 2 to 4 acute GVHD. Of the 36 who were HHV-6 negative, only eight (22.2%) developed grades 2 to 4 acute GVHD. CMV and HHV-6 were detected in 13 patients, and eight (61.5%) developed grades 2 to 4 acute GVHD. Of the 23 who were negative for both CMV and HHV-6, only three (13%) developed grades 2 to 4 acute GVHD. In all experiments, the difference between the groups was significant (P<0.05, P<0.05 and P<0.01, respectively). We conclude that herpes virus infection, in particular CMV concurrent with HHV-6 reactivation, is predictive of moderate to severe acute GVHD.

Lactobacillus rhamnosus GG probiotic enteric regimen does not appreciably alter the gut microbiome or provide protection against GVHD after allogeneic hematopoietic stem cell transplantation.

PubMed

Gorshein, Elan; Wei, Catherine; Ambrosy, Susan; Budney, Shanna; Vivas, Juliana; Shenkerman, Angelika; Manago, Jacqueline; McGrath, Mary Kate; Tyno, Anne; Lin, Yong; Patel, Vimal; Gharibo, Mecide; Schaar, Dale; Jenq, Robert R; Khiabanian, Hossein; Strair, Roger

2017-05-01

Graft-versus-host disease (GVHD) is a major adverse effect associated with allogeneic stem cell transplant. Previous studies in mice indicated that administration of the probiotic Lactobacillus rhamnosus GG can reduce the incidence of GVHD after hematopoietic stem cell transplant. Here we report results from the first randomized probiotic enteric regimen trial in which allogenic hematopoietic stem cell patients were supplemented with Lactobacillus rhamnosus GG. Gut microbiome analysis confirmed a previously reported gut microbiome association with GVHD. However, the clinical trial was terminated when interim analysis did not detect an appreciable probiotic-related change in the gut microbiome or incidence of GVHD. Additional studies are necessary to determine whether probiotics can alter the incidence of GVHD after allogeneic stem cell transplant. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

T-cell expression of AhR inhibits the maintenance of pTreg cells in the gastrointestinal tract in acute GVHD.

PubMed

Dant, Trisha A; Lin, Kaifeng L; Bruce, Danny W; Montgomery, Stephanie A; Kolupaev, Oleg V; Bommiasamy, Hemamalini; Bixby, Lisa M; Woosley, John T; McKinnon, Karen P; Gonzalez, Frank J; Blazar, Bruce R; Vincent, Benjamin G; Coghill, James M; Serody, Jonathan S

2017-07-20

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that affects the function and development of immune cells. Here, we show that recipient mice receiving AhR -/- T cells have improved survival and decreased acute graft-versus-host disease (aGVHD) in 2 different murine allogeneic bone marrow transplant (BMT) models. We also show that CD4 + T cells lacking AhR demonstrate reduced accumulation in secondary lymphoid tissue because of low levels of proliferation 4 days after BMT. Additionally, we found a significant increase in the quantity of peripherally induced regulatory donor T (pT reg ) cells in the colon of recipients transplanted with AhR -/- T cells 14 days after transplant. Blockade of AhR using a clinically available AhR antagonist greatly enhanced the in vitro generation of inducible T reg (iT reg ) cells from naïve CD4 + human T cells. We have identified AhR as a novel target on donor T cells that is critical to the pathogenesis of aGVHD.

Prediction of acute GVHD and relapse by metabolic biomarkers after allogeneic hematopoietic stem cell transplantation.

PubMed

Wu, Xiaojin; Xie, Yiyu; Wang, Chang; Han, Yue; Bao, Xiebing; Ma, Shoubao; Yilmaz, Ahmet; Yang, Bingyu; Ji, Yuhan; Xu, Jinge; Liu, Hong; Chen, Suning; Zhang, Jianying; Yu, Jianhua; Wu, Depei

2018-05-03

There are very few studies investigating metabolic biomarkers to predict acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Metabolic models can provide a framework for analyzing the information-rich omics data sets in this setting. Four hundred and fifty-six samples from one hundred and fourteen consecutive patients who underwent HSCT from January 2012 to May 2014 were collected for this study. The changes in serum metabolite levels were investigated using a gas chromatography-mass spectrometry-based metabolomics approach and underwent statistical analysis. Significant metabolic changes were observed on day 7. The stearic acid/palmitic acid (SA/PA) ratio was effective in the diagnosis of grade II-IV aGVHD. Multivariate analysis showed that patients with high SA/PA ratios on day 7 after HSCT were less likely to develop II-IV aGVHD than patients with low SA/PA ratios (odds ratio [OR] = 0.06, 95% CI 0.02-0.18, P < 0.001). After the adjustment for clinical characteristics, the SA/PA ratio had no significant effect on overall survival (hazard ratio [HR] = 1.95, 95% CI 0.92-4.14, P = 0.08), and patients in the high SA/PA ratio group were significantly more likely to relapse than those in the low ratio group (HR = 2.26, 95% CI 1.04-4.91, P = 0.04). Our findings suggest that the SA/PA ratio on day 7 after HSCT is an excellent biomarker to predict both aGVHD and relapse. The serum SA/PA ratio measured on day 7 after transplantation may improve risk stratification for aGVHD and relapse after allogeneic stem cell transplantation. National Natural Science Foundation of China (81470346, 81773361), Priority Academic Program Development of Jiangsu Higher Education Institutions, Jiangsu Natural Science Foundation (BK20161204), Innovation Capability Development Project of Jiangsu Province (BM2015004), Jiangsu Medical Junior Talent Person award (QNRC2016707), and NIH (AI129582 and NS106170).

GVHD after HLA-matched sibling BMT or PBSCT: Comparison of North American Caucasian and Japanese Populations

PubMed Central

Kanda, Junya; Brazauskas, Ruta; Hu, Zhen-Huan; Kuwatsuka, Yachiyo; Nagafuji, Koji; Kanamori, Heiwa; Kanda, Yoshinobu; Miyamura, Koichi; Murata, Makoto; Fukuda, Takahiro; Sakamaki, Hisashi; Kimura, Fumihiko; Seo, Sachiko; Aljurf, Mahmoud; Yoshimi, Ayami; Milone, Giuseppe; Wood, William A; Ustun, Celalettin; Hashimi, Shahrukh; Pasquini, Marcelo; Bonfim, Carmem; Dalal, Jignesh; Hahn, Theresa; Atsuta, Yoshiko; Saber, Wael

2016-01-01

The risk of acute graft-versus-host disease (GVHD) after HLA-matched sibling bone marrow (BM) transplantation is lower in Japanese than in Caucasian patients. However, race may have differential effect on GVHD dependent on the graft source. North American Caucasian and Japanese patients receiving their first allogeneic BM or peripheral blood stem cell (PBSC) transplantations from an HLA-matched sibling for leukemia were eligible. BM was used in 13% and 53% of Caucasian and Japanese patients, respectively. In multivariate analysis, the interaction term between race and graft source was not significant in any of the models, indicating that graft source does not affect the impact of race on outcomes. The risk of grades III–IV acute GVHD was significantly lower in Japanese than in Caucasian patients (hazard ratio (HR) 0.74, 95% confidence interval (CI) 0.57–0.96), which resulted in lower risk of non-relapse mortality in Japanese patients (HR 0.69, 95% CI 0.54–0.89). The risk of relapse was also lower in this group. Lower risk of non-relapse mortality and relapse resulted in lower overall mortality rates among Japanese patients. In conclusion, irrespective of graft source, the risk of severe acute GVHD is lower in Japanese patients, which results in lower risk of non-relapse mortality. PMID:26762681

Mesenchymal Stem Cells (MSCs) Attenuate Cutaneous Sclerodermatous Graft-Versus-Host Disease (Scl-GVHD) through Inhibition of Immune Cell Infiltration in a Mouse Model.

PubMed

Lim, Ji-Young; Ryu, Da-Bin; Lee, Sung-Eun; Park, Gyeongsin; Min, Chang-Ki

2017-09-01

Human chronic graft-versus-host disease (GVHD) shares clinical characteristics with a murine sclerodermatous GVHD model that is characterized by skin thickening and lung fibrosis. A B10.D2 → BALB/c transplant model of sclerodermatous GVHD was used to address the therapeutic effect of mesenchymal stem cells (MSCs) on the development of chronic GVHD. The clinical and pathological severity of cutaneous sclerodermatous GVHD was significantly attenuated in MSC-treated recipients relative to sclerodermatous GVHD control subjects. After MSC treatment, skin collagen production was significantly reduced, with consistent down-regulation of Tgfb expression. Effects of MSCs on molecular markers implicated in persistent transforming growth factor-β signaling and fibrosis, such as PTEN, phosphorylated Smad-2/3, and matrix metalloproteinase-1, were observed in skin tissue. MSCs neither migrate to the skin nor affect the in vivo expansion of immune effector cells, but they inhibited the infiltration of immune effector cells into skin via down-regulation of CCR4 and CCR8 expression on CD4 + T cells and CCR1 on CD11b + monocyte/macrophages. MSCs diminished expression of chemokines such as CCL1, CCL3, CCL8, CCL17, and CCL22 in skin. MSCs were also dependent on stimulated splenocytes to suppress fibroblast proliferation. Our findings indicate that MSCs attenuate the cutaneous sclerodermatous GVHD by selectively blocking immune cell migration and down-regulating chemokines and chemokine receptors. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

α-1-Antitrypsin (AAT)–modified donor cells suppress GVHD but enhance the GVL effect: a role for mitochondrial bioenergetics

PubMed Central

Karoopongse, Ekapun; Lesnikova, Marina; Margineantu, Daciana; Welte, Tobias; Dinarello, Charles A.; Hockenbery, David; Janciauskiene, Sabina; Deeg, H. Joachim

2014-01-01

Hematopoietic cell transplantation is curative in many patients. However, graft-versus-host disease (GVHD), triggered by alloreactive donor cells, has remained a major complication. Here, we show an inverse correlation between plasma α-1-antitrypsin (AAT) levels in human donors and the development of acute GVHD in the recipients (n = 111; P = .0006). In murine models, treatment of transplant donors with human AAT resulted in an increase in interleukin-10 messenger RNA and CD8+CD11c+CD205+ major histocompatibility complex class II+ dendritic cells (DCs), and the prevention or attenuation of acute GVHD in the recipients. Ablation of DCs (in AAT-treated CD11c-DTR donors) decreased CD4+CD25+FoxP3+ regulatory T cells to one-third and abrogated the anti-GVHD effect. The graft-versus-leukemia (GVL) effect of donor cells (against A20 tumor cells) was maintained or even enhanced with AAT treatment of the donor, mediated by an expanded population of NK1.1+, CD49B+, CD122+, CD335+ NKG2D-expressing natural killer (NK) cells. Blockade of NKG2D significantly suppressed the GVL effect. Metabolic analysis showed a high glycolysis–high oxidative phosphorylation profile for NK1.1+ cells, CD4+CD25+FoxP3+ T cells, and CD11c+ DCs but not for effector T cells, suggesting a cell type–specific effect of AAT. Thus, via altered metabolism, AAT exerts effective GVHD protection while enhancing GVL effects. PMID:25224412

Topical Tacrolimus and Periodontal Therapy in the Management of a Case of Oral Chronic GVHD Characterized by Specific Gingival Localization

PubMed Central

Conrotto, Davide; Broccoletti, Roberto; Carcieri, Paola; Giaccone, Luisa; Arduino, Paolo G.

2014-01-01

Background. Chronic graft versus host disease (cGVHD) is a complication following bone marrow transplantation. The oral lesions are difficult to control with a systemic pharmacological therapy. Case Description. A 63-year-old female patient, who underwent an allogeniec transplantation for acute myeloid leukemia, developed a chronic oral and cutaneous GVHD. The patient was treated with topical tacrolimus 0.1%, twice daily for two months, and underwent a protocol of oral hygiene characterized by 3 appointments of scaling, root planning, and daily oral hygiene instructions. The patient showed marked resolution of gingival lesions and a significant improvement of related pain and gingival inflammatory indexes. Clinical Implications. This case report suggests that treatment with topical tacrolimus and professional oral hygiene may be helpful in the management of chronic oral GVHD with severe gingival involvement. PMID:24639902

Topical tacrolimus and periodontal therapy in the management of a case of oral chronic GVHD characterized by specific gingival localization.

PubMed

Conrotto, Davide; Broccoletti, Roberto; Carcieri, Paola; Giaccone, Luisa; Arduino, Paolo G

2014-01-01

Background. Chronic graft versus host disease (cGVHD) is a complication following bone marrow transplantation. The oral lesions are difficult to control with a systemic pharmacological therapy. Case Description. A 63-year-old female patient, who underwent an allogeniec transplantation for acute myeloid leukemia, developed a chronic oral and cutaneous GVHD. The patient was treated with topical tacrolimus 0.1%, twice daily for two months, and underwent a protocol of oral hygiene characterized by 3 appointments of scaling, root planning, and daily oral hygiene instructions. The patient showed marked resolution of gingival lesions and a significant improvement of related pain and gingival inflammatory indexes. Clinical Implications. This case report suggests that treatment with topical tacrolimus and professional oral hygiene may be helpful in the management of chronic oral GVHD with severe gingival involvement.

Donor-Recipient Matching for KIR Genotypes Reduces Chronic GVHD and Missing Inhibitory KIR Ligands Protect against Relapse after Myeloablative, HLA Matched Hematopoietic Cell Transplantation

PubMed Central

Faridi, Rehan Mujeeb; Kemp, Taylor J.; Dharmani-Khan, Poonam; Lewis, Victor; Rajalingam, Raja; Berka, Noureddine; Storek, Jan; Masood Khan, Faisal

2016-01-01

Background Allogeneic hematopoietic cell transplantation (HCT) can be curative for many hematologic diseases. However, complications such as graft-versus-host disease (GVHD) and relapse of primary malignancy remain significant and are the leading causes of morbidity and mortality. Effects of killer Ig-like receptors (KIR)-influenced NK cells on HCT outcomes have been extensively pursued over the last decade. However, the relevance of the reported algorithms on HLA matched myeloablative HCT with rabbit antithymocyte globulin (ATG) is used for GVHD prophylaxis remains elusive. Here we examined the role of KIR and KIR-ligands of donor-recipient pairs in modifying the outcomes of ATG conditioned HLA matched sibling and unrelated donor HCT Methods and Findings The study cohort consisted of 281 HLA matched sibling and unrelated donor-recipient pairs of first allogeneic marrow or blood stem cell transplantation allocated into ‘discovery’ (135 pairs) and ‘validation’ (146 pairs) cohorts. High resolution HLA typing was obtained from the medical charts and KIR gene repertoires were obtained by a Luminex® based SSO method. All surviving patients were followed-up for a minimum of two years. KIR and HLA class I distributions of HCT pairs were stratified as per applicable definitions and were tested for their association with cause specific outcomes [acute GVHD grade II-IV (aGVHD), chronic GVHD needing systemic therapy (cGVHD) and relapse] using a multivariate competing risks regression model as well as with survival outcomes [relapse-free survival (RFS), cGVHD & relapse free survival (cGRFS) and overall survival (OS)] by multivariate Cox proportional hazards regression model. A significant association between KIR genotype mismatching (KIR-B/x donor into KIR-AA recipient or vice versa) and cGVHD was found in both discovery (p = 0.001; SHR = 2.78; 95%CI: 1.50–5.17) and validation cohorts (p = 0.005; SHR = 2.61; 95%CI: 1.33–5.11). High incidence of cGVHD associated

Donor-Recipient Matching for KIR Genotypes Reduces Chronic GVHD and Missing Inhibitory KIR Ligands Protect against Relapse after Myeloablative, HLA Matched Hematopoietic Cell Transplantation.

PubMed

Faridi, Rehan Mujeeb; Kemp, Taylor J; Dharmani-Khan, Poonam; Lewis, Victor; Tripathi, Gaurav; Rajalingam, Raja; Daly, Andrew; Berka, Noureddine; Storek, Jan; Masood Khan, Faisal

2016-01-01

Allogeneic hematopoietic cell transplantation (HCT) can be curative for many hematologic diseases. However, complications such as graft-versus-host disease (GVHD) and relapse of primary malignancy remain significant and are the leading causes of morbidity and mortality. Effects of killer Ig-like receptors (KIR)-influenced NK cells on HCT outcomes have been extensively pursued over the last decade. However, the relevance of the reported algorithms on HLA matched myeloablative HCT with rabbit antithymocyte globulin (ATG) is used for GVHD prophylaxis remains elusive. Here we examined the role of KIR and KIR-ligands of donor-recipient pairs in modifying the outcomes of ATG conditioned HLA matched sibling and unrelated donor HCT. The study cohort consisted of 281 HLA matched sibling and unrelated donor-recipient pairs of first allogeneic marrow or blood stem cell transplantation allocated into 'discovery' (135 pairs) and 'validation' (146 pairs) cohorts. High resolution HLA typing was obtained from the medical charts and KIR gene repertoires were obtained by a Luminex® based SSO method. All surviving patients were followed-up for a minimum of two years. KIR and HLA class I distributions of HCT pairs were stratified as per applicable definitions and were tested for their association with cause specific outcomes [acute GVHD grade II-IV (aGVHD), chronic GVHD needing systemic therapy (cGVHD) and relapse] using a multivariate competing risks regression model as well as with survival outcomes [relapse-free survival (RFS), cGVHD & relapse free survival (cGRFS) and overall survival (OS)] by multivariate Cox proportional hazards regression model. A significant association between KIR genotype mismatching (KIR-B/x donor into KIR-AA recipient or vice versa) and cGVHD was found in both discovery (p = 0.001; SHR = 2.78; 95%CI: 1.50-5.17) and validation cohorts (p = 0.005; SHR = 2.61; 95%CI: 1.33-5.11). High incidence of cGVHD associated with KIR genotype mismatching was applicable

Graft-versus-host disease targets ovary and causes female infertility in mice.

PubMed

Shimoji, Sonoko; Hashimoto, Daigo; Tsujigiwa, Hidetsugu; Miyawaki, Kohta; Kato, Koji; Takahashi, Shuichiro; Ogasawara, Reiki; Jiromaru, Takashi; Iwasaki, Hiromi; Miyamoto, Toshihiro; Akashi, Koichi; Teshima, Takanori

2017-03-02

Infertility associated with ovarian failure is a serious late complication for female survivors of allogeneic hematopoietic stem cell transplantation (SCT). Although pretransplant conditioning regimen has been appreciated as a cause of ovarian failure, increased application of reduced-intensity conditioning allowed us to revisit other factors possibly affecting ovarian function after allogeneic SCT. We have addressed whether donor T-cell-mediated graft-versus-host disease (GVHD) could be causally related to female infertility in mice. Histological evaluation of the ovaries after SCT demonstrated donor T-cell infiltration in close proximity to apoptotic granulosa cells in the ovarian follicles, resulting in impaired follicular hormone production and maturation of ovarian follicles. Mating experiments showed that female recipients of allogeneic SCT deliver significantly fewer newborns than recipients of syngeneic SCT. GVHD-mediated ovary insufficiency and infertility were independent of conditioning. Pharmacologic GVHD prophylaxis protected the ovary from GVHD and preserved fertility. These results demonstrate for the first time that GVHD targets the ovary and impairs ovarian function and fertility and has important clinical implications in young female transplant recipients with nonmalignant diseases, in whom minimally toxic regimens are used. © 2017 by The American Society of Hematology.

Conditioning with Fludarabine-Busulfan versus Busulfan-Cyclophosphamide Is Associated with Lower aGVHD and Higher Survival but More Extensive and Long Standing Bone Marrow Damage

PubMed Central

Ye, YongBin; Wang, Jing; Huang, YuXian; Weng, GuangYang; Zhang, MingWan

2016-01-01

Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and a major cause of nonrelapse mortality after allo-HSCT. A conditioning regimen plays a pivotal role in the development of aGVHD. To provide a platform for studying aGVHD and evaluating the impact of different conditioning regimens, we established a murine aGVHD model that simulates the clinical situation and can be conditioned with Busulfan-Cyclophosphamide (Bu-Cy) and Fludarabine-Busulfan (Flu-Bu). In our study, BALB/c mice were conditioned with Bu-Cy or Flu-Bu and transplanted with 2 × 107 bone marrow cells and 2 × 107 splenocytes from either allogeneic (C57BL/6) or syngeneic (BALB/c) donors. The allogeneic recipients conditioned with Bu-Cy had shorter survivals (P < 0.05), more severe clinical manifestations, and higher hepatic and intestinal pathology scores, associated with increased INF-γ expression and diminished IL-4 expression in serum, compared to allogeneic recipients conditioned with Flu-Bu. Moreover, higher donor-derived T-cell infiltration and severely impaired B-cell development were seen in the bone marrow of mice, exhibiting aGVHD and conditioned with Flu-Bu. Our study showed that the conditioning regimen with Bu-Cy resulted in more severe aGVHD while the Flu-Bu regimen was associated with more extensive and long standing bone marrow damage. PMID:27843940

Verification of the new grading scale for ocular chronic graft-versus-host disease developed by the German-Austrian-Swiss consensus conference on chronic GVHD.

PubMed

Blecha, Christiane; Wolff, Daniel; Holler, Barbara; Holler, Ernst; Weber, Daniela; Vogt, Regine; Helbig, Horst; Dietrich-Ntoukas, Tina

2016-02-01

The purpose of the study was to validate a recently proposed new grading system for ocular manifestations of chronic graft-versus-host disease (cGVHD). Diagnosis of cGVHD was based on the NIH consensus criteria. In addition, a grading scale was applied, which has been developed by the German-Austrian-Swiss Consensus Conference on Clinical Practice in cGVHD. Sixty-six patients (male n = 46, female n = 20, mean age 48 years) with ocular cGVHD were included. Application of the proposed Consensus Conference grading revealed inflammatory activity in all patients with mild (33 %), moderate (44 %), or severe inflammation (23 %). Clinical scoring by the NIH scoring system showed that 6 % of patients had mild symptoms; 59 % of patients had moderate dry eye symptoms partially affecting activities of daily living, without vision impairment; and 35 % of patients had severe dry eye symptoms significantly affecting daily activities. Clinical characterization and grading by the Consensus Conference grading scale revealed that ocular cGVHD (1) frequently leads to severe ocular surface disease based on impaired function of the lacrimal glands and involvement of cornea, conjunctiva, and lids; (2) is mostly associated with ongoing inflammatory activity; (3) often leads to functional impairment and reduced quality of life; and (4) is associated with an increased risk for severe, sight-threatening complications.

[Durable remission attained with plasmapheresis and intravenous immunoglobulin therapy in a patient with acute exacerbation of GVHD-related myasthenia gravis].

PubMed

Nakashima, Jun; Itonaga, Hidehiro; Fujioka, Machiko; Chiwata, Masahiko; Sawayama, Yasushi; Yoshimura, Shunsuke; Iwanaga, Hiroshi; Taguchi, Jun; Yoshida, Shinichiro; Miyazaki, Yasushi

2018-01-01

A 17-year-old male underwent a second bone marrow transplantation using a 6/8 allele HLA-matched unrelated donor. On day 100 after transplantation, steroid treatment for chronic graft-versus-host disease (GVHD) was started. On day 766, the patient experienced general fatigue, followed by double vision, ptosis, and dysphagia on day 810. Based on the positivity of the acetylcholine receptor antibody and a waning electromyography pattern, he was diagnosed with GVHD-related myasthenia gravis (MG). On day 861, we initiated plasmapheresis (PE), followed by the administration of intravenous immunoglobulin (IVIg) ; this treatment attenuated the bulbar symptoms of MG. Although the steroid treatment was continued, we restarted the administration of tacrolimus. On day 2,739 after transplantation, we stopped the steroid treatment, and the patient remained in remission for MG following the cessation of the steroid treatment on day 2,897. This case suggests that PE followed by IVIg could be an effective therapeutic alternative for MG associated with GVHD.

Benefit of STR-based chimerism analysis to identify TA-GVHD as a cause of death: Utility of various biological specimens.

PubMed

Raina, Anupuma; Chaudhary, Garima; Dogra, Tirath Das; Khandelwal, Deepchand; Balayan, Ajay; Jain, Vandana; Kanga, Uma; Seth, Tulika

2016-04-01

Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare condition. It can occur after blood transfusion in immune-compromised and occasionally even in immune-competent patients, and is associated with a mortality rate of >90%. The diagnosis of TA-GVHD is often delayed because of its non-specific clinical features. A case of an immune-competent child who developed TA-GVHD is reported here. DNA profiling (short tandem repeat analysis), a technique that has a wide application in forensic medicine, was performed to detect the presence of donor cells in this patient. The findings suggest that more studies are needed with this tool, and the diagnostic potential of using other multiple biological specimens for DNA profiling such as the hair follicle and buccal swab should be evaluated. This is the first case report where the donor's DNA fingerprinting pattern was substantiated from a patient's hair follicle sample. Chimerism was also present in the blood and buccal swab specimens. © The Author(s) 2015.

Larger number of invariant natural killer T cells in PBSC allografts correlates with improved GVHD-free and progression-free survival.

PubMed

Malard, Florent; Labopin, Myriam; Chevallier, Patrice; Guillaume, Thierry; Duquesne, Alix; Rialland, Fanny; Derenne, Sophie; Peterlin, Pierre; Leauté, Anne-Gaelle; Brissot, Eolia; Gregoire, Marc; Moreau, Philippe; Saas, Philippe; Gaugler, Béatrice; Mohty, Mohamad

2016-04-07

We studied the impact of a set of immune cells contained within granulocyte colony-stimulating factor-mobilized peripheral blood stem cell grafts (naïve and memory T-cell subsets, B cells, regulatory T cells, invariant natural killer T cells [iNKTs], NK cells, and dendritic cell subsets) in patients (n = 80) undergoing allogeneic stem cell transplantation (SCT), using the composite end point of graft-versus-host disease (GVHD)-free and progression-free survival (GPFS) as the primary end point. We observed that GPFS incidences in patients receiving iNKT doses above and below the median were 49% vs 22%, respectively (P= .007). In multivariate analysis, the iNKT dose was the only parameter with a significant impact on GPFS (hazard ratio = 0.48; 95% confidence interval, 0.27-0.85;P= .01). The incidences of severe grade III to IV acute GVHD and National Institutes of Health grade 2 to 3 chronic GVHD (12% and 16%, respectively) were low and associated with the use of antithymocyte globulin in 91% of patients. No difference in GVHD incidence was reported according to the iNKT dose. In conclusion, a higher dose of iNKTs within the graft is associated with an improved GPFS. These data may pave the way for prospective and active interventions aiming to manipulate the graft content to improve allo-SCT outcome. © 2016 by The American Society of Hematology.

GVHD (Graft-Versus-Host Disease): A Guide for Patients and Families After Stem Cell Transplant

MedlinePlus

... the first 100 days after your transplant or infusion of T-cells (in a donor lymphocyte infusion, or DLI). Acute GVHD commonly affects your skin, ... mouth or put on your skin or an infusion through a vascular access device. Also, treatment may ...

Modulation of Immunoregulatory Properties of Mesenchymal Stromal Cells by Toll-Like Receptors: Potential Applications on GVHD

PubMed Central

2016-01-01

In the last decade, the immunomodulatory properties of mesenchymal stromal cells (MSCs) have attracted a lot of attention, due to their potential applicability in the treatment of graft-versus-host disease (GVHD), a condition frequently associated with opportunistic infections. The present review addresses how Pathogen-Associated Molecular Patterns (PAMPS) modulate the immunosuppressive phenotype of human MSCs by signaling through Toll-like receptors (TLRs). Overall, we observed that regardless of the source tissue, human MSCs express TLR2, TLR3, TLR4, and TLR9. Stimulation of distinct TLRs on MSCs elicits distinct inflammatory signaling pathways, differentially influencing the expression of inflammatory factors and the ability of MSCs to suppress the proliferation of immune system cells. The capacity to enhance the immunosuppressive phenotype of MSCs through TLRs stimulation might be properly elucidated in order to improve the MSC-based immunotherapy against GVHD. PMID:27738438

HLA-inferred extended haplotype disparity level is more relevant than the level of HLA mismatch alone for the patients survival and GvHD in T cell-replate hematopoietic stem cell transplantation from unrelated donor.

PubMed

Nowak, Jacek; Nestorowicz, Klaudia; Graczyk-Pol, Elzbieta; Mika-Witkowska, Renata; Rogatko-Koros, Marta; Jaskula, Emilia; Koscinska, Katarzyna; Madej, Sylwia; Tomaszewska, Agnieszka; Nasilowska-Adamska, Barbara; Szczepinski, Andrzej; Halaburda, Kazimierz; Dybko, Jaroslaw; Kuliczkowski, Kazimierz; Czerw, Tomasz; Giebel, Sebastian; Holowiecki, Jerzy; Baranska, Malgorzata; Pieczonka, Anna; Wachowiak, Jacek; Czyz, Anna; Gil, Lidia; Lojko-Dankowska, Anna; Komarnicki, Mieczyslaw; Bieniaszewska, Maria; Kucharska, Agnieszka; Hellmann, Andrzej; Gronkowska, Anna; Jedrzejczak, Wieslaw W; Markiewicz, Miroslaw; Koclega, Anna; Kyrcz-Krzemien, Slawomira; Mielcarek, Monika; Kalwak, Krzysztof; Styczynski, Jan; Wysocki, Mariusz; Drabko, Katarzyna; Wojcik, Beata; Kowalczyk, Jerzy; Gozdzik, Jolanta; Pawliczak, Daria; Gwozdowicz, Slawomir; Dziopa, Joanna; Szlendak, Urszula; Witkowska, Agnieszka; Zubala, Marta; Gawron, Agnieszka; Warzocha, Krzysztof; Lange, Andrzej

2018-06-01

Serious risks in unrelated hematopoietic stem cell transplantation (HSCT) including graft versus host disease (GvHD) and mortality are associated with HLA disparity between donor and recipient. The increased risks might be dependent on disparity in not-routinely-tested multiple polymorphisms in genetically dense MHC region, being organized in combinations of two extended MHC haplotypes (Ehp). We assessed the clinical role of donor-recipient Ehp disparity levels in N = 889 patients by the population-based detection of HLA allele phase mismatch. We found increased GvHD incidences and mortality rates with increasing Ehp mismatch level even with the same HLA mismatch level. In multivariate analysis HLA mismatch levels were excluded from models and Ehp disparity level remained independent prognostic factor for high grade acute GvHD (p = 0.000037, HR = 10.68, 95%CI 5.50-32.5) and extended chronic GvHD (p < 0.000001, HR = 15.51, CI95% 5.36-44.8). In group with single HLA mismatch, patients with double Ehp disparity had worse 5-year overall survival (45% vs. 56%, p = 0.00065, HR = 4.05, CI95% 1.69-9.71) and non-relapse mortality (40% vs. 31%, p = 0.00037, HR = 5.63, CI95% 2.04-15.5) than patients with single Ehp disparity. We conclude that Ehp-linked factors contribute to the high morbidity and mortality in recipients given HLA-mismatched unrelated transplant and Ehp matching should be considered in clinical HSCT. Copyright © 2018. Published by Elsevier Inc.

40 CFR 156.85 - Non-target organisms.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 23 2010-07-01 2010-07-01 false Non-target organisms. 156.85 Section 156.85 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) PESTICIDE PROGRAMS... Non-target organisms. (a) Requirement. Where a hazard exists to non-target organisms, EPA may require...

40 CFR 156.85 - Non-target organisms.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 24 2011-07-01 2011-07-01 false Non-target organisms. 156.85 Section 156.85 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) PESTICIDE PROGRAMS... Non-target organisms. (a) Requirement. Where a hazard exists to non-target organisms, EPA may require...

Targeting Deacetylases to Improve Outcomes after Allogeneic Bone Marrow Transplantation

PubMed Central

Reddy, Pavan

2013-01-01

Graft-versus-host disease (GVHD) is the major complication of allogeneic bone marrow transplantation (BMT). GVHD is a complex immunologically mediated biological process. Recent data have shown that histone deacetylase inhibitors (HDACis) have potent anti-inflammatory effects. We have been studying the role of acetylation through inhibition of histone deacetylases (HDACs) in modulating immunity, specifically, GVHD. HDAC inhibition regulates GVHD, at least in part, through suppression of the function of host antigen presenting cells such as dendritic cells (DCs). HDACis reduce DC responses by enhancing the expression of indoleamine 2,3 dioxygenase (IDO) in a STAT-3–dependent manner. They also alter the function of other immune cells such as T regulatory cells and NK cells, which also play important roles in the biology of GVHD. Based on these observations, a clinical trial has been launched to evaluate its impact on clinical GVHD. The clinical features, biology of GVHD, the experimental studies with HDACis, and preliminary observations from humans are discussed. PMID:23874019

C-Rel is an essential transcription factor for the development of acute graft-versus-host disease in mice

PubMed Central

Yu, Yu; Wang, Dapeng; Kaosaard, Kane; Liu, Chen; Fu, Jianing; Haarberg, Kelley; Anasetti, Claudio; Beg, Amer A.; Yu, Xue-Zhong

2014-01-01

Transcription factor of the Rel/NF-κB family are known to play different roles in immunity and inflammation, although the putative role of c-Rel in transplant tolerance and GVHD remains elusive. We report here that T cells deficient for c-Rel have a dramatically reduced ability to cause acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT) using major and minor histocompatibility mismatched murine models. In the study to understand the underlying mechanisms, we found that c-Rel-/- T cells had reduced ability to expand in lymphoid organs and to infiltrate in GVHD target organs in allogeneic recipients. c-Rel-/- T cells were defective in the differentiation into Th1 cells after encountering alloantigens, but were enhanced in the differentiation towards Foxp3+ regulatory T cells (Tregs). Furthermore, c-Rel-/- T cells had largely preserved activity to mediate graft-versus leukemia (GVL) response. Taken together, our findings indicate that c-Rel plays an essential role in T cells in the induction of acute GVHD, and suggest that c-Rel can be a potential target for therapeutic intervention in allogeneic HCT in clinic. PMID:23716202

Bim regulates the survival and suppressive capability of CD8+ FOXP3+ regulatory T cells during murine GVHD.

PubMed

Agle, Kimberle; Vincent, Benjamin G; Piper, Clint; Belle, Ludovic; Zhou, Vivian; Shlomchik, Warren; Serody, Jonathan S; Drobyski, William R

2018-05-16

CD8 + Foxp3 + T cells (Tregs) are a potent regulatory population whose functional and ontological similarities to CD4 + Fox3 + T cells have not been well delineated. Using an experimental model of graft versus host disease (GVHD), we observed that CD8 + Tregs were significantly less potent than CD4 + Tregs for the suppression of GVHD. To define the mechanistic basis for this observation, we examined the T cell repertoire and the transcriptional profile of in vivo-derived CD4 + and CD8 + Tregs that emerged early during this disease. Polyclonal and alloantigen-induced CD8 + Tregs had repertoire diversity that was similar to that of conventional CD8 + T cells, indicating that a restricted repertoire was not the proximate cause of decreased suppression. Transcriptional profiling revealed that CD8 + Tregs possessed a canonical Treg transcriptional signature that was similar to that observed in CD4 + Tregs, yet distinct from conventional CD8 + T cells. Pathway analysis, however, demonstrated that CD8 + Tregs had differential gene expression in pathways involved in cell death and survival. This was further confirmed by detailed mRNA sequence analysis and protein expression studies which demonstrated that CD8 + Tregs had increased expression of Bim and reduced expression of Mcl-1. Transplantation with CD8 + Foxp3 + Bim -/- Tregs resulted in prolonged Treg survival and reduced GVHD lethality compared to wild type CD8 + Tregs, providing functional confirmation that increased expression of Bim was responsible for reduced in vivo efficacy. Thus, Bim regulates the survival and suppressive capability of CD8 + Tregs which may have implications for their use in regulatory T cell therapy. Copyright © 2018 American Society of Hematology.

Marrow grafts from HLA-identical siblings for severe aplastic anemia: does limiting the number of transplanted marrow cells reduce the risk of chronic GvHD?

PubMed

Gallo, S; Woolfrey, A E; Burroughs, L M; Storer, B E; Flowers, M E D; Hari, P; Pulsipher, M A; Heimfeld, S; Kiem, H-P; Sandmaier, B M; Storb, R

2016-12-01

A total of 21 patients with severe aplastic anemia (SAA) underwent marrow transplantation from HLA-identical siblings following a standard conditioning regimen with cyclophosphamide (50 mg/kg/day × 4 days) and horse antithymocyte globulin (30 mg/kg/day × 3 days). Post-grafting immunosuppression consisted of a short course of methotrexate (MTX) combined with cyclosporine (CSP). The transplant protocol tested the hypothesis that the incidence of chronic GvHD could be reduced by limiting the marrow grafts to ⩽2.5 × 10 8 nucleated marrow cells/kg. None of the patients rejected the graft, all had sustained engraftment and all are surviving at a median of 4 (range 1-8) years after transplantation. Chronic GvHD developed in 16% of patients given ⩽2.5 × 10 8 nucleated marrow cells/kg. Post-grafting immunosuppression has been discontinued in 20 of the 21 patients. In conclusion, limiting the number of transplanted marrow cells may have resulted in minimal improvement in the incidence and severity of chronic GvHD.

Dermatologic manifestations of solid organ transplantation-associated graft-versus-host disease: A systematic review.

PubMed

Kim, Grace Y; Schmelkin, Leah A; Davis, Mark D P; El-Azhary, Rokea A; Farrell, Ann M; Meves, Alexander; Lehman, Julia S

2018-06-01

Graft-versus-host-disease (GVHD) after solid organ transplantation (SOT) is extremely rare. To investigate the dermatologic manifestations and clinical outcomes of SOT GVHD. Systematic literature review of SOT GVHD. After full-text article review, we included 61 articles, representing 115 patients and 126 transplanted organs. The most commonly transplanted organ was the liver (n = 81). Among 115 patients, 101 (87.8%) developed skin involvement. The eruption appeared an average of 48.3 days (range, 3-243 days) posttransplant and was pruritic in 5 of 101 (4.9%) cases. The eruption was described as morbilliform in 2 patients (1.9%), confluent in 6 (5.9%), and desquamative in 4 (3.9%) cases. In many cases, specific dermatologic descriptions were lacking. The mortality rate was 72.2%. Relative time of death was reported in 23 patients who died during the follow-up period. These patients died an average of 99.2 days (range, 22-270 days) posttransplant, or 50.9 days after the appearance of dermatologic symptoms. Frequent causes of death were sepsis and multiorgan failure. Incomplete descriptions of skin findings and potential publication bias resulting in publication of only the most severe cases. GVHD is a potentially fatal condition that can occur after SOT and often presents with a skin rash. We recommend that dermatologists have a low threshold to consider and pursue this diagnosis in the setting of post-SOT skin eruption. Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

A Review of Ocular Graft-Versus-Host Disease.

PubMed

Munir, Saleha Z; Aylward, James

2017-05-01

: Graft-versus-host disease (GVHD) is a major complication that occurs following allogeneic hematopoietic stem cell transplantation, which is a potential curative therapy used in a variety of malignant or benign hematological diseases. Graft-versus-host disease primarily occurs in many organs, but most notably in the skin, lungs, gastrointestinal tract, liver, eyes, mucosa, and musculoskeletal system. Ocular manifestations of GVHD may precede other systemic GVHD findings, and it may be a poor prognosis for mortality. While all parts of the eye may be affected, ocular GVHD occurs primarily in the ocular surface. Dry eye disease or keratoconjunctivitis sicca is the most common presenting manifestation of chronic ocular GVHD. Dry eye disease in ocular GVHD is a multifactorial process, which involves destruction and fibrosis of lacrimal glands and conjunctiva, leading to tear film deficiency and instability. Depending on the severity of ocular involvement and response to treatment, ocular GVHD may cause decreased quality of life. Management of GVHD begins with prevention by understanding risk factors and by implementing prophylactic treatment after allogeneic hematopoietic stem cell transplantation. A multidisciplinary approach to the prevention and treatment of GVHD is important, and there are currently no preventive therapies available for ocular GVHD. Once diagnosed, ocular GVHD treatment strategies target ocular surface lubrication and support, tear film stabilization, inflammation reduction, and surgical intervention. The goal of this review is to define ocular GVHD and its categorical manifestations, as well as to describe the importance of comprehensive assessment, diagnosis, and ophthalmologic treatment and management of ocular GVHD with a multidisciplinary approach.

Scurvy: a new problem for patients with chronic GVHD involving mucous membranes; an easy problem to resolve.

PubMed

Kletzel, Morris; Powers, Kim; Hayes, Meghan

2014-08-01

Vitamin C deficiency in developed countries is typically observed in patients with unique clinical conditions such as cystic fibrosis or anorexia nervosa, or in patients on long-term tube feeds. We report here a clinical observation in six pediatric and adolescent patients (median age 17.5 yr, range 9.8-23.5 yr) with chronic GVHD with mucous membrane involvement found to be vitamin C deficient. These patients' baseline serum vitamin C levels ranged from <0.12 to 0.94 mg/dL (normal value 0.20-1.90 mg/dL), with a mean level 0.56 ± 0.36 mg/dL and a median level 0.6 mg/dL. Among these patients, signs and symptoms of mucositis failed to respond to standard chronic GVHD therapy. After receiving treatment with 2000 mg of ascorbic acid by mouth, daily patients displayed increased serum vitamin C levels. Clinically, this correlated with a remarkable improvement in patients' mucositis and ability to eat. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Artificial neural network study on organ-targeting peptides

NASA Astrophysics Data System (ADS)

Jung, Eunkyoung; Kim, Junhyoung; Choi, Seung-Hoon; Kim, Minkyoung; Rhee, Hokyoung; Shin, Jae-Min; Choi, Kihang; Kang, Sang-Kee; Lee, Nam Kyung; Choi, Yun-Jaie; Jung, Dong Hyun

2010-01-01

We report a new approach to studying organ targeting of peptides on the basis of peptide sequence information. The positive control data sets consist of organ-targeting peptide sequences identified by the peroral phage-display technique for four organs, and the negative control data are prepared from random sequences. The capacity of our models to make appropriate predictions is validated by statistical indicators including sensitivity, specificity, enrichment curve, and the area under the receiver operating characteristic (ROC) curve (the ROC score). VHSE descriptor produces statistically significant training models and the models with simple neural network architectures show slightly greater predictive power than those with complex ones. The training and test set statistics indicate that our models could discriminate between organ-targeting and random sequences. We anticipate that our models will be applicable to the selection of organ-targeting peptides for generating peptide drugs or peptidomimetics.

CSF-1–dependant donor-derived macrophages mediate chronic graft-versus-host disease

PubMed Central

Alexander, Kylie A.; Flynn, Ryan; Lineburg, Katie E.; Kuns, Rachel D.; Teal, Bianca E.; Olver, Stuart D.; Lor, Mary; Raffelt, Neil C.; Koyama, Motoko; Leveque, Lucie; Le Texier, Laetitia; Melino, Michelle; Markey, Kate A.; Varelias, Antiopi; Engwerda, Christian; Serody, Jonathan S.; Janela, Baptiste; Ginhoux, Florent; Clouston, Andrew D.; Blazar, Bruce R.; Hill, Geoffrey R.; MacDonald, Kelli P.A.

2014-01-01

Chronic GVHD (cGVHD) is the major cause of late, nonrelapse death following stem cell transplantation and characteristically develops in organs such as skin and lung. Here, we used multiple murine models of cGVHD to investigate the contribution of macrophage populations in the development of cGVHD. Using an established IL-17–dependent sclerodermatous cGVHD model, we confirmed that macrophages infiltrating the skin are derived from donor bone marrow (F4/80+CSF-1R+CD206+iNOS–). Cutaneous cGVHD developed in a CSF-1/CSF-1R–dependent manner, as treatment of recipients after transplantation with CSF-1 exacerbated macrophage infiltration and cutaneous pathology. Additionally, recipients of grafts from Csf1r–/– mice had substantially less macrophage infiltration and cutaneous pathology as compared with those receiving wild-type grafts. Neither CCL2/CCR2 nor GM-CSF/GM-CSFR signaling pathways were required for macrophage infiltration or development of cGVHD. In a different cGVHD model, in which bronchiolitis obliterans is a prominent manifestation, F4/80+ macrophage infiltration was similarly noted in the lungs of recipients after transplantation, and lung cGVHD was also IL-17 and CSF-1/CSF-1R dependent. Importantly, depletion of macrophages using an anti–CSF-1R mAb markedly reduced cutaneous and pulmonary cGVHD. Taken together, these data indicate that donor macrophages mediate the development of cGVHD and suggest that targeting CSF-1 signaling after transplantation may prevent and treat cGVHD. PMID:25157821

Prevalence and determinants of fatigue in patients with moderate to severe chronic GvHD.

PubMed

Im, A; Mitchell, S A; Steinberg, S M; Curtis, L; Berger, A; Baird, K; Kuzmina, Z; Joe, G; Comis, L E; Juckett, M; Avila, D; Baruffaldi, J; Masuch, L; Pirsl, F; Pavletic, S Z

2016-05-01

Although fatigue is common after allogeneic hematopoietic cell transplantation, little is known about fatigue in patients with chronic GvHD (cGvHD). The aim of this study was to explore factors associated with fatigue in cGvHD. Data were drawn from a sequentially recruited, cross-sectional study of adults with moderate or severe cGvHD (n=263). Respondents were classified as fatigued or not fatigued based on their response to a single item regarding loss of energy from the Lee cGvHD Symptom Scale. In univariate analysis, factors significantly associated with fatigue included performance status, number of prior cGvHD therapies, cGvHD symptom bother, self-assessed physical and mental health, nutritional status, walk velocity and self-reported physical activity. There were no significant associations between fatigue and disease-related cGvHD variables. Multivariable logistic regression demonstrated that being less active and having pulmonary and/or muscle/joint symptoms were independently associated with fatigue. In conclusion, clinically significant fatigue was prevalent in more than one-third of subjects with cGvHD, and was disabling. Absence of association with measures of cGvHD severity underscores the need to elucidate the pathogenesis of fatigue and its relationship with inflammatory activity. Pulmonary and muscle/joint symptoms and physical inactivity represent potential targets for intervention in clinical studies.

IL-10+ regulatory B cells are enriched in cord blood and may protect against cGVHD after cord blood transplantation.

PubMed

Sarvaria, Anushruti; Basar, Rafet; Mehta, Rohtesh S; Shaim, Hila; Muftuoglu, Muharrem; Khoder, Ahmad; Sekine, Takuye; Gokdemir, Elif; Kondo, Kayo; Marin, David; Daher, May; Alousi, Amin M; Alsuliman, Abdullah; Liu, Enli; Oran, Betul; Olson, Amanda; Jones, Roy B; Popat, Uday; Hosing, Chitra; Champlin, Richard; Shpall, Elizabeth J; Rezvani, Katayoun

2016-09-08

Cord blood (CB) offers a number of advantages over other sources of hematopoietic stem cells, including a lower rate of chronic graft-versus-host disease (cGVHD) in the presence of increased HLA disparity. Recent research in experimental models of autoimmunity and in patients with autoimmune or alloimmune disorders has identified a functional group of interleukin-10 (IL-10)-producing regulatory B cells (Bregs) that negatively regulate T-cell immune responses. At present, however, there is no consensus on the phenotypic signature of Bregs, and their prevalence and functional characteristics in CB remain unclear. Here, we demonstrate that CB contains an abundance of B cells with immunoregulatory function. Bregs were identified in both the naive and transitional B-cell compartments and suppressed T-cell proliferation and effector function through IL-10 production as well as cell-to-cell contact involving CTLA-4. We further show that the suppressive capacity of CB-derived Bregs can be potentiated through CD40L signaling, suggesting that inflammatory environments may induce their function. Finally, there was robust recovery of IL-10-producing Bregs in patients after CB transplantation, to higher frequencies and absolute numbers than seen in the peripheral blood of healthy donors or in patients before transplant. The reconstituting Bregs showed strong in vitro suppressive activity against allogeneic CD4(+) T cells, but were deficient in patients with cGVHD. Together, these findings identify a rich source of Bregs and suggest a protective role for CB-derived Bregs against cGVHD development in CB recipients. This advance could propel the development of Breg-based strategies to prevent or ameliorate this posttransplant complication. © 2016 by The American Society of Hematology.

National Institutes of Health chronic graft-versus-host disease staging in severely affected patients: organ and global scoring correlate with established indicators of disease severity and prognosis.

PubMed

Baird, Kristin; Steinberg, Seth M; Grkovic, Lana; Pulanic, Drazen; Cowen, Edward W; Mitchell, Sandra A; Williams, Kirsten M; Datiles, Manuel B; Bishop, Rachel; Bassim, Carol W; Mays, Jacqueline W; Edwards, Dean; Cole, Kristen; Avila, Daniele N; Taylor, Tiffany; Urban, Amanda; Joe, Galen O; Comis, Leora E; Berger, Ann; Stratton, Pamela; Zhang, Dan; Shelhamer, James H; Gea-Banacloche, Juan C; Sportes, Claude; Fowler, Daniel H; Gress, Ronald E; Pavletic, Steven Z

2013-04-01

Between 2004 and 2010, 189 adult patients were enrolled on the National Cancer Institute's cross-sectional chronic graft-versus-host disease (cGVHD) natural history study. Patients were evaluated by multiple disease scales and outcome measures, including the 2005 National Institutes of Health (NIH) Consensus Project cGVHD severity scores. The purpose of this study was to assess the validity of the NIH scoring variables as determinants of disease severity in severely affected patients in efforts to standardize clinician evaluation and staging of cGVHD. Out of 189 patients enrolled, 125 met the criteria for severe cGVHD on the NIH global score, 62 of whom had moderate disease, with a median of 4 (range, 1-8) involved organs. Clinician-assigned average NIH organ score and the corresponding organ scores assigned by subspecialists were highly correlated (r = 0.64). NIH global severity scores showed significant associations with nearly all functional and quality of life outcome measures, including the Lee Symptom Scale, Short Form-36 Physical Component Scale, 2-minute walk, grip strength, range of motion, and Human Activity Profile. Joint/fascia, skin, and lung involvement affected function and quality of life most significantly and showed the greatest correlation with outcome measures. The final Cox model with factors jointly predictive for survival included the time from cGVHD diagnosis (>49 versus ≤49 months, hazard ratio [HR] = 0.23; P = .0011), absolute eosinophil count at the time of NIH evaluation (0-0.5 versus >0.5 cells/μL, HR = 3.95; P = .0006), and NIH lung score (3 versus 0-2, HR = 11.02; P < .0001). These results demonstrate that NIH organs and global severity scores are reliable measures of cGVHD disease burden. The strong association with subspecialist evaluation suggests that NIH organ and global severity scores are appropriate for clinical and research assessments, and may serve as a surrogate for more complex subspecialist examinations. In this

BLT-humanized C57BL/6 Rag2-/-γc-/-CD47-/- mice are resistant to GVHD and develop B- and T-cell immunity to HIV infection.

PubMed

Lavender, Kerry J; Pang, Wendy W; Messer, Ronald J; Duley, Amanda K; Race, Brent; Phillips, Katie; Scott, Dana; Peterson, Karin E; Chan, Charles K; Dittmer, Ulf; Dudek, Timothy; Allen, Todd M; Weissman, Irving L; Hasenkrug, Kim J

2013-12-12

The use of C57BL/6 Rag2(-/-)γc(-/-) mice as recipients for xenotransplantation with human immune systems (humanization) has been problematic because C57BL/6 SIRPα does not recognize human CD47, and such recognition is required to suppress macrophage-mediated phagocytosis of transplanted human hematopoietic stem cells (HSCs). We show that genetic inactivation of CD47 on the C57BL/6 Rag2(-/-)γc(-/-) background negates the requirement for CD47-signal recognition protein α (SIRPα) signaling and induces tolerance to transplanted human HSCs. These triple-knockout, bone marrow, liver, thymus (TKO-BLT) humanized mice develop organized lymphoid tissues including mesenteric lymph nodes, splenic follicles and gut-associated lymphoid tissue that demonstrate high levels of multilineage hematopoiesis. Importantly, these mice have an intact complement system and showed no signs of graft-versus-host disease (GVHD) out to 29 weeks after transplantation. Sustained, high-level HIV-1 infection was observed via either intrarectal or intraperitoneal inoculation. TKO-BLT mice exhibited hallmarks of human HIV infection including CD4(+) T-cell depletion, immune activation, and development of HIV-specific B- and T-cell responses. The lack of GVHD makes the TKO-BLT mouse a significantly improved model for long-term studies of pathogenesis, immune responses, therapeutics, and vaccines to human pathogens.

Photochemical inactivation of lymphocytes by riboflavin with visible light for TA-GVHD prevention.

PubMed

Mo, Qin; Huang, Yuwen; Wang, Li; Cheng, Zhenzhen; Wu, Xiaofei; Jia, Yao; Wang, Xun; Zhang, Bo

2017-09-01

Transfusion-associated graft-versus-host disease (TA-GVHD) is a life-threatening complication caused by the input of a number of immunocompetent allogeneic lymphocytes. This study focus on the photochemical effects of riboflavin excited by visible light (RB+L) treatment on human lymphocytes, to study the feasibility of using RB+L treatment to prevent adverse immune reactions caused by transfused lymphocytes. 100μM riboflavin was added to lymphocyte suspensions. After exposure to 400-580nm visible light with a total energy of 40J/mL, cells were cultured and the ability of proliferation and cytokine secretion were assayed upon stimuli. Meanwhile, lymphocytes were also treated by gamma-irradiation as parallel to testify the inactivation effect of RB+L. Results showed that γ-irradiation and RB+L treated cells showed a decline in cell viability. After stimulation of phytohemagglutinin (PHA) or anti-CD3 together with anti-CD28, proliferative ability of RB+L treated cells was strongly inhibited when compared to untreated cells. The inhibitive rates of proliferation in RB+L group were also higher than those of cells treated by γ-irradiation. Results of CFSE assays also illustrated hardly any cell division of RB+L and γ-irradiation treated lymphocytes. Besides low level productions of IL-4 and IL-12, cytokine production of TNF-α, IFN-γ and IL-10 by incubation with PHA or IL-1β, IL-2, IL-6, IL-8, IL-10, TNF-α and IFN-γ stimulated by anti-CD3 plus anti-CD28 were suppressed after treatment of RB+L significantly. It was suggested that RB+L/γ-irradiation treatment induced cell apoptosis. These results indicated that RB+L treatment functionally inactivated lymphocytes by inhibiting cell proliferation and cytokine production. RB+L might be an alternative for TA-GVHD prevention. Copyright © 2017 Elsevier B.V. All rights reserved.

World Health Organization cardiovascular risk stratification and target organ damage.

PubMed

Piskorz, D; Bongarzoni, L; Citta, L; Citta, N; Citta, P; Keller, L; Mata, L; Tommasi, A

2016-01-01

Prediction charts allow treatment to be targeted according to simple markers of cardiovascular risk; many algorithms do not recommend screening asymptomatic target organ damage which could change dramatically the assessment. To demonstrate that target organ damage is present in low cardiovascular risk hypertensive patients and it is more frequent and severe as global cardiovascular risk increases. Consecutive hypertensive patients treated at a single Latin American center. Cardiovascular risk stratified according to 2013 WHO/ISH risk prediction chart America B. Left ventricular mass assessed by Devereux method, left ventricular hypertrophy considered >95g/m(2) in women and >115g/m(2) in men. Transmitral diastolic peak early flow velocity to average septal/lateral peak early diastolic relaxation velocity (E/e' ratio) measured cut off value >13. Systolic function assessed by tissue Doppler average interventricular septum/lateral wall mitral annulus rate systolic excursion (s wave). A total of 292 patients were included of whom 159 patients (54.5%) had cardiovascular risk of <10%, 90 (30.8%) had cardiovascular risk of 10-20% and 43 (14.7%) had cardiovascular risk of >20%. Left ventricular hypertrophy was detected in 17.6% low risk patients, 27.8% in medium risk and 23.3% in high risk (p<0.05), abnormal E/e' ratio was found in 13.8%, 31.1% and 27.9%, respectively (p<0.05). Mean s wave was 8.03+8, 8.1+9 and 8.7+1cm/s for low, intermediate and high risk patients, respectively (p<0.025). Target organ damage is more frequent and severe in high risk; one over four subjects was misclassified due to the presence of asymptomatic target organ damage. Copyright © 2015 SEHLELHA. Published by Elsevier España, S.L.U. All rights reserved.

Treatment of cutaneous and/or soft tissue manifestations of corticosteroids refractory chronic graft versus host disease (cGVHD) by a total nodal irradiation (TNI).

PubMed

Peyraga, Guillaume; Lizee, Thibaut; Gustin, Pierre; Clement-Colmou, Karen; Di Bartolo, Christelle; Supiot, Stephane; Mahe, Marc-Andre; François, Sylvie; Mege, Martine

2017-04-01

The management of corticosteroids refractory chronic graft versus host disease (cGVHD) remains controversial. Retrospective analysis of patients treated at the Integrated Center of Oncology by total nodal irradiation (TNI) was performed to evaluate its therapy potency. TNI delivers a dose of 1 Gy in a single session. The delimitation of the fields is clinical (upper limit: external auditory meatus; lower limit: mid-femur). No pre-therapeutic dosimetry scanner was necessary. Evaluation of the efficacy was by clinical measures at 6 months after the treatment. Twelve patients were treated by TNI between January 2010 and December 2013. TNI was used in second-line treatment or beyond. The median time between allograft and TNI was 31.2 months, and the median time between the first manifestations of cGVHD and TNI was about 24.2 months. Of the 12 patients, nine had a clinical response at 6 months (75%), including five complete clinical responses (41.6%). Five patients could benefit from a reduction of corticosteroid doses. Three patients had hematologic toxicity. TNI could be considered as an option for the treatment of a cutaneous and/or soft tissues corticosteroids refractory cGVHD. However, prospective randomized and double-blind trials remain essential to answer the questions about TNI safety and effectiveness. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Role of Toll-like receptor 4 signaling in cutaneous chronic graft-versus-host disease.

PubMed

Weng, Jianyu; Lai, Peilong; Geng, Suxia; Luo, Chenwei; Wu, Suijing; Ling, Wei; Deng, Chengxin; Huang, Xin; Lu, Zesheng; Du, Xin

2015-06-01

Cutaneous damage is one of the characterized manifestations in chronic graft-versus-host disease (cGVHD). When local effective immunity in the skin is altered to a dysimmune reaction, cutaneous injuries occur. Toll-like receptor 4 signaling is regarded as a central mediator of inflammation and organ injury. In this study, we found that TLR4 mRNA in peripheral blood from patients with cutaneous cGVHD was markedly increased compared with that from non-GVHD patients and healthy controls. In addition, NF-κB expression, TLR4 downstream signaling, and TLR4-mediated cytokines, including IL-6 and ICAM-1, were upregulated. Moreover, ICAM-1 was widely distributed in skin biopsies from patients with cutaneous cGVHD. We also found that LPS induced TLR4-mediated NF-κB activation and IL-6 and ICAM-1 secretion in human fibroblasts in vitro. Thus, TLR4, NF-κB, IL-6, and ICAM-1 contribute to the inflammatory response that occurs in cutaneous cGVHD, indicating the TLR4 pathway may be a novel target for cutaneous cGVHD therapy. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Peripheral tissues reprogram CD8+ T cells for pathogenicity during graft-versus-host disease

PubMed Central

Conlan, Thomas; Jardine, Laura; Tkacz, Claire; Ferrer, Ivana R.; Lomas, Cara; Ward, Sophie; West, Heather; Dertschnig, Simone; Means, Terry K.; Kaplan, Daniel H.; Bennett, Clare L.

2018-01-01

Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic stem cell transplantation induced by the influx of donor-derived effector T cells (TE) into peripheral tissues. Current treatment strategies rely on targeting systemic T cells; however, the precise location and nature of instructions that program TE to become pathogenic and trigger injury are unknown. We therefore used weighted gene coexpression network analysis to construct an unbiased spatial map of TE differentiation during the evolution of GVHD and identified wide variation in effector programs in mice and humans according to location. Idiosyncrasy of effector programming in affected organs did not result from variation in T cell receptor repertoire or the selection of optimally activated TE. Instead, TE were reprogrammed by tissue-autonomous mechanisms in target organs for site-specific proinflammatory functions that were highly divergent from those primed in lymph nodes. In the skin, we combined the correlation-based network with a module-based differential expression analysis and showed that Langerhans cells provided in situ instructions for a Notch-dependent T cell gene cluster critical for triggering local injury. Thus, the principal determinant of TE pathogenicity in GVHD is the final destination, highlighting the need for target organ–specific approaches to block immunopathology while avoiding global immune suppression. PMID:29515032

Human herpes virus-6 infection in marrow graft recipients: role in pathogenesis of graft-versus-host disease. Newcastle upon Tyne Bone Marrow Transport Group.

PubMed

Appleton, A L; Sviland, L; Peiris, J S; Taylor, C E; Wilkes, J; Green, M A; Pearson, A D; Kelly, P J; Malcolm, A J; Proctor, S J

1995-12-01

To investigate the hypothesis that target organ infection with human herpes virus-6 (HHV-6) exacerbates the clinical severity of GVHD, skin and rectal biopsies from 34 allogeneic bone marrow transplant (BMT) recipients and 23 comparative autologous recipients were studied. Biopsies and heparinised blood samples were obtained from all patients prior to and at regular intervals after BMT, and whenever GVHD was suspected. HHV-6 antigen was detected in cryostat sections by immunohistochemistry, and HHV-6 DNA in peripheral blood leucocytes (PBL) and biopsies by nested PCR. Twenty-eight (90%) of the 31 patients who engrafted developed clinical GVHD, which was mild in five, moderately severe in nine and severe in 14. Overall, HHV-6 DNA was detected in PBl in 74% of autologous recipients and 76% of allogeneic recipients, and in biopsy tissue in 48% of autos and 71% of allos. However, HHV-6 DNA was detected in skin and/or rectal biopsies more frequently in allogeneic recipients with severe GVHD (92%) than in those with either moderate (55%) or mild GVHD (22%), suggesting an association (P = 0.004) between HHV-6 DNA in biopsy tissue and GVHD severity. A significant linear trend (P = 0.03) was identified between detection of HHV-6 DNA in biopsy tissue obtained prior to or concomitant with the onset of GVHD and increased GVHD severity, suggesting that HHV-6 was causally linked to GVHD rather than reactivated as a consequence of GVHD therapy. Thus this study supports a role for HHV-6 in the initiation and/or exacerbation of GVHD, and suggests that the presence of HHV-6 DNA in the skin or rectum may be a factor in determining GVHD severity. If confirmed, these findings may have implications for the management of allogeneic BMT recipients.

The proteome pattern cGvHD_MS14 allows early and accurate prediction of chronic GvHD after allogeneic stem cell transplantation.

PubMed

Weissinger, E M; Human, C; Metzger, J; Hambach, L; Wolf, D; Greinix, H T; Dickinson, A M; Mullen, W; Jonigk, D; Kuzmina, Z; Kreipe, H; Schweier, P; Böhm, O; Türüchanow, I; Ihlenburg-Schwarz, D; Raad, J; Durban, A; Schiemann, M; Könecke, C; Diedrich, H; Holler, E; Beutel, G; Krauter, J; Ganser, A; Stadler, M

2017-03-01

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be curative, but is associated with significant morbidity and mortality. Chronic graft-versus-host disease (cGvHD), characterized by inflammation and fibrosis of multiple target organs, considerably contributes to the morbidity and mortality even years after allo-HSCT. Diagnosis of cGvHD is based on clinical features and histology of biopsies. Here, we report the generation of a urinary cGvHD-specific proteome-pattern (cGvHD_MS14) established by capillary electrophoresis-mass spectrometry to predict onset and severity of cGvHD as an unbiased laboratory test. cGvHD_MS14 was evaluated on samples from 412 patients collected prospectively in four transplant centers. Sensitivity and specificity was 84 and 76% by cGvHD_MS14 classification. Sensitivity further increased to 93% by combination of cGvHD_MS14 with relevant clinical variables to a logistic regression model. cGvHD was predicted up to 55 days prior to clinical diagnosis. Acute GvHD is not recognized by cGvHD_MS14. cGvHD_MS14 consists of 14 differentially excreted peptides, six of those have been sequenced to date and are fragments from thymosin β-4, eukaryotic translation initiation factor 4γ2, fibrinogen β-chain or collagens. In conclusion, the cGvHD_MS14-pattern allows early, highly sensitive and specific prediction of cGvHD as an independent diagnostic criterion of clinical diagnosis potentially allowing early therapeutic intervention.

Allogeneic peripheral blood progenitor cell transplantation: analysis of short-term engraftment and acute GVHD incidence in 33 cases. allo-PBPCT Spanish Group.

PubMed

Urbano-Ispizua, A; Solano, C; Brunet, S; Hernández, F; Sanz, G; Alegre, A; Petit, J; Besalduch, J; Vivancos, P; Díaz, M A; Moraleda, J M; Carreras, E; Ojeda, E; de la Rubia, J; Benet, I; Domingo-Albós, A; García-Conde, J; Rozman, C

1996-07-01

The results of 33 allogeneic peripheral blood progenitor cells transplants (allo-PBPCT) in adult patients with hematologic malignancies were analyzed in a retrospective and multicenter study. In 21 of 33 cases (63%) the disease was refractory or in advanced stage and eight of the 33 cases (24%) were second transplants after relapse. Donors were treated with a median of 10 (4-16) micrograms/kg/day of rhG-CSF subcutaneously for 5-7 days. Three required a central venous line for harvesting. Peripheral blood leukapheresis product contained a median of 5.9 (1.8-13) 10(6)/kg CD34+ cells and a median of 309.5 (153-690) 10(6)/kg CD3+ cells. After a myeloablative regimen, all patients received PBPC from HLA-identical donors as the sole source of progenitor cells. Cyclosporin A (CsA) alone (n = 2), CsA and steroids (n = 9), and CsA and methotrexate (MTX) (n = 22) were used for GVHD prophylaxis. Growth factors post-transplant were given to 11 patients (33%). The median follow-up of the patients was 3 months. Actuarial median day for hemopoietic recovery was: neutrophils to >0.5 (>1) x 10(9)/l, day 14 (15); platelets to >20 (>50) x 10(9)/l, day 14 (21). The quantity of CD34+ cells infused did not significantly affect the engraftment kinetics, from a starting cutoff of 2.5 x 10(6)/kg. The speed of neutrophil recovery seemed to be influenced strongly by using rhG-CSF post-transplant and marginally by the type of GVHD prophylaxis. Actuarial probability for grade II-IV acute GVHD of the whole group was 37% (95% Cl, 20-54%).

A PET Imaging Strategy to Visualize Activated T Cells in Acute Graft-versus-Host Disease Elicited by Allogenic Hematopoietic Cell Transplant.

PubMed

Ronald, John A; Kim, Byung-Su; Gowrishankar, Gayatri; Namavari, Mohammad; Alam, Israt S; D'Souza, Aloma; Nishikii, Hidekazu; Chuang, Hui-Yen; Ilovich, Ohad; Lin, Chih-Feng; Reeves, Robert; Shuhendler, Adam; Hoehne, Aileen; Chan, Carmel T; Baker, Jeanette; Yaghoubi, Shahriar S; VanBrocklin, Henry F; Hawkins, Randall; Franc, Benjamin L; Jivan, Salma; Slater, James B; Verdin, Emily F; Gao, Kenneth T; Benjamin, Jonathan; Negrin, Robert; Gambhir, Sanjiv Sam

2017-06-01

A major barrier to successful use of allogeneic hematopoietic cell transplantation is acute graft-versus-host disease (aGVHD), a devastating condition that arises when donor T cells attack host tissues. With current technologies, aGVHD diagnosis is typically made after end-organ injury and often requires invasive tests and tissue biopsies. This affects patient prognosis as treatments are dramatically less effective at late disease stages. Here, we show that a novel PET radiotracer, 2'-deoxy-2'-[18F]fluoro-9-β-D-arabinofuranosylguanine ([18F]F-AraG), targeted toward two salvage kinase pathways preferentially accumulates in activated primary T cells. [18F]F-AraG PET imaging of a murine aGVHD model enabled visualization of secondary lymphoid organs harboring activated donor T cells prior to clinical symptoms. Tracer biodistribution in healthy humans showed favorable kinetics. This new PET strategy has great potential for early aGVHD diagnosis, enabling timely treatments and improved patient outcomes. [18F]F-AraG may be useful for imaging activated T cells in various biomedical applications. Cancer Res; 77(11); 2893-902. ©2017 AACR . ©2017 American Association for Cancer Research.

Ibrutinib treatment ameliorates murine chronic graft-versus-host disease

PubMed Central

Dubovsky, Jason A.; Flynn, Ryan; Du, Jing; Harrington, Bonnie K.; Zhong, Yiming; Kaffenberger, Benjamin; Yang, Carrie; Towns, William H.; Lehman, Amy; Johnson, Amy J.; Muthusamy, Natarajan; Devine, Steven M.; Jaglowski, Samantha; Serody, Jonathan S.; Murphy, William J.; Munn, David H.; Luznik, Leo; Hill, Geoffrey R.; Wong, Henry K.; MacDonald, Kelli K.P.; Maillard, Ivan; Koreth, John; Elias, Laurence; Cutler, Corey; Soiffer, Robert J.; Antin, Joseph H.; Ritz, Jerome; Panoskaltsis-Mortari, Angela; Byrd, John C.; Blazar, Bruce R.

2014-01-01

Chronic graft-versus-host disease (cGVHD) is a life-threatening impediment to allogeneic hematopoietic stem cell transplantation, and current therapies do not completely prevent and/or treat cGVHD. CD4+ T cells and B cells mediate cGVHD; therefore, targeting these populations may inhibit cGVHD pathogenesis. Ibrutinib is an FDA-approved irreversible inhibitor of Bruton’s tyrosine kinase (BTK) and IL-2 inducible T cell kinase (ITK) that targets Th2 cells and B cells and produces durable remissions in B cell malignancies with minimal toxicity. Here, we evaluated whether ibrutinib could reverse established cGVHD in 2 complementary murine models, a model interrogating T cell–driven sclerodermatous cGVHD and an alloantibody-driven multiorgan system cGVHD model that induces bronchiolar obliterans (BO). In the T cell–mediated sclerodermatous cGVHD model, ibrutinib treatment delayed progression, improved survival, and ameliorated clinical and pathological manifestations. In the alloantibody-driven cGVHD model, ibrutinib treatment restored pulmonary function and reduced germinal center reactions and tissue immunoglobulin deposition. Animals lacking BTK and ITK did not develop cGVHD, indicating that these molecules are critical to cGVHD development. Furthermore, ibrutinib treatment reduced activation of T and B cells from patients with active cGVHD. Our data demonstrate that B cells and T cells drive cGVHD and suggest that ibrutinib has potential as a therapeutic agent, warranting consideration for cGVHD clinical trials. PMID:25271622

Macromolecular target prediction by self-organizing feature maps.

PubMed

Schneider, Gisbert; Schneider, Petra

2017-03-01

Rational drug discovery would greatly benefit from a more nuanced appreciation of the activity of pharmacologically active compounds against a diverse panel of macromolecular targets. Already, computational target-prediction models assist medicinal chemists in library screening, de novo molecular design, optimization of active chemical agents, drug re-purposing, in the spotting of potential undesired off-target activities, and in the 'de-orphaning' of phenotypic screening hits. The self-organizing map (SOM) algorithm has been employed successfully for these and other purposes. Areas covered: The authors recapitulate contemporary artificial neural network methods for macromolecular target prediction, and present the basic SOM algorithm at a conceptual level. Specifically, they highlight consensus target-scoring by the employment of multiple SOMs, and discuss the opportunities and limitations of this technique. Expert opinion: Self-organizing feature maps represent a straightforward approach to ligand clustering and classification. Some of the appeal lies in their conceptual simplicity and broad applicability domain. Despite known algorithmic shortcomings, this computational target prediction concept has been proven to work in prospective settings with high success rates. It represents a prototypic technique for future advances in the in silico identification of the modes of action and macromolecular targets of bioactive molecules.

TLR/MyD88-mediated Innate Immunity in Intestinal Graft-versus-Host Disease.

PubMed

Lee, Young-Kwan; Kang, Myungsoo; Choi, Eun Young

2017-06-01

Graft-versus-host disease (GHVD) is a severe complication after allogeneic hematopoietic stem cell transplantation. The degree of inflammation in the gastrointestinal tract, a major GVHD target organ, correlates with the disease severity. Intestinal inflammation is initiated by epithelial damage caused by pre-conditioning irradiation. In combination with damages caused by donor-derived T cells, such damage disrupts the epithelial barrier and exposes innate immune cells to pathogenic and commensal intestinal bacteria, which release ligands for Toll-like receptors (TLRs). Dysbiosis of intestinal microbiota and signaling through the TLR/myeloid differentiation primary response gene 88 (MyD88) pathways contribute to the development of intestinal GVHD. Understanding the changes in the microbial flora and the roles of TLR signaling in intestinal GVHD will facilitate the development of preventative and therapeutic strategies.

Application of Proteomics in Acute Graft-Versus-Host Disease Management: An Integrative Review and Nursing Implications.

PubMed

Kalariya, Nilesh; Brassil, Kelly

2015-12-01

After allogeneic hematopoietic stem cell transplantation, one of the major barriers to clinical management of acute graft-versus-host disease (aGVHD) is a lack of reliable and validated noninvasive tests for diagnosis and prognosis. Proteomic studies have indicated a strong correlation between the level of certain body fluid proteins and clinical outcomes after aGVHD. Specific proteins have been identified that could be robust biomarkers for overall prognosis or for differential diagnosis of target organs in aGVHD. The authors aimed to evaluate the literature related to proteomic biomarkers that are indicated in the occurrence, severity, and management of aGVHD. PubMed and CINAHL® databases were searched for articles published from January 2004 to June 2014. Eight articles matching the inclusion criteria were identified, and the findings of these articles were summarized and their clinical implications noted. Proteomics appears to be a promising tool to assist oncology nurses and nurse practitioners with patient education, develop personalized plans of care to reduce morbidity, initiate communication regarding end-of-life decisions, and improve overall nursing management of the population of patients with aGVHD.

Curcumin Attenuates Acute Graft-versus-Host Disease Severity via In Vivo Regulations on Th1, Th17 and Regulatory T Cells

PubMed Central

Lee, Sung-Hee; Yang, Eun-Ji; Min, Jun-Ki; Cho, Seok-Goo; Yang, Chul-Woo; Park, Sung-Hwan; Kim, Ho-Youn; Cho, Mi-La

2013-01-01

Background In this study we examined the in vivo and in vitro effects and mechanisms of action of curcumin on the development of acute graft-versus-host disease (GVHD) using a murine model. Methodology/Principal Findings Mixed lymphocyte reactions were used to determine the in vitro effects of curcumin. Treatment with curcumin attenuated alloreactive T cell proliferation and inhibited the production of interferon (IFN)-γ and interleukin (IL)-17. In a murine acute GVHD model, transplantation of curcumin-treated allogeneic splenocytes into irradiated recipient mice significantly reduced the clinical severity scores of acute GVHD manifested in the liver, skin, colon and lung as compared with animals receiving vehicle-treated splenocytes. c-Fos and c-Jun expression levels in the skin and intestine, which are major target organs, were analyzed using immunohistochemical staining. Expression of both proteins was reduced in epithelial tissues of skin and intestine from curcumin-treated GVHD animals. The IFN-γ-expressing CD4+ splenocytes and IFN-γ-expressing lymph node cells were dramatically decreased in curcumin-treated mice. In contrast, CD4+Foxp3+ splenocytes were increased in the curcumin-treated acute GVHD animals. Flow cytometric analysis revealed that animals transplanted with curcumin-treated allogeneic splenocytes showed increased populations of CD4+ regulatory T cells (Tregs) as well as CD8+ Treg cells, compared to animals administered vehicle-treated splenocytes. Curcumin-treated acute GVHD animals could have a change in B cell subpopulations. Conclusion/Significance In the present study, we investigated the efficacy and mechanism of action of curcumin treatment against acute GVHD. The acute GVHD mice administered with curcumin-treated splenocytes showed significantly reduced severity of acute GVHD. Curcumin exerted in vivo preventive effects on acute GVHD by reciprocal regulation of T helper 1 (Th1) and Treg (both CD4+ and CD8+ Treg) cell lineages as well as

Targeting Inflammatory T Helper Cells via Retinoic Acid-Related Orphan Receptor Gamma t Is Ineffective to Prevent Allo-Response-Driven Colitis.

PubMed

Buchele, Vera; Abendroth, Benjamin; Büttner-Herold, Maike; Vogler, Tina; Rothamer, Johanna; Ghimire, Sakhila; Ullrich, Evelyn; Holler, Ernst; Neurath, Markus F; Hildner, Kai

2018-01-01

Intestinal graft-versus-host disease (GvHD) is a life-threatening, inflammatory donor T cell-mediated complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the light of the reported efficacy of interleukin-23 (IL-23)-blockade to mitigate syngeneic intestinal inflammation in inflammatory bowel disease patients, targeting IL-23 and thereby interleukin-17a (IL-17a) producing T helper (Th17) cells as the T cell subset assumed to be mostly regulated by IL-23, has emerged as a putatively general concept to harness immune-mediated mucosal inflammation irrespective of the underlying trigger. However, the role of Th17 cells during allo-response driven colitis remains ambiguous due to a series of studies with inconclusive results. Interestingly, we recently identified granulocyte-macrophage colony-stimulating factor (GM-CSF + ) T cells to be promoted by interleukin-7 (IL-7) signaling and controlled by the activating protein-1 transcription factor family member basic leucine zipper transcription factor ATF-like (BATF) as critical mediators of intestinal GvHD in mice. Given the dual role of BATF, the contribution of IL-23-mediated signaling within donor T cells and bona fide Th17 cells remains to be delineated from the regulation of GM-CSF + T cells in the absence of BATF. Here, we found in a complete MHC class I-mismatched model that genetic inactivation of the IL-23 receptor (IL-23R) or the transcription factor retinoic acid-related orphan receptor gamma t (RORγt) within donor T cells similarly ablated Th17 cell formation in vivo but preserved the T cells' ability to induce intestinal GvHD in a compared to wild-type controls indistinguishable manner. Importantly, RORγt-independent manifestation of intestinal GvHD was completely dependent on BATF-regulated GM-CSF + T cells as BATF/RORγt double-deficient T cells failed to induce colitis and the antibody-mediated blockage of IL-7/IL-7R interaction and GM-CSF significantly diminished signs

Soil microbial community structure and target organisms under different fumigation treatments

USDA-ARS?s Scientific Manuscript database

Several high-value crop producers in California rely heavily on soil fumigants to control key diseases, nematodes, weeds and volunteer crops. Fumigants with broad biocidal activity can affect both target and non-target soil organisms. The ability of non-target soil organisms to recover after fumigat...

Self-organizing team formation for target observation

NASA Astrophysics Data System (ADS)

Bowyer, Richard S.; Bogner, Robert E.

2001-08-01

Target observation is a problem where the application of multiple sensors can improve the probability of detection and observation of the target. Team formation is one method by which seemingly unsophisticated heterogeneous sensors may be organized to achieve a coordinated observation system. The sensors, which we shall refer to as agents, are situated in an area of interest with the goal of observing a moving target. We apply a team approach to this problem, which combines the strengths of individual agents into a cohesive entity - the team. In autonomous systems, the mechanisms that underlie the formation of a team are of interest. Teams may be formed by various mechanisms, which include an externally imposed grouping of agents, or an internally, self-organized (SO) grouping of agents. Internally motivated mechanisms are particularly challenging, but offer the benefit of being unsupervised, an important quality for groups of autonomous cooperating machines. This is the focus of our research. By studying natural systems such as colonies of ants, we obtain insight into these mechanisms of self organization. We propose that the team is an expression of a distributed agent-self, and that a particular realization of the agent-self exists, whilst the environmental conditions are conducive to that existence. We describe an algorithms for agent team formation that is inspired by the self-organizing behavior of ants, and describe simulation results for team formation amongst a lattice of networked sensors.

[Graft-versus-host disease, a rare complication of lung transplantation].

PubMed

Morisse-Pradier, H; Nove-Josserand, R; Philit, F; Senechal, A; Berger, F; Callet-Bauchu, E; Traverse-Glehen, A; Maury, J-M; Grima, R; Tronc, F; Mornex, J-F

2016-02-01

Graft-versus-host disease (GVHD) is a classic and frequent multisystemic complication of bone marrow allografts. It has also been reported after the transplantation of solid organs such as the liver or gut. Recent cases of GVHD have been reported after lung and heart-lung transplant. Skin, liver, gastrointestinal tract and bone marrow are the organ preferentially affected by GVHD. Corticosteroid is the first line treatment of GVHD. The prognosis reported in solid organ transplants is poor with infectious complications favoured by immunosuppressive therapy. In this article, we report a case of a patient with cystic fibrosis who presented a probable GVHD 18 months after a lung transplant and a literature review of similar cases. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Intestinal microbiota-related effects on graft-versus-host disease.

PubMed

Shono, Yusuke; Docampo, Melissa D; Peled, Jonathan U; Perobelli, Suelen M; Jenq, Robert R

2015-05-01

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an increasingly important treatment for conditions including hematopoietic malignancies and inherited hematopoietic disorders, and is considered to be the most effective form of tumor immunotherapy available to date. However, graft-versus-host disease (GVHD) remains a major source of morbidity and mortality following allo-HSCT, and understanding the mechanisms of GVHD has been highlighted as a key research priority. During development of GVHD, activation of various immune cells, especially donor T cells, leads to damage of target organs including skin, liver, hematopoietic system, and of particular clinical importance, gut. In addition to histocompatibility complex differences between the donor and recipient, pretransplant conditioning with chemotherapy and irradiation also contributes to GVHD by damaging the gut, resulting in systemic exposure to microbial products normally confined to the intestinal lumen. The intestinal microbiota is a modulator of gastrointestinal immune homeostasis. It also promotes the maintenance of epithelial cells. Recent reports provide growing evidence of the impact of intestinal microbiota on GVHD pathophysiology. This review summarizes current knowledge of changes and effects of intestinal microbiota in the setting of allo-HSCT. We will also discuss potential future strategies of intestinal microbiota manipulation that might be advantageous in decreasing allo-HSCT-related morbidity and mortality.

Intestinal microbiota-related effects on graft-versus-host disease

PubMed Central

Shono, Yusuke; Docampo, Melissa D.; Peled, Jonathan U.; Perobelli, Suelen M.; Jenq, Robert R.

2016-01-01

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an increasingly important treatment for conditions including hematopoietic malignancies and inherited hematopoietic disorders, and is considered to be the most effective form of tumor immunotherapy available to date. However, graft-versus-host disease (GVHD) remains a major source of morbidity and mortality following allo-HSCT, and understanding the mechanisms of GVHD has been highlighted as a key research priority. During development of GVHD, activation of various immune cells, especially donor T cells, leads to damage of target organs including skin, liver, hematopoietic system, and of particular clinical importance, gut. In addition to histocompatibility complex differences between the donor and recipient, pre-transplant conditioning with chemotherapy and irradiation also contributes to GVHD by damaging the gut, resulting in systemic exposure to microbial products normally confined to the intestinal lumen. The intestinal microbiota is a modulator of gastrointestinal immune homeostasis. It also promotes the maintenance of epithelial cells. Recent reports provide growing evidence of the impact of intestinal microbiota on GVHD pathophysiology. This review summarizes current knowledge of changes and effects of intestinal microbiota in the setting of allo-HSCT. We will also discuss potential future strategies of intestinal-microbiota manipulation that might be advantageous in decreasing allo-HSCT related morbidity and mortality. PMID:25812838

Oral Disease Profiles in Chronic Graft versus Host Disease

PubMed Central

Fassil, H.; Mays, J.W.; Edwards, D.; Baird, K.; Steinberg, S.M.; Cowen, E.W.; Naik, H.; Datiles, M.; Stratton, P.; Gress, R.E.; Pavletic, S.Z.

2015-01-01

At least half of patients with chronic graft-versus-host-disease (cGVHD), the leading cause of morbidity and non-relapse mortality after allogeneic stem cell transplantation, have oral manifestations: mucosal lesions, salivary dysfunction, and limited mouth-opening. cGVHD may manifest in a single organ or affect multiple organ systems, including the mouth, eyes, and the skin. The interrelationship of the 3 oral manifestations of cGVHD with each other and with the specific manifestations of extraoral cGVHD has not been studied. In this analysis, we explored, in a large group of patients with cGVHD, the potential associations between: (1) oral mucosal disease and erythematous skin disease, (2) salivary gland dysfunction and lacrimal gland dysfunction, and (3) limited mouth-opening and sclerotic skin cGVHD. Study participants, enrolled in a cGVHD Natural History Protocol (NCT00331968, n = 212), underwent an oral examination evaluating: (1) mucosal cGVHD [NIH Oral Mucosal Score (OMS)], (2) salivary dysfunction (saliva flow and xerostomia), and (3) maximum mouth-opening measurement. Parameters for dysfunction (OMS > 2, saliva flow ≤ 1 mL/5 min, mouth-opening ≤ 35 mm) were analyzed for association with skin cGVHD involvement (erythema and sclerosis, skin symptoms), lacrimal dysfunction (Schirmer’s tear test, xerophthalmia), Lee cGVHD Symptom Scores, and NIH organ scores. Oral mucosal disease (31% prevalence) was associated with skin erythema (P < 0.001); salivary dysfunction (11% prevalence) was associated with lacrimal dysfunction (P = 0.010) and xerostomia with xerophthalmia (r = 0.32, P = 0.001); and limited mouth-opening (17% prevalence) was associated with skin sclerosis (P = 0.008) and skin symptoms (P = 0.001). There was no association found among these 3 oral cGVHD manifestations. This analysis supports the understanding of oral cGVHD as 3 distinct diseases: mucosal lesions, salivary gland dysfunction, and mouth sclerosis. Clear classification of oral cGVHD

Oral disease profiles in chronic graft versus host disease.

PubMed

Bassim, C W; Fassil, H; Mays, J W; Edwards, D; Baird, K; Steinberg, S M; Cowen, E W; Naik, H; Datiles, M; Stratton, P; Gress, R E; Pavletic, S Z

2015-04-01

At least half of patients with chronic graft-versus-host-disease (cGVHD), the leading cause of morbidity and non-relapse mortality after allogeneic stem cell transplantation, have oral manifestations: mucosal lesions, salivary dysfunction, and limited mouth-opening. cGVHD may manifest in a single organ or affect multiple organ systems, including the mouth, eyes, and the skin. The interrelationship of the 3 oral manifestations of cGVHD with each other and with the specific manifestations of extraoral cGVHD has not been studied. In this analysis, we explored, in a large group of patients with cGVHD, the potential associations between: (1) oral mucosal disease and erythematous skin disease, (2) salivary gland dysfunction and lacrimal gland dysfunction, and (3) limited mouth-opening and sclerotic skin cGVHD. Study participants, enrolled in a cGVHD Natural History Protocol (NCT00331968, n = 212), underwent an oral examination evaluating: (1) mucosal cGVHD [NIH Oral Mucosal Score (OMS)], (2) salivary dysfunction (saliva flow and xerostomia), and (3) maximum mouth-opening measurement. Parameters for dysfunction (OMS > 2, saliva flow ≤ 1 mL/5 min, mouth-opening ≤ 35 mm) were analyzed for association with skin cGVHD involvement (erythema and sclerosis, skin symptoms), lacrimal dysfunction (Schirmer's tear test, xerophthalmia), Lee cGVHD Symptom Scores, and NIH organ scores. Oral mucosal disease (31% prevalence) was associated with skin erythema (P < 0.001); salivary dysfunction (11% prevalence) was associated with lacrimal dysfunction (P = 0.010) and xerostomia with xerophthalmia (r = 0.32, P = 0.001); and limited mouth-opening (17% prevalence) was associated with skin sclerosis (P = 0.008) and skin symptoms (P = 0.001). There was no association found among these 3 oral cGVHD manifestations. This analysis supports the understanding of oral cGVHD as 3 distinct diseases: mucosal lesions, salivary gland dysfunction, and mouth sclerosis. Clear classification of oral cGVHD

PBSCT is associated with poorer survival and increased chronic GvHD than BMT in Japanese paediatric patients with acute leukaemia and an HLA-matched sibling donor.

PubMed

Shinzato, Aki; Tabuchi, Ken; Atsuta, Yoshiko; Inoue, Masami; Inagaki, Jiro; Yabe, Hiromasa; Koh, Katsuyoshi; Kato, Koji; Ohta, Hideaki; Kigasawa, Hisato; Kitoh, Toshiyuki; Ogawa, Atsushi; Takahashi, Yoshiyuki; Sasahara, Yoji; Kato, Shun-Ichi; Adachi, Souichi

2013-09-01

Peripheral blood stem cells (PBSC) may be used as an alternative to bone marrow (BM) for allogeneic transplantation. Since peripheral blood stem cell bank from unrelated volunteer donor has been started in Japan, use of PBSC allografts may be increased. Therefore we surveyed the outcomes of Japanese leukemia children after PBSC and BM transplantation. This retrospective study compared the outcomes of 661 children (0-18 years) with acute lymphoblastic leukaemia (ALL) or acute myeloid leukaemia (AML) who received their first allogeneic peripheral blood stem cell transplantation (PBSCT; n = 90) or bone marrow transplantation (BMT; n = 571) from HLA-matched siblings between January 1996 and December 2007. Neutrophil recovery was faster after PBSCT than after BMT (ALL: P < 0.0001; AML: P = 0.0002), as was platelet recovery (ALL: P = 0.0008; AML: P = 0.0848). However, the cumulative incidence of chronic graft-versus-host disease (GvHD) was higher after PBSCT than after BMT (ALL: 26.0% vs. 9.9%, P = 0.0066; AML: 41.6% vs. 11.1%, P < 0.0001). The 5-year disease-free survival (DFS) was lower after PBSCT than after BMT for ALL (40.6% vs. 57.1%, P = 0.0257). The 5-year overall survival (OS) was lower after PBSCT than after BMT for ALL (42.4% vs. 63.7%, P = 0.0032) and AML (49.8% vs. 71.8%, P = 0.0163). Multivariate analysis revealed the use of PBSC was a significant risk factor for DFS and OS. PBSCT and BMT did not differ in relapse rate, acute GvHD for ALL and AML, or in DFS for AML. PBSC allografts in Japanese children engraft faster but are associated with poorer survival and increased chronic GvHD. Copyright © 2013 Wiley Periodicals, Inc.

Long-term followup of a phase I/II randomized, placebo-controlled trial of palifermin to prevent graft-versus-host disease (GVHD) after related donor allogeneic hematopoietic cell transplantation (HCT)

PubMed Central

Levine, John E.; Blazar, Bruce R.; DeFor, Todd; Ferrara, James L.M.; Weisdorf, Daniel J.

2008-01-01

We previously conducted a randomized, double-blind, placebo-controlled study conducted from 2000–2003 of palifermin, a recombinant human keratinocyte growth factor, dosed from 240 mcg/kg to 720 mcg/kg, in 100 allogeneic hematopoietic stem cell transplantation (HCT) recipients. Treatment with palifermin showed beneficial effects on mucositis, but no significant effect on engraftment, acute GVHD, or early survival. In addition to the effect of palifermin on mucosa, other pleotrophic effects, including more rapid immune reconstitution, have been seen in experimental transplant models. Therefore, we investigated whether with longer follow-up we could detect additional differences between the palifermin treated and placebo cohorts. We found no differences in CMV or invasive fungal infections, chronic GVHD, or long-term survival between cohorts. We conclude that the benefits of palifermin appear to primarily be limited to ameliorating mucotoxicity when given to allogeneic HCT recipients. PMID:18721764

Programmed cell death 1 (PD-1) regulates the effector function of CD8 T cells via PD-L1 expressed on target keratinocytes.

PubMed

Okiyama, Naoko; Katz, Stephen I

2014-09-01

Programmed cell death 1 (PD-1) is an inhibitory molecule expressed by activated T cells. Its ligands (PD-L1 and -L2; PD-Ls) are expressed not only by a variety of leukocytes but also by stromal cells. To assess the role of PD-1 in CD8 T cell-mediated diseases, we used PD-1-knockout (KO) OVA-specific T cell-receptor transgenic (Tg) CD8 T cells (OT-I cells) in a murine model of mucocutaneous graft-versus-host disease (GVHD). We found that mice expressing OVA on epidermal keratinocytes (K14-mOVA mice) developed markedly enhanced GVHD-like disease after transfer of PD-1-KO OT-I cells as compared to those mice transferred with wild-type OT-I cells. In addition, K14-mOVA × OT-I double Tg (DTg) mice do not develop GVHD-like disease after adoptive transfer of OT-I cells, while transfer of PD-1-KO OT-I cells caused GVHD-like disease in a Fas/Fas-L independent manner. These results suggest that PD-1/PD-Ls-interactions have stronger inhibitory effects on pathogenic CD8 T cells than does Fas/Fas-L-interactions. Keratinocytes from K14-mOVA mice with GVHD-like skin lesions express PD-L1, while those from mice without the disease do not. These findings reflect the fact that primary keratinocytes express PD-L1 when stimulated by interferon-γ in vitro. When co-cultured with K14-mOVA keratinocytes for 2 days, PD-1-KO OT-I cells exhibited enhanced proliferation and activation compared to wild-type OT-I cells. In addition, knockdown of 50% PD-L1 expression on the keratinocytes with transfection of PD-L1-siRNA enhanced OT-I cell proliferation. In aggregate, our data strongly suggest that PD-L1, expressed on activated target keratinocytes presenting autoantigens, regulates autoaggressive CD8 T cells, and inhibits the development of mucocutaneous autoimmune diseases. Published by Elsevier Ltd.

Target organs in chronic bioassays of 533 chemical carcinogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gold, L.S.; Slone, T.H.; Manley, N.B.

1991-06-01

A compendium of carcinogenesis bioassay results organized by target organ is presented for 533 chemicals that are carcinogenic in at least one species. This compendium is based primarily on experiments in rats or mice; results in hamsters, nonhuman primates, and dogs are also reported. The compendium can be used to identify chemicals that induce tumors at particular sites, and to determine whether target sites are the same for chemicals positive in more than one species. The Carcinogenic Potency Database (CPDB), which includes results of 3969 experiments, is used in the analysis. The published CPDB includes details on each test, andmore » literature references. Chemical carcinogens are reported for 35 different target organs in rats or mice. More than 80% of the carcinogens in each of these species are positive in at least one of the 8 most frequent target sites; liver, lung, mammary gland, stomach, vascular system, kidney, hematopoietic system, and urinary bladder. An analysis is presented of how well one can predict the carcinogenic response in mice from results in rats, or vice versa. Among chemicals tested in both species, 76% of rat carcinogens are positive in mice, and 71% of mouse carcinogens are positive in rats. Prediction is less accurate to the same target site: 52% of rat carcinogens are positive in the same site in mice, and 48% of mouse carcinogens are positive in the same site in rats. The liver is the most frequent site in common between rats and mice.« less

Transsynaptic Teneurin Signaling in Neuromuscular Synapse Organization and Target Choice

PubMed Central

Mosca, Timothy J.; Hong, Weizhe; Dani, Vardhan S.; Favaloro, Vincenzo; Luo, Liqun

2012-01-01

Synapse assembly requires transsynaptic signals between the pre- and postsynapse1, but the understanding of essential organizational molecules remains incomplete2. Teneurins are conserved, EGF-repeat containing transmembrane proteins with large extracellular domains3. Here we show that two Drosophila Teneurins, Ten-m and Ten-a, are required for neuromuscular synapse organization and target selection. Ten-a is presynaptic while Ten-m is mostly postsynaptic; neuronal Ten-a and muscle Ten-m form a complex in vivo. Pre- or postsynaptic Teneurin perturbations cause severe synapse loss and impair many facets of organization transsynaptically and cell-autonomously. These include defects in active zone apposition, release sites, membrane and vesicle organization, and synaptic transmission. Moreover, the presynaptic microtubule and postsynaptic spectrin cytoskeletons are severely disrupted, suggesting a mechanism whereby Teneurins organize the cytoskeleton, which in turn affects other aspects of synapse development. Supporting this, Ten-m physically interacts with α-spectrin. Genetic analyses of teneurin and neuroligin reveal their differential roles that synergize to promote synapse assembly. Finally, at elevated endogenous levels, Ten-m regulates specific motoneuron-muscle target selection. Our study identifies the Teneurins as a key bi-directional transsynaptic signal in general synapse organization, and demonstrates that such a molecule can also regulate target selection. PMID:22426000

The interferon-dependent orchestration of innate and adaptive immunity after transplantation.

PubMed

Robb, Renee J; Hill, Geoffrey R

2012-06-07

The therapeutic GVL effect after allogeneic stem cell transplantation is limited by the development of GVHD. The ultimate aim of current research is to separate the 2 processes in a meaningful fashion. The IFNs are a pleiotropic group of cytokines that were originally recognized because of their ability to interfere with viral replication. However, it is now established that these cytokines play an important role in orchestrating both innate and adaptive immunity. Multiple studies have investigated the effects of both types I and II IFN on GVHD and GVL in preclinical transplant models. The results indicate variable effects that are dependent on the period of activity within the developing immune response, the presence and type of pretransplant conditioning and the differential mechanisms, and IFN sensitivity of immune pathology within individual target organs during GVHD. This Perspective discusses the current literature on the IFNs and their potential modulation within clinical transplantation, focusing particularly on enhancing the therapeutic GVL effects.

Mammalian target of rapamycin inhibitor-associated stomatitis in hematopoietic stem cell transplantation patients receiving sirolimus prophylaxis for graft-versus-host disease.

PubMed

Villa, Alessandro; Aboalela, Ali; Luskin, Katharine A; Cutler, Corey S; Sonis, Stephen T; Woo, Sook Bin; Peterson, Douglas E; Treister, Nathaniel S

2015-03-01

The mammalian target of rapamycin (mTOR) inhibitor sirolimus is effective in reducing incidence of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Agents that inhibit the mTOR pathway are known to be associated with significant and potentially dose-limiting toxicities, including stomatitis. The objective of this study was to report the clinical features and management outcomes of sirolimus-associated oral ulcers in the context of post-HSCT prophylaxis of GVHD. Seventeen patients, from a study cohort of 967, who were treated with sirolimus as prophylaxis for GVHD after allogeneic HSCT at the Dana-Farber/Brigham and Women's Cancer Center developed oral ulcers and were referred to the oral medicine clinic for evaluation and treatment over a period of 6 years. Clinical characteristics (appearance, anatomic site, size) and therapeutic outcomes (time to complete resolution) were documented. Median time to onset of oral ulceration was 55 days after allogeneic HSCT (range, 6 to 387 days); 92.9% of ulcers were located on nonkeratinized mucosa, with the ventrolateral tongue the most common site of involvement. Thirteen patients were treated with topical corticosteroid therapy; 12 of these patients also required intralesional corticosteroid injections. Clinical improvement (resolution of the lesions and improvement of symptoms) was noted in all cases, with no reported adverse events. Median time to complete resolution after onset of therapy was 14 days (range, 2 to 70 days). Patients receiving sirolimus for GVHD prophylaxis may develop painful oral ulcerations, which can be effectively managed with topical steroid treatment. Further prospective studies are needed to better elucidate the incidence of this complication, identify risk factors, and evaluate the effectiveness of interventions. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

A Canine Model of Chronic Graft-versus-Host Disease.

PubMed

Graves, Scott S; Rezvani, Andrew; Sale, George; Stone, Diane; Parker, Maura; Rosinski, Steven; Spector, Michele; Swearingen, Bruce; Kean, Leslie; Storb, Rainer

2017-03-01

In long-term survivors of allogeneic hematopoietic cell transplantation (HCT), chronic graft-versus-host disease (GVHD) is the major cause of morbidity and mortality and a major determinant of quality of life. Chronic GVHD responds poorly to current immunosuppressive drugs, and while T cell depletion may be preventive, this gain is offset by increased relapse rates. A significant impediment to progress in treating chronic GVHD has been the limitations of existing animal models. The goal of this study was to develop a reproducible comprehensive model of chronic GVHD in the dog. Ten recipient dogs received 920 cGy total body irradiation, infusion of marrow, and an infusion of buffy coat cells from a dog leukocyte antigen (DLA)-mismatched unrelated donor. Postgrafting immunosuppression consisted of methotrexate (days 1, 3, 6, 11) and cyclosporine. The duration of cyclosporine administration was limited to 80 days instead of the clinically used 180 days. This was done to contain costs, as chronic GVHD was expected to develop at earlier time points. All recipients were given ursodiol for liver protection. One dog had graft failure and 9 dogs showed stable engraftment. Eight of the 9 developed de novo chronic GVHD. Dogs progressed with clinical signs of chronic GVHD over a period of 43 to 164 (median, 88) days after discontinuation of cyclosporine. Target organs showed the spectrum of chronic GVHD manifestations that are typically seen clinically. These included lichenoid changes of the skin, fasciitis, ocular involvement (xerophthalmia), conjunctivitis, bronchiolitis obliterans, salivary gland involvement, gingivitis, esophageal involvement, and hepatic involvement. Peripheral blood lymphocyte surface antigen expression of CD28 and inducible costimulator was elevated in dogs with GHVD compared with those in normal dogs, but not significantly so. Serum levels of IL-8 and monocyte chemotactic protein-1 in GVHD-affected dogs at time of euthanasia were elevated, whereas

MicroRNA-155 Modulates Acute Graft-versus-Host Disease by Impacting T Cell Expansion, Migration, and Effector Function.

PubMed

Zitzer, Nina C; Snyder, Katiri; Meng, Xiamoei; Taylor, Patricia A; Efebera, Yvonne A; Devine, Steven M; Blazar, Bruce R; Garzon, Ramiro; Ranganathan, Parvathi

2018-06-15

MicroRNA-155 (miR-155) is a small noncoding RNA critical for the regulation of inflammation as well as innate and adaptive immune responses. MiR-155 has been shown to be dysregulated in both donor and recipient immune cells during acute graft-versus-host disease (aGVHD). We previously reported that miR-155 is upregulated in donor T cells of mice and humans with aGVHD and that mice receiving miR-155-deficient (miR155 -/- ) splenocytes had markedly reduced aGVHD. However, molecular mechanisms by which miR-155 modulates T cell function in aGVHD have not been fully investigated. We identify that miR-155 expression in both donor CD8 + T cells and conventional CD4 + CD25 - T cells is pivotal for aGVHD pathogenesis. Using murine aGVHD transplant experiments, we show that miR-155 strongly impacts alloreactive T cell expansion through multiple distinct mechanisms, modulating proliferation in CD8 + donor T cells and promoting exhaustion in donor CD4 + T cells in both the spleen and colon. Additionally, miR-155 drives a proinflammatory Th1 phenotype in donor T cells in these two sites, and miR-155 -/- donor T cells are polarized toward an IL-4-producing Th2 phenotype. We further demonstrate that miR-155 expression in donor T cells regulates CCR5 and CXCR4 chemokine-dependent migration. Notably, we show that miR-155 expression is crucial for donor T cell infiltration into multiple target organs. These findings provide further understanding of the role of miR-155 in modulating aGVHD through T cell expansion, effector cytokine production, and migration. Copyright © 2018 by The American Association of Immunologists, Inc.

Effective prevention of GVHD using in vivo T-cell depletion with anti-lymphocyte globulin in HLA-identical or -mismatched sibling peripheral blood stem cell transplantation.

PubMed

Wolschke, C; Zabelina, T; Ayuk, F; Alchalby, H; Berger, J; Klyuchnikov, E; Pein, U-M; Schumacher, S; Amtsfeld, G; Adjallé, R; Wortmann, F; Lellek, H; Randenborgh, A; Zander, A; Kröger, N

2014-01-01

To investigate the impact of anti-lymphocyte globulin (ATG-Fresenius) as part of the HLA-sibling transplantation, we evaluated 238 patients (median age 48 years) with different diagnoses (AML, ALL, CML and lymphoproliferative disorders). A total of 79 patients received ATG and 159 patients did not. In the ATG group, there were more HLA-mismatched donors (6% vs 1%, p=0.02), bad risk patients (70% vs 55%, P=0.04), reduced intensity conditioning (RIC) regimens (65% vs 34%, P=<0.001) and older patients (median age 51 vs 48 years, P=0.002). The median time to leukocyte engraftment was significantly faster in the non-ATG group (13 vs 15 days, P < 0.001). EBV reactivation was more often seen in the ATG group (9% vs 2%, P=0.05). Cumulative incidence of acute and chronic GVHD was less observed in the ATG group (27% vs 40%, P=0.004, and 33% vs 54%, P=0.002). The cumulative incidence rates of non-relapse mortality and of relapse at 5 years were 20 and 34%, respectively, for ATG and 34 and 29%, respectively, for non-ATG (P=0.06 and P=0.3). ATG can prevent GVHD without an obvious risk of relapse but should be confirmed in a randomized study.

Low Body Mass Index Is Associated with Increased Risk of Acute GVHD after Umbilical Cord Blood Transplantation in Children and Young Adults with Acute Leukemia: A Study on Behalf of Eurocord and the EBMT Pediatric Disease Working Party.

PubMed

Paviglianiti, Annalisa; Dalle, Jean Hugues; Ayas, Mouhab; Boelens, Jan Jaap; Volt, Fernanda; Iori, Anna Paola; de Souza, Mair Pedro; Diaz, Miguel Angel; Michel, Gerard; Locatelli, Franco; Jubert, Charlotte; Yakoub-Agha, Ibrahim; Bittencourt, Henrique; Bertrand, Yves; Kenzey, Chantal; Tozatto Maio, Karina; Hayashi, Hiromi; Rocha, Vanderson; Bader, Peter; Gluckman, Eliane; Ruggeri, Annalisa

2018-04-01

Body mass index (BMI) may influence outcomes after allogeneic hematopoietic stem cell transplantation (HSCT). However, the impact of BMI on survival in children undergoing HSCT is not well defined, with conflicting results being reported on this issue. We analyzed 855 patients age 2 to 20 years with diagnosis of acute leukemia who underwent umbilical cord blood transplantation (UCBT) from 1990 to 2015. Patients were classified according to BMI as normal (fifth to 85th percentile), underweight (less than fifth percentile), overweight (85th to 95th percentile), and obese (>95th percentile) using growth charts for age and sex. All patients received single-unit UCBT after a myeloablative conditioning regimen. Diagnosis was acute lymphoblastic leukemia in 68% of the patients. Sixty-one percent of patients (n = 523) were in the normal BMI category, 11% (n = 96) were underweight, 16% (n = 137) overweight, and 12% (n = 99) obese. The cumulative incidence of grade II to IV acute graft-versus-host disease (aGVHD) was 35% (32% to 38%). According to pretransplantation BMI, aGVHD was 46% (33% to 59%) for underweight, 34% (31% to 42%) for normal, 36% (18% to 38%) for overweight, and 27% (15% to 37%) for obese (P = .04). In multivariate analysis, a BMI less than the fifth percentile was associated with higher incidence of acute grade II to IV GVHD compared with normal-BMI patients (hazard ratio,  1.61; 95% confidence interval, 1.15 to 2.26; P = .006). Our results show that being underweight at the time of transplantation is associated with an increased risk of aGVHD, highlighting the importance of nutritional status before UCBT. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Self-organization and progenitor targeting generate stable patterns in planarian regeneration.

PubMed

Atabay, Kutay Deniz; LoCascio, Samuel A; de Hoog, Thom; Reddien, Peter W

2018-04-27

During animal regeneration, cells must organize into discrete and functional systems. We show that self-organization, along with patterning cues, govern progenitor behavior in planarian regeneration. Surgical paradigms allowed the manipulation of planarian eye regeneration in predictable locations and numbers, generating alternative stable neuroanatomical states for wild-type animals with multiple functional ectopic eyes. We used animals with multiple ectopic eyes and eye transplantation to demonstrate that broad progenitor specification, combined with self-organization, allows anatomy maintenance during regeneration. We propose a model for regenerative progenitors involving (i) migratory targeting cues, (ii) self-organization into existing or regenerating eyes, and (iii) a broad zone, associated with coarse progenitor specification, in which eyes can be targeted by progenitors. These three properties help explain how tissues can be organized during regeneration. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Human mesenchymal stromal cells attenuate graft-versus-host disease and maintain graft-versus-leukemia activity following experimental allogeneic bone marrow transplantation1

PubMed Central

Auletta, Jeffery J.; Eid, Saada K.; Wuttisarnwattana, Patiwet; Silva, Ines; Metheny, Leland; Keller, Matthew D.; Guardia-Wolff, Rocio; Liu, Chen; Wang, Fangjing; Bowen, Theodore; Lee, Zhenghong; Solchaga, Luis A.; Ganguly, Sudipto; Tyler, Megan; Wilson, David L.; Cooke, Kenneth R.

2014-01-01

We sought to define the effects and underlying mechanisms of human, marrow-derived mesenchymal stromal cells (hMSCs) on graft-versus-host disease (GvHD) and graft-versus-leukemia (GvL) activity. Irradiated B6D2F1 mice given C57BL/6 BM and splenic T-cells and treated with hMSCs had reduced systemic GvHD, donor T-cell expansion, and serum TNFα and IFNγ levels. Bioluminescence imaging demonstrated that hMSCs redistributed from lungs to abdominal organs within 72h; and target tissues harvested from hMSC-treated alloBMT mice had less GvHD than untreated controls. Cryo-imaging more precisely revealed that hMSCs preferentially distributed to splenic marginal zones and regulated T-cell expansion in the white pulp. Importantly, hMSCs had no effect on in vitro cytotoxic T-cell activity and preserved potent GvL effects in vivo. Mixed leukocyte cultures containing hMSCs exhibited decreased T-cell proliferation, reduced TNFα, IFNγ, and IL-10, but increased PGE2 levels. Indomethacin and E-prostanoid 2 (EP2) receptor antagonisms both reversed while EP2 agonism restored hMSC-mediated in vitro T-cell suppression, confirming the role for PGE2. Furthermore, cyclo-oxygenase inhibition following alloBMT abrogated the protective effects of hMSCs. Together, our data show that hMSCs preserve GvL activity and attenuate GvHD and reveal that hMSC biodistribute to secondary lymphoid organs wherein they attenuate alloreactive T-cell proliferation likely through PGE2 induction. PMID:25336340

Serum uric acid and target organ damage in essential hypertension

PubMed Central

Ofori, Sandra N; Odia, Osaretin J

2014-01-01

Background Hypertension is a major risk factor for cardiovascular mortality, as it acts through its effects on target organs, such as the heart and kidneys. Hyperuricemia increases cardiovascular risk in patients with hypertension. Objective To assess the relationship between serum uric acid and target organ damage (left ventricular hypertrophy and microalbuminuria) in untreated patients with essential hypertension. Patients and methods: A cross-sectional study was carried out in 130 (85 females, 45 males) newly diagnosed, untreated patients with essential hypertension. Sixty-five healthy age- and sex-matched non-hypertensive individuals served as controls for comparison. Left ventricular hypertrophy was evaluated by cardiac ultrasound scan, and microalbuminuria was assessed in an early morning midstream urine sample by immunoturbidimetry. Blood samples were collected for assessing uric acid levels. Results Mean serum uric acid was significantly higher among the patients with hypertension (379.7±109.2 μmol/L) than in the controls (296.9±89.8 μmol/L; P<0.001), and the prevalence of hyperuricemia was 46.9% among the hypertensive patients and 16.9% among the controls (P<0.001). Among the hypertensive patients, microalbuminuria was present in 54.1% of those with hyperuricemia and in 24.6% of those with normal uric acid levels (P=0.001). Similarly, left ventricular hypertrophy was more common in the hypertensive patients with hyperuricemia (70.5% versus 42.0%, respectively; P=0.001). There was a significant linear relationship between mean uric acid levels and the number of target organ damage (none versus one versus two: P=0.012). Conclusion These results indicate that serum uric acid is associated with target organ damage in patients with hypertension, even at the time of diagnosis; thus, it is a reliable marker of cardiovascular damage in our patient population. PMID:24833906

Serum uric acid and target organ damage in essential hypertension.

PubMed

Ofori, Sandra N; Odia, Osaretin J

2014-01-01

Hypertension is a major risk factor for cardiovascular mortality, as it acts through its effects on target organs, such as the heart and kidneys. Hyperuricemia increases cardiovascular risk in patients with hypertension. To assess the relationship between serum uric acid and target organ damage (left ventricular hypertrophy and microalbuminuria) in untreated patients with essential hypertension. A cross-sectional study was carried out in 130 (85 females, 45 males) newly diagnosed, untreated patients with essential hypertension. Sixty-five healthy age- and sex-matched non-hypertensive individuals served as controls for comparison. Left ventricular hypertrophy was evaluated by cardiac ultrasound scan, and microalbuminuria was assessed in an early morning midstream urine sample by immunoturbidimetry. Blood samples were collected for assessing uric acid levels. Mean serum uric acid was significantly higher among the patients with hypertension (379.7±109.2 μmol/L) than in the controls (296.9±89.8 μmol/L; P<0.001), and the prevalence of hyperuricemia was 46.9% among the hypertensive patients and 16.9% among the controls (P<0.001). Among the hypertensive patients, microalbuminuria was present in 54.1% of those with hyperuricemia and in 24.6% of those with normal uric acid levels (P=0.001). Similarly, left ventricular hypertrophy was more common in the hypertensive patients with hyperuricemia (70.5% versus 42.0%, respectively; P=0.001). There was a significant linear relationship between mean uric acid levels and the number of target organ damage (none versus one versus two: P=0.012). These results indicate that serum uric acid is associated with target organ damage in patients with hypertension, even at the time of diagnosis; thus, it is a reliable marker of cardiovascular damage in our patient population.

Quality of life of patients with graft-versus-host disease (GvHD) post-hematopoietic stem cell transplantation.

PubMed

Proença, Sibéli de Fátima Ferraz Simão; Machado, Celina Mattos; Coelho, Raquel de Castro Figueiredo Pereira; Sarquis, Leila Maria Mansano; Guimarães, Paulo Ricardo Bittencourt; Kalinke, Luciana Puchalski

2016-01-01

Assessing the quality of life of adult patients with hematological cancer in the 100 days after transplantation of hematopoietic stem cells and verifying whether the variable graft-versus-host disease (GvHD) is predictive of worse results. An observational correlational and quantitative study with 36 adult participants diagnosed with hematologic cancer who underwent hematopoietic stem cell transplantation from September 2013 to June 2015. The mean age was 37 years, 52.78% were female, and 61.11% were diagnosed with leukemia. Quality of life scores showed a significant impact between pre-transplantation and pre-hospital discharge, and also within the 100 days post-transplantation. The statistical analysis between the scores for the groups with and without GvHD showed a significant difference between the presence of the complication and worse results. Quality of life is altered as a result of hematopoietic stem cells transplantation, especially in patients who have graft-versus-host disease. Avaliar a qualidade de vida de pacientes adultos com câncer hematológico nos 100 dias do transplante de células-tronco hematopoéticas e verificar se a variável doença do enxerto contra o hospedeiro é preditiva de piores resultados. Estudo observacional, correlacional e quantitativo, com 36 participantes adultos, diagnosticados com câncer hematológico que se submeteram ao transplante de células-tronco hematopoéticas de setembro de 2013 a junho de 2015. A média de idade foi 37 anos, 52,78% eram do sexo feminino, e 61,11% com diagnóstico de leucemia. Os escores de qualidade de vida demonstraram impacto significativo entre o pré-transplante e a pré-alta hospitalar e entre os 100 dias pós-transplante. A análise estatística entre os escores dos grupos com e sem doença do enxerto contra o hospedeiro evidenciou significância entre a presença desta complicação e piores resultados. A qualidade de vida é alterada em decorrência do transplante de c

An integrated miRNA functional screening and target validation method for organ morphogenesis.

PubMed

Rebustini, Ivan T; Vlahos, Maryann; Packer, Trevor; Kukuruzinska, Maria A; Maas, Richard L

2016-03-16

The relative ease of identifying microRNAs and their increasing recognition as important regulators of organogenesis motivate the development of methods to efficiently assess microRNA function during organ morphogenesis. In this context, embryonic organ explants provide a reliable and reproducible system that recapitulates some of the important early morphogenetic processes during organ development. Here we present a method to target microRNA function in explanted mouse embryonic organs. Our method combines the use of peptide-based nanoparticles to transfect specific microRNA inhibitors or activators into embryonic organ explants, with a microRNA pulldown assay that allows direct identification of microRNA targets. This method provides effective assessment of microRNA function during organ morphogenesis, allows prioritization of multiple microRNAs in parallel for subsequent genetic approaches, and can be applied to a variety of embryonic organs.

Ibrutinib for chronic graft-versus-host disease after failure of prior therapy.

PubMed

Miklos, David; Cutler, Corey S; Arora, Mukta; Waller, Edmund K; Jagasia, Madan; Pusic, Iskra; Flowers, Mary E; Logan, Aaron C; Nakamura, Ryotaro; Blazar, Bruce R; Li, Yunfeng; Chang, Stephen; Lal, Indu; Dubovsky, Jason; James, Danelle F; Styles, Lori; Jaglowski, Samantha

2017-11-23

Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem cell transplantation with few effective options available after failure of corticosteroids. B and T cells play a role in the pathophysiology of cGVHD. Ibrutinib inhibits Bruton tyrosine kinase in B cells and interleukin-2-inducible T-cell kinase in T cells. In preclinical models, ibrutinib reduced severity of cGVHD. This multicenter, open-label study evaluated the safety and efficacy of ibrutinib in patients with active cGVHD with inadequate response to corticosteroid-containing therapies. Forty-two patients who had failed 1 to 3 prior treatments received ibrutinib (420 mg) daily until cGVHD progression. The primary efficacy end point was cGVHD response based on 2005 National Institutes of Health criteria. At a median follow-up of 13.9 months, best overall response was 67%; 71% of responders showed a sustained response for ≥20 weeks. Responses were observed across involved organs evaluated. Most patients with multiple cGVHD organ involvement had a multiorgan response. Median corticosteroid dose in responders decreased from 0.29 mg/kg per day at baseline to 0.12 mg/kg per day at week 49; 5 responders discontinued corticosteroids. The most common adverse events were fatigue, diarrhea, muscle spasms, nausea, and bruising. Plasma levels of soluble factors associated with inflammation, fibrosis, and cGVHD significantly decreased over time with ibrutinib. Ibrutinib resulted in clinically meaningful responses with acceptable safety in patients with ≥1 prior treatments for cGVHD. Based on these results, ibrutinib was approved in the United States for treatment of adult patients with cGVHD after failure of 1 or more lines of systemic therapy. This trial was registered at www.clinicaltrials.gov as #NCT02195869. © 2017 by The American Society of Hematology.

Extracellular Vesicles Released from Human Umbilical Cord-Derived Mesenchymal Stromal Cells Prevent Life-Threatening Acute Graft-Versus-Host Disease in a Mouse Model of Allogeneic Hematopoietic Stem Cell Transplantation.

PubMed

Wang, Li; Gu, Zhenyang; Zhao, Xiaoli; Yang, Nan; Wang, Feiyan; Deng, Ailing; Zhao, Shasha; Luo, Lan; Wei, Huaping; Guan, Lixun; Gao, Zhe; Li, Yonghui; Wang, Lili; Liu, Daihong; Gao, Chunji

2016-12-15

Mesenchymal stromal cells (MSCs) are attractive agents for the prophylaxis of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, safety concerns remain about their clinical application. In this study, we explored whether extracellular vesicles released from human umbilical cord-derived MSCs (hUC-MSC-EVs) could prevent aGVHD in a mouse model of allo-HSCT. hUC-MSC-EVs were intravenously administered to recipient mice on days 0 and 7 after allo-HSCT, and the prophylactic effects of hUC-MSC-EVs were assessed by observing the in vivo manifestations of aGVHD, histologic changes in target organs, and recipient mouse survival. We evaluated the effects of hUC-MSC-EVs on immune cells and inflammatory cytokines by flow cytometry and ProcartaPlex™ Multiplex Immunoassays, respectively. The in vitro effects of hUC-MSC-EVs were determined by mitogen-induced proliferation assays. hUC-MSC-EVs alleviated the in vivo manifestations of aGVHD and the associated histologic changes and significantly reduced the mortality of the recipient mice. Recipients treated with hUC-MSC-EVs had significantly lower frequencies and absolute numbers of CD3 + CD8 + T cells; reduced serum levels of IL-2, TNF-α, and IFN-γ; a higher ratio of CD3 + CD4 + and CD3 + CD8 + T cells; and higher serum levels of IL-10. An in vitro experiment demonstrated that hUC-MSC-EVs inhibited the mitogen-induced proliferation of splenocytes in a dose-dependent manner, and the cytokine changes were similar to those observed in vivo. This study indicated that hUC-MSC-EVs can prevent life-threatening aGVHD by modulating immune responses. These data provide the first evidence that hUC-MSC-EVs represent an ideal alternative in the prophylaxis of aGVHD after allo-HSCT.

Gut microbiota and graft-versus-host disease: broad-spectrum antibiotic use increases post-allogeneic hematopoietic stem cell transplant graft-versus-host disease-related mortality.

PubMed

Shono, Yusuke

2017-01-01

Intestinal bacteria can modulate the risk of infection and graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Allo-HSCT recipients often develop neutropenic fever, which is treated with antibiotics that may target anaerobic bacteria in the gut. We retrospectively examined 857 allo-HSCT recipients and found that treatment using broad-spectrum antibiotics was associated with increased GVHD-related mortality at 5 years. Analysis of stool specimens from allo-HSCT recipients showed that broad-spectrum antibiotic administration was associated with perturbation of gut microbial composition. Studies in mice also demonstrated aggravated GVHD mortality with broad-spectrum antibiotics use. Broad-spectrum antibiotics treatment of mice with GVHD led to a loss of the protective mucus lining of the colon, compromised intestinal barrier function, as well as increased a commensal bacterium with mucus-degrading capabilities, raising the possibility that mucus degradation may contribute to murine GVHD. We demonstrate an underappreciated risk of antibiotics in allo-HSCT recipients that may exacerbate GVHD in the colon.

Graft-versus-host disease in the ovary potentially causes female infertility after allogeneic hematopoietic stem cell transplantation.

PubMed

Shimoji, Sonoko; Hashimoto, Daigo; Teshima, Takanori

2017-01-01

Ovarian failure-associated infertility is a serious late complication for female patients who have undergone allogeneic hematopoietic stem cell transplantation (SCT). Although the role of a pretransplant conditioning regimen has been well appreciated, the increasing application of reduced-intensity conditioning has led us to reconsider other factors possibly affecting ovarian function after allogeneic SCT. We recently reported that graft-versus-host disease (GVHD) targets granulosa cells of the ovarian follicles, thereby significantly reducing ovarian reserves and fertility after SCT. We also found that ovarian GVHD impairs fertility independently of the toxicities of the conditioning regimens, and pharmacological GVHD prophylaxis preserves fertility after SCT. For the first time, these results demonstrated that GVHD targets the ovary and impairs ovarian functions and fertility, thereby having important clinical implications in young female transplant recipients with nonmalignant diseases, for whom minimally toxic regimens are used. Here we review recently published articles regarding clinical and basic researches on female infertility after SCT.

Is the presence of 6 or fewer crypt apoptotic bodies sufficient for diagnosis of graft versus host disease? A decade of experience at a single institution.

PubMed

Lin, Jingmei; Fan, Rong; Zhao, Zijin; Cummings, Oscar W; Chen, Shaoxiong

2013-04-01

Histopathology assessment is crucial for the diagnosis of graft versus host disease (GVHD), as the presence of crypt apoptosis is the cardinal criterion required. However, crypt apoptosis is not limited to GVHD; it also occurs in other conditions such as infection, drug reaction, or inflammatory reactions unrelated to GVHD. To better determine whether the presence of 6 or fewer apoptotic bodies is sufficient for the diagnosis of GVHD, we retrospectively reviewed 78 colon biopsies from 66 patients who received either hematopoietic stem cell (HSCT) or cord blood cell transplantation and whose colon biopsies exhibited apoptotic bodies. Among them, 41 cases contained 6 or fewer apoptotic bodies in the colon biopsy. These biopsies were compared with 141 colon biopsy controls that showed no significant pathologic changes as well as 16 colon biopsies with cytomegalovirus colitis from patients without a history of bone marrow transplantation. Among the 41 cases reviewed, 7 patients had coexisting GVHD in other organs (skin or liver). However, gastrointestinal symptoms of at least 4 HSCT patients whose colon biopsies contained 6 or fewer apoptotic bodies completely resolved in the absence of further intervention for GVHD. The discrepancy between pathologic findings and the clinical course may be due to confounding factors, such as infection or medication-induced injury. Our data suggest that identifying 6 or fewer crypt apoptotic bodies in colon biopsies from HSCT patients is worth reporting in order to alert the clinicians of the possibility of GVHD but not sufficient to render a diagnosis on the pathologic grounds alone. The colon biopsies containing 6 or fewer apoptotic bodies represent a heterogenous group. We suggest this group to be classified as indeterminate for GVHD, instead of diagnosing GVHD outright. Synthesis of all clinical, endoscopic, and pathologic information, including the status of infection, coexisting GVHD involvement in the other organs, and

Novel T lymphocyte proliferation assessment using whole mouse cryo-imaging

NASA Astrophysics Data System (ADS)

Wuttisarnwattana, Patiwet; Raza, Syed A.; Eid, Saada; Cooke, Kenneth R.; Wilson, David L.

2014-03-01

New imaging technologies enable one to assess T-cell proliferation, an important feature of the immunological response. However, none of the traditional imaging modalities allow one to examine quantiatively T-cell function with microscopic resolution and single cell sensitivity over an entire mouse. To address this need, we established T-cells proliferation assays using 3D microscopic cryo-imaging. Assays include: (1) biodistribution of T-cells, (2) secondary lymphoid organ (SLO) volume measurement, (3) carboxyfluorescein succinimidyl ester (CFSE) dilution per cell as cells divide. To demonstrate the application, a graft-versus-host-disease (GVHD) model was used. 3D visualization show that T-cells specifically homed to the SLOs (spleen and lymph nodes) as well as GVHD target organs (such as GI-tract, liver, skin and thymus).The spleen was chosen as representative of the SLOs. For spleen size analysis, volumes of red and white pulp were measured. Spleen volumes of the allogeneic mice (with GVHD) were significantly larger than those of the syngeneic mice (without GVHD) at 72 to 120 hours post-transplant. For CFSE dilution approach, we employed color-coded volume rendering and probability density function (PDF) of single cell intensity to assess T-cell proliferation in the spleen. As compared to syngeneic T-cells, the allogeneic T-cells quickly aggregated in the spleen as indicated by increasing of CFSE signal over the first 48 hours. Then they rapidly proliferated as evidenced by reduced CFSE intensity (at 48-96 hours). Results suggest that assays can be used to study GVHD treatments using T-cell proliferation and biodistibution as assays. In summary, this is the first time that we are able to track and visualize T-cells in whole mouse with single cell sensitivity. We believe that our technique can be an alternative choice to traditional in vitro immunological proliferation assays by providing assessment of proliferation in an in vivo model.

Transplantation of polarized type 2 donor T cells reduces mortality caused by experimental graft-versus-host disease.

PubMed

Krenger, W; Cooke, K R; Crawford, J M; Sonis, S T; Simmons, R; Pan, L; Delmonte, J; Karandikar, M; Ferrara, J L

1996-11-15

Acute graft-versus-host disease (GVHD) is thought to be initiated by alloreactive type 1 T cells that secrete gamma-interferon (IFN-gamma). IFN-gamma induces the production of inflammatory cytokines, e.g., tumor necrosis factor-alpha and interleukin (IL)-1, which are the distal mediators of GVHD. We demonstrate that the transplantation of polarized type 2 murine T cells (i.e., cells secreting IL-4 but not IFN-gamma) together with T-cell-depleted bone marrow results in a significant increase in survival (P<0.001) after bone marrow transplantation across minor histocompatibility barriers (B10.BR-->CBA/J). Further analysis demonstrated that increased survival in recipients of polarized type 2 T cells correlated with diminished production of both IFN-gamma and tumor necrosis factor-alpha but with increases in IL-4 2 weeks after transplantation. Despite improved survival, histologic changes of GVHD were evident in oral mucosal and hepatic tissues at 7 weeks after bone marrow transplantation. These data provide further evidence that inflammatory cytokines in the immediate posttransplant period are pivotal to the development of mortality but that they do not correlate with individual target organ damage.

Inhibition of BTK and ITK with Ibrutinib Is Effective in the Prevention of Chronic Graft-versus-Host Disease in Mice

PubMed Central

Nguyen, Hung; Bastian, David; Heinrichs, Jessica; Wu, Yongxia; Liu, Chen; McDonald, Daniel G.; Pidala, Joseph; Yu, Xue-Zhong

2015-01-01

Bruton’s Tyrosine Kinase (BTK) and IL-2 Inducible T-cell Kinase (ITK) are enzymes responsible for the phosphorylation and activation of downstream effectors in the B-cell receptor (BCR) signaling and T cell receptor (TCR) signaling pathways, respectively. Ibrutinib is an FDA-approved potent inhibitor of both BTK and ITK that impairs B-cell and T-cell function. CD4 T cells and B cells are essential for the induction of chronic graft-versus-host disease (cGVHD). We evaluated these targets by testing the ability of Ibrutinib to prevent or ameliorate cGVHD, which is one of the major complications for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). We found that Ibrutinib significantly alleviated cGVHD across four different mouse models, accompanied by increased long-term survival and reduced clinical score. The clinical improvements in Ibrutinib-treated recipients were associated with decreased serum-autoantibodies, costimulatory molecule activation, B-cell proliferation, and glomerulonephritis compared to vehicle controls. Ibrutinib was also able to alleviate the clinical manifestations in acute GVHD (aGVHD), where the recipients were given grafts with or without B cells, suggesting that an inhibitory effect of Ibrutinib on T cells contributes to a reduction in both aGVHD and cGVHD pathogenesis. An effective prophylactic regimen is still lacking to both reduce the incidence and severity of human cGVHD following allo-HSCT. Our study shows that Ibrutinib is an effective prophylaxis against several mouse models of cGVHD with minimal toxicity and could be a promising strategy to combat human cGVHD clinically. PMID:26348529

Inhibition of BTK and ITK with Ibrutinib Is Effective in the Prevention of Chronic Graft-versus-Host Disease in Mice.

PubMed

Schutt, Steven D; Fu, Jianing; Nguyen, Hung; Bastian, David; Heinrichs, Jessica; Wu, Yongxia; Liu, Chen; McDonald, Daniel G; Pidala, Joseph; Yu, Xue-Zhong

2015-01-01

Bruton's Tyrosine Kinase (BTK) and IL-2 Inducible T-cell Kinase (ITK) are enzymes responsible for the phosphorylation and activation of downstream effectors in the B-cell receptor (BCR) signaling and T cell receptor (TCR) signaling pathways, respectively. Ibrutinib is an FDA-approved potent inhibitor of both BTK and ITK that impairs B-cell and T-cell function. CD4 T cells and B cells are essential for the induction of chronic graft-versus-host disease (cGVHD). We evaluated these targets by testing the ability of Ibrutinib to prevent or ameliorate cGVHD, which is one of the major complications for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). We found that Ibrutinib significantly alleviated cGVHD across four different mouse models, accompanied by increased long-term survival and reduced clinical score. The clinical improvements in Ibrutinib-treated recipients were associated with decreased serum-autoantibodies, costimulatory molecule activation, B-cell proliferation, and glomerulonephritis compared to vehicle controls. Ibrutinib was also able to alleviate the clinical manifestations in acute GVHD (aGVHD), where the recipients were given grafts with or without B cells, suggesting that an inhibitory effect of Ibrutinib on T cells contributes to a reduction in both aGVHD and cGVHD pathogenesis. An effective prophylactic regimen is still lacking to both reduce the incidence and severity of human cGVHD following allo-HSCT. Our study shows that Ibrutinib is an effective prophylaxis against several mouse models of cGVHD with minimal toxicity and could be a promising strategy to combat human cGVHD clinically.

Interleukin-22 in Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation

PubMed Central

Lamarthée, Baptiste; Malard, Florent; Saas, Philippe; Mohty, Mohamad; Gaugler, Béatrice

2016-01-01

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potential curative treatment for hematologic malignancies and non-malignant diseases. Because of the lower toxicity of reduced intensity conditioning, the number of transplants is in constant increase. However, allo-HSCT is still limited by complications, such as graft-versus-host disease (GVHD), which is associated with important morbidity and mortality. Acute GVHD is an exacerbated inflammatory response that leads to the destruction of healthy host tissues by donor immune cells. Recently, the contribution of innate immunity in GVHD triggering has been investigated by several groups and resulted in the identification of new cellular and molecular effectors involved in GVHD pathogenesis. Interleukin-22 (IL-22) is produced by both immune and adaptive cells and has both protective and inflammatory properties. Its role in GVHD processes has been investigated, and the data suggest that its effect depends on the timing, the target tissue, and the origin of the producing cells (donor/host). In this review, we discuss the role of IL-22 in allo-HSCT and GVHD. PMID:27148267

Interleukin-22 in Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation.

PubMed

Lamarthée, Baptiste; Malard, Florent; Saas, Philippe; Mohty, Mohamad; Gaugler, Béatrice

2016-01-01

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potential curative treatment for hematologic malignancies and non-malignant diseases. Because of the lower toxicity of reduced intensity conditioning, the number of transplants is in constant increase. However, allo-HSCT is still limited by complications, such as graft-versus-host disease (GVHD), which is associated with important morbidity and mortality. Acute GVHD is an exacerbated inflammatory response that leads to the destruction of healthy host tissues by donor immune cells. Recently, the contribution of innate immunity in GVHD triggering has been investigated by several groups and resulted in the identification of new cellular and molecular effectors involved in GVHD pathogenesis. Interleukin-22 (IL-22) is produced by both immune and adaptive cells and has both protective and inflammatory properties. Its role in GVHD processes has been investigated, and the data suggest that its effect depends on the timing, the target tissue, and the origin of the producing cells (donor/host). In this review, we discuss the role of IL-22 in allo-HSCT and GVHD.

Gender-related differences in adolescent hypertension and in target organ effects.

PubMed

Juhász, Mária; Katona, Eva; Settakis, Georgios; Paragh, György; Molnár, Csilla; Fülesdi, Béla; Páll, Dénes

2010-04-01

To assess whether a gender difference exists in adolescent hypertension and its target organ damage and to compare potential confounding factors and target organ damage in hypertensive and normotensive adolescent girls. From the Debrecen Hypertension Study, the anthropometric, blood pressure, and laboratory data as well as intima-media thickness (IMT) and left ventricular mass index (LVMI) of 58 hypertensive boys, 56 hypertensive girls, and 30 normotensive girls were analyzed. Both systolic and mean blood pressure values were higher in adolescent hypertensive boys than in girls. This difference was also present when comparing 24-hour average blood pressure values. Plasma concentrations of nitric oxide (NO) and endothelin-1 were not different in the two gender groups. IMT of the carotid arteries were similar in hypertensive boys and girls, but a significantly higher LVMI was detected in boys. A significant difference was detected in anthropometric data (height, weight, and body mass index [BMI]), plasma concentration of NO (lower levels in hypertensives), and IMT in hypertensive and normotensive girls (higher IMT in hypertensive girls). There is a difference between the severity of hypertension between hypertensive adolescent girls and boys. Hypertensive girls differ from normotensive girls not only in blood pressure values but also in risk factors and subclinical target organ effects. Further studies are needed to explain the gender differences in adolescent hypertension. The potential role of sex hormones in hypertensive teenagers also needs to be clarified in future works.

Ultralow-Power Near Infrared Lamp Light Operable Targeted Organic Nanoparticle Photodynamic Therapy.

PubMed

Huang, Ling; Li, Zhanjun; Zhao, Yang; Zhang, Yuanwei; Wu, Shuang; Zhao, Jianzhang; Han, Gang

2016-11-09

Tissue penetration depth is a major challenge in practical photodynamic therapy (PDT). A biocompatible and highly effective near infrared (NIR)-light-absorbing carbazole-substituted BODIPY (Car-BDP) molecule is reported as a class of imaging-guidable deep-tissue activatable photosensitizers for PDT. Car-BDP possesses an intense, broad NIR absorption band (600-800 nm) with a remarkably high singlet oxygen quantum yield (Φ Δ = 67%). After being encapsulated with biodegradable PLA-PEG-FA polymers, Car-BDP can form uniform and small organic nanoparticles that are water-soluble and tumor-targetable. Rather than using laser light, such nanoparticles offer an unprecedented deep-tissue, tumor targeting photodynamic therapeutic effect by using an exceptionally low-power-density and cost-effective lamp light (12 mW cm -2 ). In addition, these nanoparticles can be simultaneously traced in vivo due to their excellent NIR fluorescence. This study signals a major step forward in photodynamic therapy by developing a new class of NIR-absorbing biocompatible organic nanoparticles for effective targeting and treatment of deep-tissue tumors. This work also provides a potential new platform for precise tumor-targeting theranostics and novel opportunities for future affordable clinical cancer treatment.

Expression of CD30 in patients with acute graft-versus-host disease.

PubMed

Chen, Yi-Bin; McDonough, Sean; Hasserjian, Robert; Chen, Heidi; Coughlin, Erin; Illiano, Christina; Park, In Sun; Jagasia, Madan; Spitzer, Thomas R; Cutler, Corey S; Soiffer, Robert J; Ritz, Jerome

2012-07-19

Acute GVHD (aGVHD) remains a major source of morbidity after allogeneic hematopoietic cell transplantation. CD30 is a cell-surface protein expressed on certain activated T cells. We analyzed CD30 expression on peripheral blood T-cell subsets and soluble CD30 levels in 26 patients at the time of presentation of aGVHD, before the initiation of treatment, compared with 27 patients after hematopoietic cell transplantation without aGVHD (NONE). Analysis by flow cytometry showed that patients with aGVHD had a greater percentage of CD30 expressing CD8(+) T cells with the difference especially pronounced in the central memory subset (CD8(+)CD45RO(+)CD62L(+)): GVHD median 12.4% (range, 0.8%-33.4%) versus NONE 2.1% (0.7%, 17.5%), P < .001. There were similar levels of CD30 expression in naive T cells, CD4(+) T cells, and regulatory (CD4(+)CD127(low)CD25(+)) T cells. Plasma levels of soluble CD30 were significantly greater in patients with GVHD: median 61.7 ng/mL (range, 9.8-357.1 ng/mL) versus 17.4 (range, 3.7-142.4 ng/mL) in NONE (P < .001). Immunohistochemical analysis of affected intestinal tissue showed many CD30(+) infiltrating lymphocytes present. These results suggest that CD30 expression on CD8(+) T-cell subsets or plasma levels of soluble CD30 may be a potential biomarker for aGVHD. CD30 may also represent a target for novel therapeutic approaches for aGVHD.

Expression of CD30 in patients with acute graft-versus-host disease

PubMed Central

McDonough, Sean; Hasserjian, Robert; Chen, Heidi; Coughlin, Erin; Illiano, Christina; Park, In Sun; Jagasia, Madan; Spitzer, Thomas R.; Cutler, Corey S.; Soiffer, Robert J.; Ritz, Jerome

2012-01-01

Acute GVHD (aGVHD) remains a major source of morbidity after allogeneic hematopoietic cell transplantation. CD30 is a cell-surface protein expressed on certain activated T cells. We analyzed CD30 expression on peripheral blood T-cell subsets and soluble CD30 levels in 26 patients at the time of presentation of aGVHD, before the initiation of treatment, compared with 27 patients after hematopoietic cell transplantation without aGVHD (NONE). Analysis by flow cytometry showed that patients with aGVHD had a greater percentage of CD30 expressing CD8+ T cells with the difference especially pronounced in the central memory subset (CD8+CD45RO+CD62L+): GVHD median 12.4% (range, 0.8%-33.4%) versus NONE 2.1% (0.7%, 17.5%), P < .001. There were similar levels of CD30 expression in naive T cells, CD4+ T cells, and regulatory (CD4+CD127lowCD25+) T cells. Plasma levels of soluble CD30 were significantly greater in patients with GVHD: median 61.7 ng/mL (range, 9.8-357.1 ng/mL) versus 17.4 (range, 3.7-142.4 ng/mL) in NONE (P < .001). Immunohistochemical analysis of affected intestinal tissue showed many CD30+ infiltrating lymphocytes present. These results suggest that CD30 expression on CD8+ T-cell subsets or plasma levels of soluble CD30 may be a potential biomarker for aGVHD. CD30 may also represent a target for novel therapeutic approaches for aGVHD. PMID:22661699

The apelin-APJ axis: A novel potential therapeutic target for organ fibrosis.

PubMed

Huang, Shifang; Chen, Linxi; Lu, Liqun; Li, Lanfang

2016-05-01

Apelin, an endogenous ligand of the G-protein-coupled receptor APJ, is expressed in a diverse number of organs. The apelin-APJ axis helps to control the processes of pathological and physiological fibrosis, including renal fibrosis, cardiac fibrosis, liver fibrosis and pulmonary fibrosis. However, the role of apelin-APJ in organ fibrosis remains controversial due to conflicting study results. The apelin-APJ axis is a detrimental mechanism which promotes liver fibrosis mainly via up-regulation the expression of collagen-II and platelet-derived growth factor receptor β (PDGFRβ). On the contrary, the apelin-APJ axis is beneficial for renal fibrosis, cardiac fibrosis and pulmonary fibrosis. The apelin-APJ axis alleviates renal fibrosis by restraining the expression of transforming growth factor-β1 (TGF-β1). In addition, the apelin-APJ axis attenuates cardiac fibrosis through multiple pathways. Furthermore, the apelin-APJ axis has beneficial effects on experimental bronchopulmonary dysplasia (BPD) and acute respiratory distress syndrome (ARDS) which suggest the apelin-APJ axis potentially alleviates pulmonary fibrosis. In this article, we review the controversies associated with apelin-APJ in organ fibrosis and introduce the drugs that target apelin-APJ. We conclude that future studies should place more emphasis on the relationship among apelin isoforms, APJ receptor subtypes and organ fibrosis. The apelin-APJ axis will be a potential therapeutic target and those drugs targeted for apelin-APJ may constitute a novel therapeutic strategy for renal fibrosis, cardiac fibrosis, liver fibrosis and pulmonary fibrosis. Copyright © 2016 Elsevier B.V. All rights reserved.

Expanded Target-Chemical Analysis Reveals Extensive Mixed-Organic-Contaminant Exposure in U.S. Streams

EPA Science Inventory

Surface-water from 38 streams nation-wide was assessed using 14 target-organic methods (719 compounds). Designedbioactive anthropogenic contaminants (biocides, pharmaceuticals) comprised 57% of 406 organics detected at least once. The 10 most-frequently detected anthropogenic-org...

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: V. The 2014 Ancillary Therapy and Supportive Care Working Group Report

PubMed Central

Carpenter, Paul A.; Kitko, Carrie L.; Elad, Sharon; Flowers, Mary E.D.; Gea-Banacloche, Juan C.; Halter, Jörg P.; Hoodin, Flora; Johnston, Laura; Lawitschka, Anita; McDonald, George B.; Opipari, Anthony W.; Savani, Bipin N.; Schultz, Kirk R.; Smith, Sean R.; Syrjala, Karen L.; Treister, Nathaniel; Vogelsang, Georgia B.; Williams, Kirsten M.; Pavletic, Steven Z.; Martin, Paul J.; Lee, Stephanie J.; Couriel, Daniel R.

2016-01-01

The 2006 National Institutes of Health (NIH) Consensus paper presented recommendations by the Ancillary Therapy and Supportive Care Working Group to support clinical research trials in chronic graft-versus-host disease (GVHD). Topics covered in that inaugural effort included the prevention and management of infections and common complications of chronic GVHD, as well as recommendations for patient education and appropriate follow-up. Given the new literature that has emerged during the past 8 years, we made further organ-specific refinements to these guidelines. Minimum frequencies are suggested for monitoring key parameters relevant to chronic GVHD during systemic immunosuppressive therapy and, thereafter, referral to existing late effects consensus guidelines is advised. Using the framework of the prior consensus, the 2014 NIH recommendations are organized by organ or other relevant systems and graded according to the strength and quality of supporting evidence. PMID:25838185

Haploidentical HCT using an αβ T-cell-depleted graft with targeted αβ(+) cells by add-back after a reduced intensity preparative regimen containing low-dose TBI.

PubMed

Im, H J; Koh, K N; Suh, J K; Lee, S W; Choi, E S; Jang, S; Kwon, S W; Park, C-J; Seo, J J

2016-09-01

Between 2012 and 2015, 42 pediatric patients underwent haploidentical hematopoietic cell transplantation using an αβ(+) T-cell-depleted graft with targeted αβ cells at 1-5 × 10(5)/kg by add-back; 31 had hematologic malignancy (HM), 8 had non-malignant disease (NM) and 3 had solid tumors. All patients received uniform reduced-intensity conditioning with fludarabine, cyclophosphamide, rabbit anti-thymocyte globulin and low-dose TBI. All 42 patients achieved neutrophil engraftment at a median of 10 days. The cumulative incidences (CIs) of ⩾grade II and ⩾grade III acute GvHD were 31±7.1% (SE) and 12±5.0%, respectively, and 1-year CI of chronic GvHD was 15±5.8%. One patient died of CMV pneumonia, leading to transplant-related mortality (TRM) of 2.6±2.5%. Sixteen patients relapsed and 11 died of disease. At a median follow-up of 19 months (range, 5-43 months), the estimated 2-year event-free survival for NM and HM were 88±11.7 and 50±10.1%, respectively. Our study demonstrated that haploidentical hematopoietic cell transplantation after ex vivo depletion of αβ(+) T cells with targeted dose noticeably reduced the graft failure rate and TRM in pediatric patients and could be applied to patients lacking a suitable related or unrelated donor.

The myeloid-binding peptide adenoviral vector enables multi-organ vascular endothelial gene targeting.

PubMed

Lu, Zhi Hong; Kaliberov, Sergey; Zhang, Jingzhu; Muz, Barbara; Azab, Abdel K; Sohn, Rebecca E; Kaliberova, Lyudmila; Du, Yingqiu; Curiel, David T; Arbeit, Jeffrey M

2014-08-01

Vascular endothelial cells (ECs) are ideal gene therapy targets as they provide widespread tissue access and are the first contact surfaces following intravenous vector administration. Human recombinant adenovirus serotype 5 (Ad5) is the most frequently used gene transfer system because of its appreciable transgene payload capacity and lack of somatic mutation risk. However, standard Ad5 vectors predominantly transduce liver but not the vasculature following intravenous administration. We recently developed an Ad5 vector with a myeloid cell-binding peptide (MBP) incorporated into the knob-deleted, T4 fibritin chimeric fiber (Ad.MBP). This vector was shown to transduce pulmonary ECs presumably via a vector handoff mechanism. Here we tested the body-wide tropism of the Ad.MBP vector, its myeloid cell necessity, and vector-EC expression dose response. Using comprehensive multi-organ co-immunofluorescence analysis, we discovered that Ad.MBP produced widespread EC transduction in the lung, heart, kidney, skeletal muscle, pancreas, small bowel, and brain. Surprisingly, Ad.MBP retained hepatocyte tropism albeit at a reduced frequency compared with the standard Ad5. While binding specifically to myeloid cells ex vivo, multi-organ Ad.MBP expression was not dependent on circulating monocytes or macrophages. Ad.MBP dose de-escalation maintained full lung-targeting capacity but drastically reduced transgene expression in other organs. Swapping the EC-specific ROBO4 for the CMV promoter/enhancer abrogated hepatocyte expression but also reduced gene expression in other organs. Collectively, our multilevel targeting strategy could enable therapeutic biological production in previously inaccessible organs that pertain to the most debilitating or lethal human diseases.

Morphological self-organizing feature map neural network with applications to automatic target recognition

NASA Astrophysics Data System (ADS)

Zhang, Shijun; Jing, Zhongliang; Li, Jianxun

2005-01-01

The rotation invariant feature of the target is obtained using the multi-direction feature extraction property of the steerable filter. Combining the morphological operation top-hat transform with the self-organizing feature map neural network, the adaptive topological region is selected. Using the erosion operation, the topological region shrinkage is achieved. The steerable filter based morphological self-organizing feature map neural network is applied to automatic target recognition of binary standard patterns and real-world infrared sequence images. Compared with Hamming network and morphological shared-weight networks respectively, the higher recognition correct rate, robust adaptability, quick training, and better generalization of the proposed method are achieved.

Subcellular Targeting of Methylmercury Lyase Enhances Its Specific Activity for Organic Mercury Detoxification in Plants1

PubMed Central

Bizily, Scott P.; Kim, Tehryung; Kandasamy, Muthugapatti K.; Meagher, Richard B.

2003-01-01

Methylmercury is an environmental pollutant that biomagnifies in the aquatic food chain with severe consequences for humans and other animals. In an effort to remove this toxin in situ, we have been engineering plants that express the bacterial mercury resistance enzymes organomercurial lyase MerB and mercuric ion reductase MerA. In vivo kinetics experiments suggest that the diffusion of hydrophobic organic mercury to MerB limits the rate of the coupled reaction with MerA (Bizily et al., 2000). To optimize reaction kinetics for organic mercury compounds, the merB gene was engineered to target MerB for accumulation in the endoplasmic reticulum and for secretion to the cell wall. Plants expressing the targeted MerB proteins and cytoplasmic MerA are highly resistant to organic mercury and degrade organic mercury at 10 to 70 times higher specific activity than plants with the cytoplasmically distributed wild-type MerB enzyme. MerB protein in endoplasmic reticulum-targeted plants appears to accumulate in large vesicular structures that can be visualized in immunolabeled plant cells. These results suggest that the toxic effects of organic mercury are focused in microenvironments of the secretory pathway, that these hydrophobic compartments provide more favorable reaction conditions for MerB activity, and that moderate increases in targeted MerB expression will lead to significant gains in detoxification. In summary, to maximize phytoremediation efficiency of hydrophobic pollutants in plants, it may be beneficial to target enzymes to specific subcellular environments. PMID:12586871

Induction of a glucocorticoid-sensitive F1-anti-parental mechanism that affects engraftment during graft-versus-host disease.

PubMed

You-Ten, K E; Seemayer, T A; Wisse, B; Bertley, F M; Lapp, W S

1995-07-01

Studies have shown that graft-vs-host disease (GVHD) in animal models induces persistent elevated levels of circulating adrenal glucocorticoids. In this report, we investigated the effects of endogenous glucocorticoids on the outcome of GVHD by adrenalectomizing (ADX) unirradiated (C57BL/6 x A)F1 (B6AF1) mice before GVHD induction. GVHD was induced by injection of 20 x 10(6) A strain parental lymphoid cells into B6AF1 mice. Our results demonstrated that non-ADX recipient mice experienced features characteristic of GVHD on day 13, which became progressively more severe by days 18 to 21. The GVHD features included severe immunosuppression, reversal in the host splenic CD4+/CD8+ ratio, histopathologic lesions in different tissues, and high parental cell chimerism in the spleens and lymph nodes. In contrast, ADX F1 recipient mice experienced GVHD features on day 13 similar to their non-ADX counterparts; however, ADX animals recovered rapidly from GVHD by days 18 to 21. Flow cytometry showed that, although a relatively high frequency of parental cells was detected in the spleens and lymph nodes of ADX mice on day 13, nearly all of the parental cells in the peripheral lymphoid organs disappeared on days 18 to 21, the time of recovery from GVHD. The marked reduction of parental cells and recovery from GVHD were prevented by treating ADX F1 mice with either exogenous glucocorticoid, anti-asialoGM1, or anti-CD8, but not anti-NK1.1 Ab. These results suggest that a dramatic recovery from GVHD was induced by a cell-mediated, steroid-sensitive F1-anti-parental mechanism. The F1-anti-parental phenomenon described herein is different from classical hybrid resistance.

Intestinal Helminths Regulate Lethal Acute Graft Versus Host Disease and Preserve Graft Versus Tumor Effect in Mice

PubMed Central

Li, Yue; Chen, Hung-lin; Bannick, Nadine; Henry, Michael; Holm, Adrian N.; Metwali, Ahmed; Urban, Joseph F.; Rothman, Paul B.; Weiner, George J.; Blazar, Bruce R.; Elliott, David E.; Ince, M. Nedim

2014-01-01

Donor T lymphocyte transfer with hematopoietic stem cells suppresses residual tumor growth (graft-versus-tumor; GVT) in cancer patients undergoing bone marrow transplantation (BMT). However, donor T cell reactivity to host organs causes severe and potentially lethal inflammation, called graft-versus-host disease (GVHD). High dose steroids or other immune suppressives are used to treat GVHD that have limited ability to control the inflammation while incurring long-term toxicity. Novel strategies are needed to modulate GVHD, preserve GVT and improve the outcome of BMT. Regulatory T cells (Tregs) control alloantigen-sensitized inflammation of GVHD, sustain GVT and prevent mortality in bone marrow transplantation. Helminths colonizing the alimentary tract dramatically increase the Treg activity, thereby modulating intestinal or systemic inflammatory responses. These observations led us to hypothesize that helminths can regulate GVHD and maintain GVT in mice. Acute GVHD was induced in helminth (Heligmosomoides polygyrus)-infected or uninfected Balb/C recipients of C57BL/6 donor grafts. Helminth infection suppressed donor T cell inflammatory cytokine generation along with reduction in GVHD lethality and maintenance of GVT. H. polygyrus colonization promoted the survival of TGFβ generating recipient Tregs after a conditioning regimen with total body irradiation and led to a TGFβ-dependent in vivo expansion/maturation of donor Tregs after BMT. Helminths did not control GVHD, when T cells unresponsive to TGFβ-mediated immune regulation were used as donor T lymphocytes. These results suggest that helminths suppress acute GVHD, employing regulatory T cells and TGFβ-dependent pathways in mice. Helminthic regulation of GVHD and GVT through intestinal immune conditioning may improve the outcome of BMT. PMID:25527786

Intestinal helminths regulate lethal acute graft-versus-host disease and preserve the graft-versus-tumor effect in mice.

PubMed

Li, Yue; Chen, Hung-Lin; Bannick, Nadine; Henry, Michael; Holm, Adrian N; Metwali, Ahmed; Urban, Joseph F; Rothman, Paul B; Weiner, George J; Blazar, Bruce R; Elliott, David E; Ince, M Nedim

2015-02-01

Donor T lymphocyte transfer with hematopoietic stem cells suppresses residual tumor growth (graft-versus-tumor [GVT]) in cancer patients undergoing bone marrow transplantation (BMT). However, donor T cell reactivity to host organs causes severe and potentially lethal inflammation called graft-versus-host disease (GVHD). High-dose steroids or other immunosuppressive drugs are used to treat GVHD that have limited ability to control the inflammation while incurring long-term toxicity. Novel strategies are needed to modulate GVHD, preserve GVT, and improve the outcome of BMT. Regulatory T cells (Tregs) control alloantigen-sensitized inflammation of GVHD, sustain GVT, and prevent mortality in BMT. Helminths colonizing the alimentary tract dramatically increase the Treg activity, thereby modulating intestinal or systemic inflammatory responses. These observations led us to hypothesize that helminths can regulate GVHD and maintain GVT in mice. Acute GVHD was induced in helminth (Heligmosomoides polygyrus)-infected or uninfected BALB/c recipients of C57BL/6 donor grafts. Helminth infection suppressed donor T cell inflammatory cytokine generation and reduced GVHD-related mortality, but maintained GVT. H. polygyrus colonization promoted the survival of TGF-β-generating recipient Tregs after a conditioning regimen with total body irradiation and led to a TGF-β-dependent in vivo expansion/maturation of donor Tregs after BMT. Helminths did not control GVHD when T cells unresponsive to TGF-β-mediated immune regulation were used as donor T lymphocytes. These results suggest that helminths suppress acute GVHD using Tregs and TGF-β-dependent pathways in mice. Helminthic regulation of GVHD and GVT through intestinal immune conditioning may improve the outcome of BMT. Copyright © 2015 by The American Association of Immunologists, Inc.

Targeted organ generation using Mixl1-inducible mouse pluripotent stem cells in blastocyst complementation.

PubMed

Kobayashi, Toshihiro; Kato-Itoh, Megumi; Nakauchi, Hiromitsu

2015-01-15

Generation of functional organs from patients' own cells is one of the ultimate goals of regenerative medicine. As a novel approach to creation of organs from pluripotent stem cells (PSCs), we employed blastocyst complementation in organogenesis-disabled animals and successfully generated PSC-derived pancreas and kidneys. Blastocyst complementation, which exploits the capacity of PSCs to participate in forming chimeras, does not, however, exclude contribution of PSCs to the development of tissues-including neural cells or germ cells-other than those specifically targeted by disabling of organogenesis. This fact provokes ethical controversy if human PSCs are to be used. In this study, we demonstrated that forced expression of Mix-like protein 1 (encoded by Mixl1) can be used to guide contribution of mouse embryonic stem cells to endodermal organs after blastocyst injection. We then succeeded in applying this method to generate functional pancreas in pancreatogenesis-disabled Pdx1 knockout mice using a newly developed tetraploid-based organ-complementation method. These findings hold promise for targeted organ generation from patients' own PSCs in livestock animals.

Interarm blood pressure difference and target organ damage in the general population.

PubMed

Johansson, Jouni K; Puukka, Pauli J; Jula, Antti M

2014-02-01

The objective of the study was to investigate interarm differences of blood pressure (BP) and its determinants, and to clarify whether both arms are equally good in assessing BP and target organ damage in the general population. We studied a representative sample of Finnish adult population with 484 study participants, ages 25-74 years. BP was measured twice by an oscillometric monitor simultaneously on both arms. Study participants underwent a clinical examination including measurements of serum lipids, glucose and indicators of target organ damage. BP was 2.3/0.2 mmHg higher on right than on left arm (P < 0.001/P = 0.15 for SBP/DBP differences). SBP and DBP measured on right and left arms correlated equally with left ventricular mass index (LVMI), interventricular septal thickness (IVST), posterior wall thickness (PWT), pulse wave velocity (PWV) and albuminuria. Higher SBP level was an independent determinant of both greater systolic and diastolic interarm BP difference. Exaggerated absolute diastolic interarm BP difference (>5 mmHg) was associated with higher BMI, arm circumference, LVMI, IVST and PWT, whereas exaggerated absolute systolic interarm BP difference (>10 mmHg) was not associated with any clinical variables. There was only a small difference in BP between arms in a healthy general population. Both arms are equally good determinants of target organ damage. BP should be measured at least once on both arms and prefer the arm with higher BP readings in the future BP measurements.

Outcome of critically ill allogeneic hematopoietic stem-cell transplantation recipients: a reappraisal of indications for organ failure supports.

PubMed

Pène, Frédéric; Aubron, Cécile; Azoulay, Elie; Blot, François; Thiéry, Guillaume; Raynard, Bruno; Schlemmer, Benoît; Nitenberg, Gérard; Buzyn, Agnès; Arnaud, Philippe; Socié, Gérard; Mira, Jean-Paul

2006-02-01

Because the overall outcome of critically ill hematologic patients has improved, we evaluated the short-term and long-term outcomes of the poor risk subgroup of allogeneic hematopoietic stem-cell transplantation (HSCT) recipients requiring admission to the intensive care unit (ICU). This was a retrospective multicenter study of allogeneic HSCT recipients admitted to the ICU between 1997 and 2003. Two hundred nine critically ill allogeneic HSCT recipients were included in the study. Admission in the ICU occurred during the engraftment period (< or = 30 days after transplantation) for 70 of the patients and after the engraftment period for 139 patients. The overall in-ICU, in-hospital, 6-month, and 1-year survival rates were 48.3%, 32.5%, 27.2%, and 21%, respectively. Mechanical ventilation was required in 122 patients and led to a dramatic decrease in survival rates, resulting in in-ICU, in-hospital, 6-month, and 1-year survival rates of 18%, 15.6%, 14%, and 10.6%, respectively. Mechanical ventilation, elevated bilirubin level, and corticosteroid treatment for the indication of active graft-versus-host disease (GVHD) were independent predictors of death in the whole cohort. In the subgroup of patients requiring mechanical ventilation, associated organ failures, such as shock and liver dysfunction, were independent predictors of death. ICU admission during engraftment period was associated with acceptable outcome in mechanically ventilated patients, whereas patients with late complications of HSCT in the setting of active GVHD had a poor outcome. Extensive unlimited intensive care support is justified for allogeneic HSCT recipients with complications occurring during the engraftment period. Conversely, initiation or maintenance of mechanical ventilation is questionable in the setting of active GVHD.

Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation.

PubMed

Kochenderfer, James N; Dudley, Mark E; Carpenter, Robert O; Kassim, Sadik H; Rose, Jeremy J; Telford, William G; Hakim, Frances T; Halverson, David C; Fowler, Daniel H; Hardy, Nancy M; Mato, Anthony R; Hickstein, Dennis D; Gea-Banacloche, Juan C; Pavletic, Steven Z; Sportes, Claude; Maric, Irina; Feldman, Steven A; Hansen, Brenna G; Wilder, Jennifer S; Blacklock-Schuver, Bazetta; Jena, Bipulendu; Bishop, Michael R; Gress, Ronald E; Rosenberg, Steven A

2013-12-12

New treatments are needed for B-cell malignancies persisting after allogeneic hematopoietic stem cell transplantation (alloHSCT). We conducted a clinical trial of allogeneic T cells genetically modified to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. T cells for genetic modification were obtained from each patient's alloHSCT donor. All patients had malignancy that persisted after alloHSCT and standard donor lymphocyte infusions (DLIs). Patients did not receive chemotherapy prior to the CAR T-cell infusions and were not lymphocyte depleted at the time of the infusions. The 10 treated patients received a single infusion of allogeneic anti-CD19-CAR T cells. Three patients had regressions of their malignancies. One patient with chronic lymphocytic leukemia (CLL) obtained an ongoing complete remission after treatment with allogeneic anti-CD19-CAR T cells, another CLL patient had tumor lysis syndrome as his leukemia dramatically regressed, and a patient with mantle cell lymphoma obtained an ongoing partial remission. None of the 10 patients developed graft-versus-host disease (GVHD). Toxicities included transient hypotension and fever. We detected cells containing the anti-CD19-CAR gene in the blood of 8 of 10 patients. These results show for the first time that donor-derived allogeneic anti-CD19-CAR T cells can cause regression of B-cell malignancies resistant to standard DLIs without causing GVHD.

Spatial Cytoskeleton Organization Supports Targeted Intracellular Transport

NASA Astrophysics Data System (ADS)

Hafner, Anne E.; Rieger, Heiko

2018-03-01

The efficiency of intracellular cargo transport from specific source to target locations is strongly dependent upon molecular motor-assisted motion along the cytoskeleton. Radial transport along microtubules and lateral transport along the filaments of the actin cortex underneath the cell membrane are characteristic for cells with a centrosome. The interplay between the specific cytoskeleton organization and the motor performance realizes a spatially inhomogeneous intermittent search strategy. In order to analyze the efficiency of such intracellular search strategies we formulate a random velocity model with intermittent arrest states. We evaluate efficiency in terms of mean first passage times for three different, frequently encountered intracellular transport tasks: i) the narrow escape problem, which emerges during cargo transport to a synapse or other specific region of the cell membrane, ii) the reaction problem, which considers the binding time of two particles within the cell, and iii) the reaction-escape problem, which arises when cargo must be released at a synapse only after pairing with another particle. Our results indicate that cells are able to realize efficient search strategies for various intracellular transport tasks economically through a spatial cytoskeleton organization that involves only a narrow actin cortex rather than a cell body filled with randomly oriented actin filaments.

Do insect repellents induce drift behaviour in aquatic non-target organisms?

PubMed

Fink, Patrick; Moelzner, Jana; Berghahn, Ruediger; von Elert, Eric

2017-01-01

Synthetic insect repellents are compounds applied to surfaces to discourage insects, mainly mosquitoes, from landing on those surfaces. As some of these repellents have repeatedly been detected in surface waters at significant concentrations, they may also exert repellent effects on aquatic non-target organisms. In running water systems, aquatic invertebrates actively enter downstream drift in order to avoid unfavourable environmental conditions. We thus tested the hypothesis that the widely used insect repellents DEET (N,N-Diethyl-m-toluamide), EBAAP (3-[N-butyl-N-acetyl]-aminopropionic acid ethyl ester) and Icaridin (1-piperidinecarboxylic acid 2-(2-hydroxyethyl)-1-methylpropyl ester) induce downstream drift behaviour in the aquatic invertebrates Gammarus pulex (Crustacea, Amphipoda) and Cloeon dipterum (Insecta, Ephemeroptera), using a laboratory-scale drift assay. We found no clear increase in the drift behaviour of both invertebrate species across a concentration gradient of eight orders of magnitude and even beyond maximum environmental concentrations for any of the three repellents. We found no evidence for a direct drift-inducing activity of insect repellents on aquatic non-target organisms. Copyright © 2016 Elsevier Ltd. All rights reserved.

Acute Toxicity of the Antifouling Compound Butenolide in Non-Target Organisms

PubMed Central

Chandramouli, Kondethimmanahalli H.; Xu, Ying; Pan, Ke; Wang, Wen-Xiong; Qian, Pei-Yuan

2011-01-01

Butenolide [5-octylfuran-2(5H)-one] is a recently discovered and very promising anti-marine-fouling compound. In this study, the acute toxicity of butenolide was assessed in several non-target organisms, including micro algae, crustaceans, and fish. Results were compared with previously reported results on the effective concentrations used on fouling (target) organisms. According to OECD's guideline, the predicted no effect concentration (PNEC) was 0.168 µg l−1, which was among one of the highest in representative new biocides. Mechanistically, the phenotype of butenolide-treated Danio rerio (zebrafish) embryos was similar to the phenotype of the pro-caspase-3 over-expression mutant with pericardial edema, small eyes, small brains, and increased numbers of apoptotic cells in the bodies of zebrafish embryos. Butenolide also induced apoptosis in HeLa cells, with the activation of c-Jun N-terminal kinases (JNK), Bcl-2 family proteins, and caspases and proteasomes/lysosomes involved in this process. This is the first detailed toxicity and toxicology study on this antifouling compound. PMID:21897857

Clinical significance of autoantibodies in a large cohort of patients with chronic graft-versus-host disease defined by NIH criteria.

PubMed

Kuzmina, Zoya; Gounden, Verena; Curtis, Lauren; Avila, Daniele; Rnp, Tiffani Taylor; Baruffaldi, Judy; Cowen, Edward W; Naik, Haley B; Hasni, Sarfaraz A; Mays, Jacqueline W; Mitchell, Sandra; Baird, Kristin; Steinberg, Seth M; Pavletic, Steven Z

2015-02-01

There is an unmet need for identifying new clinical biomarkers in chronic Graft-versus-Host-disease (cGVHD) suitable for diagnosis and disease monitoring. Circulating autoantibodies represent an ongoing immune response and suggest a pathogenic role for B cells in cGVHD. Autoantibodies could be useful markers of cGVHD disease activity, severity, or organ specificity; however, their clinical utility is not established. The focus of this study was to determine the incidence and associations of a broad array of clinical autoantibodies with cGVHD manifestations in a large patient cohort characterized by NIH criteria. A panel of 21 circulating antibodies commonly used in clinical medicine was tested in 280 cGVHD patients (70% severe) enrolled in a cross-sectional prospective natural history study. Median cGVHD duration was two years. Patients with circulating autoantibodies (62%) had significantly higher levels of IgM (P < 0.0001), IgG (P < 0.0001), and IgA (P = 0.001), elevated uric acid (P = 0.008) and total protein (P = 0.0004), and higher numbers of CD3+ (P = 0.002), CD4+ (P = 0.001), CD8+ (P = 0.023) T cells, and CD19+ B cells (P < 0.0001). Multiple antibodies were detected in 35% of patients. Prior rituximab therapy (n = 66) was associated with reduced presence of autoantibodies (48 vs. 66% P = 0.01). Only oral cGVHD was significantly associated with presence of autoantibodies in this study (P = 0.028). No significant associations were found between cGVHD activity and severity, and presence of autoantibodies. Circulating autoantibodies are common in patients with advanced cGVHD. Their presence is associated with better quantitative immunologic reconstitution but does not have utility as a clinical biomarker of cGVHD. © 2014 Wiley Periodicals, Inc.

Clinical significance of autoantibodies in a large cohort of patients with chronic graft-versus-host disease defined by NIH criteria

PubMed Central

Kuzmina, Zoya; Gounden, Verena; Curtis, Lauren; Avila, Daniele; Taylor, Tiffani; Baruffaldi, Judy; Cowen, Edward W.; Naik, Haley B.; Hasni, Sarfaraz A.; Mays, Jacqueline W.; Mitchell, Sandra; Baird, Kristin; Steinberg, Seth M.; Pavletic, Steven Z.

2017-01-01

There is an unmet need for identifying new clinical biomarkers in chronic Graft-versus-Host-disease (cGVHD) suitable for diagnosis and disease monitoring. Circulating autoantibodies represent an ongoing immune response and suggest a pathogenic role for B cells in cGVHD. Autoantibodies could be useful markers of cGVHD disease activity, severity, or organ specificity; however, their clinical utility is not established. The focus of this study was to determine the incidence and associations of a broad array of clinical autoantibodies with cGVHD manifestations in a large patient cohort characterized by NIH criteria. A panel of 21 circulating antibodies commonly used in clinical medicine was tested in 280 cGVHD patients (70% severe) enrolled in a cross-sectional prospective natural history study. Median cGVHD duration was two years. Patients with circulating autoantibodies (62%) had significantly higher levels of IgM (P < 0.0001), IgG (P < 0.0001), and IgA (P = 0.001), elevated uric acid (P = 0.008) and total protein (P = 0.0004), and higher numbers of CD31 (P = 0.002), CD41 (P = 0.001), CD81 (P = 0.023) T cells, and CD191 B cells (P < 0.0001). Multiple antibodies were detected in 35% of patients. Prior rituximab therapy (n = 66) was associated with reduced presence of autoantibodies (48 vs. 66% P = 0.01). Only oral cGVHD was significantly associated with presence of autoantibodies in this study (P = 0.028). No significant associations were found between cGVHD activity and severity, and presence of autoantibodies. Circulating autoantibodies are common in patients with advanced cGVHD. Their presence is associated with better quantitative immunologic reconstitution but does not have utility as a clinical biomarker of cGVHD. PMID:25363867

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: V. The 2014 Ancillary Therapy and Supportive Care Working Group Report.

PubMed

Carpenter, Paul A; Kitko, Carrie L; Elad, Sharon; Flowers, Mary E D; Gea-Banacloche, Juan C; Halter, Jörg P; Hoodin, Flora; Johnston, Laura; Lawitschka, Anita; McDonald, George B; Opipari, Anthony W; Savani, Bipin N; Schultz, Kirk R; Smith, Sean R; Syrjala, Karen L; Treister, Nathaniel; Vogelsang, Georgia B; Williams, Kirsten M; Pavletic, Steven Z; Martin, Paul J; Lee, Stephanie J; Couriel, Daniel R

2015-07-01

The 2006 National Institutes of Health (NIH) Consensus paper presented recommendations by the Ancillary Therapy and Supportive Care Working Group to support clinical research trials in chronic graft-versus-host disease (GVHD). Topics covered in that inaugural effort included the prevention and management of infections and common complications of chronic GVHD, as well as recommendations for patient education and appropriate follow-up. Given the new literature that has emerged during the past 8 years, we made further organ-specific refinements to these guidelines. Minimum frequencies are suggested for monitoring key parameters relevant to chronic GVHD during systemic immunosuppressive therapy and, thereafter, referral to existing late effects consensus guidelines is advised. Using the framework of the prior consensus, the 2014 NIH recommendations are organized by organ or other relevant systems and graded according to the strength and quality of supporting evidence. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Surface target-tracking guidance by self-organizing formation flight of fixed-wing UAV

NASA Astrophysics Data System (ADS)

Regina, N.; Zanzi, M.

This paper presents a new concept of ground target surveillance based on a formation flight of two Unmanned Aerial Vehicles (UAVs) of fixed-wing type. Each UAV considered in this work has its own guidance law specifically designed for two different aims. A self organizing non-symmetric collaborative surveying scheme has been developed based on pursuers with different roles: the close-up-pursuer and the distance-pursuer. The close-up-pursuer behaves according to a guidance law which takes it to continually over-fly the target, also optimizing flight endurance. On the other hand, the distancepursuer behaves so as to circle around the target by flying at a certain distance and altitude from it; moreover, its motion ensures the maximum “ seeability” of the ground based target. In addition, the guidance law designed for the distance-pursuer also implements a collision avoidance feature in order to prevent possible risks of collision with the close-up-pursuer during the tracking maneuvers. The surveying scheme is non-symmetric in the sense that the collision avoidance feature is accomplished by a guidance law implemented only on one of the two pursuers; moreover, it is collaborative because the surveying is performed by different tasks of two UAVs and is self-organizing because, due to the collision avoidance feature, target tracking does not require pre-planned collision-risk-free trajectories but trajectories are generated in real time.

Transcription Factors Expressed in Lateral Organ Boundaries: Identification of Downstream Targets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Springer, Patricia S

2010-07-12

The processes of lateral organ initiation and patterning are central to the generation of mature plant form. Characterization of the molecular mechanisms underlying these processes is essential to our understanding of plant development. Communication between the shoot apical meristem and initiating organ primordia is important both for functioning of the meristem and for proper organ patterning, and very little is known about this process. In particular, the boundary between meristem and leaf is emerging as a critical region that is important for SAM maintenance and regulation of organogenesis. The goal of this project was to characterize three boundary-expressed genes thatmore » encode predicted transcription factors. Specifically, we have studied LATERAL ORGAN BOUNDARIES (LOB), LATERAL ORGAN FUSION1 (LOF1), and LATERAL ORGAN FUSION2 (LOF2). LOB encodes the founding member of the LOB-DOMAIN (LBD) plant-specific DNA binding transcription factor family and LOF1 and LOF2 encode paralogous MYB-domain transcription factors. We characterized the genetic relationship between these three genes and other boundary and meristem genes. We also used an ectopic inducible expression system to identify direct targets of LOB.« less

Differences in DNA Binding Specificity of Floral Homeotic Protein Complexes Predict Organ-Specific Target Genes.

PubMed

Smaczniak, Cezary; Muiño, Jose M; Chen, Dijun; Angenent, Gerco C; Kaufmann, Kerstin

2017-08-01

Floral organ identities in plants are specified by the combinatorial action of homeotic master regulatory transcription factors. However, how these factors achieve their regulatory specificities is still largely unclear. Genome-wide in vivo DNA binding data show that homeotic MADS domain proteins recognize partly distinct genomic regions, suggesting that DNA binding specificity contributes to functional differences of homeotic protein complexes. We used in vitro systematic evolution of ligands by exponential enrichment followed by high-throughput DNA sequencing (SELEX-seq) on several floral MADS domain protein homo- and heterodimers to measure their DNA binding specificities. We show that specification of reproductive organs is associated with distinct binding preferences of a complex formed by SEPALLATA3 and AGAMOUS. Binding specificity is further modulated by different binding site spacing preferences. Combination of SELEX-seq and genome-wide DNA binding data allows differentiation between targets in specification of reproductive versus perianth organs in the flower. We validate the importance of DNA binding specificity for organ-specific gene regulation by modulating promoter activity through targeted mutagenesis. Our study shows that intrafamily protein interactions affect DNA binding specificity of floral MADS domain proteins. Differential DNA binding of MADS domain protein complexes plays a role in the specificity of target gene regulation. © 2017 American Society of Plant Biologists. All rights reserved.

Xenogeneic graft-versus-host-disease in NOD-scid IL-2Rγnull mice display a T-effector memory phenotype.

PubMed

Ali, Niwa; Flutter, Barry; Sanchez Rodriguez, Robert; Sharif-Paghaleh, Ehsan; Barber, Linda D; Lombardi, Giovanna; Nestle, Frank O

2012-01-01

The occurrence of Graft-versus-Host Disease (GvHD) is a prevalent and potentially lethal complication that develops following hematopoietic stem cell transplantation. Humanized mouse models of xenogeneic-GvHD based upon immunodeficient strains injected with human peripheral blood mononuclear cells (PBMC; "Hu-PBMC mice") are important tools to study human immune function in vivo. The recent introduction of targeted deletions at the interleukin-2 common gamma chain (IL-2Rγ(null)), notably the NOD-scid IL-2Rγ(null) (NSG) and BALB/c-Rag2(null) IL-2Rγ(null) (BRG) mice, has led to improved human cell engraftment. Despite their widespread use, a comprehensive characterisation of engraftment and GvHD development in the Hu-PBMC NSG and BRG models has never been performed in parallel. We compared engrafted human lymphocyte populations in the peripheral blood, spleens, lymph nodes and bone marrow of these mice. Kinetics of engraftment differed between the two strains, in particular a significantly faster expansion of the human CD45(+) compartment and higher engraftment levels of CD3(+) T-cells were observed in NSG mice, which may explain the faster rate of GvHD development in this model. The pathogenesis of human GvHD involves anti-host effector cell reactivity and cutaneous tissue infiltration. Despite this, the presence of T-cell subsets and tissue homing markers has only recently been characterised in the peripheral blood of patients and has never been properly defined in Hu-PBMC models of GvHD. Engrafted human cells in NSG mice shows a prevalence of tissue homing cells with a T-effector memory (T(EM)) phenotype and high levels of cutaneous lymphocyte antigen (CLA) expression. Characterization of Hu-PBMC mice provides a strong preclinical platform for the application of novel immunotherapies targeting T(EM)-cell driven GvHD.

Xenogeneic Graft-versus-Host-Disease in NOD-scid IL-2Rγnull Mice Display a T-Effector Memory Phenotype

PubMed Central

Ali, Niwa; Flutter, Barry; Sanchez Rodriguez, Robert; Sharif-Paghaleh, Ehsan; Barber, Linda D.; Lombardi, Giovanna; Nestle, Frank O.

2012-01-01

The occurrence of Graft-versus-Host Disease (GvHD) is a prevalent and potentially lethal complication that develops following hematopoietic stem cell transplantation. Humanized mouse models of xenogeneic-GvHD based upon immunodeficient strains injected with human peripheral blood mononuclear cells (PBMC; “Hu-PBMC mice”) are important tools to study human immune function in vivo. The recent introduction of targeted deletions at the interleukin-2 common gamma chain (IL-2Rγnull), notably the NOD-scid IL-2Rγnull (NSG) and BALB/c-Rag2 null IL-2Rγnull (BRG) mice, has led to improved human cell engraftment. Despite their widespread use, a comprehensive characterisation of engraftment and GvHD development in the Hu-PBMC NSG and BRG models has never been performed in parallel. We compared engrafted human lymphocyte populations in the peripheral blood, spleens, lymph nodes and bone marrow of these mice. Kinetics of engraftment differed between the two strains, in particular a significantly faster expansion of the human CD45+ compartment and higher engraftment levels of CD3+ T-cells were observed in NSG mice, which may explain the faster rate of GvHD development in this model. The pathogenesis of human GvHD involves anti-host effector cell reactivity and cutaneous tissue infiltration. Despite this, the presence of T-cell subsets and tissue homing markers has only recently been characterised in the peripheral blood of patients and has never been properly defined in Hu-PBMC models of GvHD. Engrafted human cells in NSG mice shows a prevalence of tissue homing cells with a T-effector memory (TEM) phenotype and high levels of cutaneous lymphocyte antigen (CLA) expression. Characterization of Hu-PBMC mice provides a strong preclinical platform for the application of novel immunotherapies targeting TEM-cell driven GvHD. PMID:22937164

Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity.

PubMed

Ghosh, Arnab; Smith, Melody; James, Scott E; Davila, Marco L; Velardi, Enrico; Argyropoulos, Kimon V; Gunset, Gertrude; Perna, Fabiana; Kreines, Fabiana M; Levy, Emily R; Lieberman, Sophie; Jay, Hillary V; Tuckett, Andrea Z; Zakrzewski, Johannes L; Tan, Lisa; Young, Lauren F; Takvorian, Kate; Dudakov, Jarrod A; Jenq, Robert R; Hanash, Alan M; Motta, Ana Carolina F; Murphy, George F; Liu, Chen; Schietinger, Andrea; Sadelain, Michel; van den Brink, Marcel R M

2017-02-01

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. However, graft-versus-host disease (GVHD) and relapse after allo-HSCT remain major impediments to the success of allo-HSCT. Chimeric antigen receptors (CARs) direct tumor cell recognition of adoptively transferred T cells. CD19 is an attractive CAR target, which is expressed in most B cell malignancies, as well as in healthy B cells. Clinical trials using autologous CD19-targeted T cells have shown remarkable promise in various B cell malignancies. However, the use of allogeneic CAR T cells poses a concern in that it may increase risk of the occurrence of GVHD, although this has not been reported in selected patients infused with donor-derived CD19 CAR T cells after allo-HSCT. To understand the mechanism whereby allogeneic CD19 CAR T cells may mediate anti-lymphoma activity without causing a significant increase in the incidence of GVHD, we studied donor-derived CD19 CAR T cells in allo-HSCT and lymphoma models in mice. We demonstrate that alloreactive T cells expressing CD28-costimulated CD19 CARs experience enhanced stimulation, resulting in the progressive loss of both their effector function and proliferative potential, clonal deletion, and significantly decreased occurrence of GVHD. Concurrently, the other CAR T cells that were present in bulk donor T cell populations retained their anti-lymphoma activity in accordance with the requirement that both the T cell receptor (TCR) and CAR be engaged to accelerate T cell exhaustion. In contrast, first-generation and 4-1BB-costimulated CAR T cells increased the occurrence of GVHD. These findings could explain the reduced risk of GVHD occurring with cumulative TCR and CAR signaling.

Graft-versus-Host Disease-Associated Vulvovaginal Symptoms after Bone Marrow Transplantation.

PubMed

Chung, Christopher P; Sargent, Rachel E; Chung, Nadia T; Lacey, James V; Wakabayashi, Mark T

2016-02-01

We conducted a retrospective review to assess the prevalence of graft-versus-host disease (GVHD)-associated gynecologic conditions among bone marrow transplantation (BMT) patients at City of Hope Medical Center. We calculated the associations among the estimated risks of various gynecologic complications, including vaginal stenosis, by performing chi-square tests and t-test statistics. Between 2010 and 2014, 180 patients were referred to the gynecologic clinic after their BMT. One hundred twenty-four patients (69%) had GVHD; among these patients, 51 (41%) experienced dyspareunia and 43 (35%) had vaginal stenosis. GVHD patients were significantly more likely to have vaginal stenosis (P < .0001), more likely to have used a vaginal dilator (P = .0008), and less likely to have urinary incontinence (UI) than those without GVHD (P < .001). There was no difference in developing pelvic organ prolapse (POP) in patients with or without GVHD (P = .4373). GVHD was a common complication after allogenic BMT. Patients with BMT were more likely to have vulvovaginal symptoms, such as dyspareunia and pelvic pain. Patients with GVHD are at high risk for vaginal stenosis requiring the use of a vaginal dilator. However, they are at low risk for developing UI and POP. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Osteopontin attenuates acute gastrointestinal graft-versus-host disease by preventing apoptosis of intestinal epithelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kawakami, Kentaro; Minami, Naoki; Matsuura, Minoru

Background and aims: Acute graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation, which often targets gastrointestinal (GI) tract. Osteopontin (OPN) plays an important physiological role in the efficient development of Th1 immune responses and cell survival by inhibiting apoptosis. The role of OPN in acute GI-GVHD is poorly understood. In the present study, we investigated the role of OPN in donor T cells in the pathogenicity of acute GI-GVHD. Methods: OPN knockout (KO) mice and C57BL/6 (B6) mice were used as donors, and (C57BL/6 × DBA/2) F1 (BDF1) mice were used as allograft recipients. Mice with acutemore » GI-GVHD were divided into three groups: the control group (BDF1→BDF1), B6 group (B6→BDF1), and OPN-KO group (OPN-KO→BDF1). Bone marrow cells and spleen cells from donors were transplanted to lethally irradiated recipients. Clinical GVHD scores were assessed daily. Recipients were euthanized on day 7 after transplantation, and colons and small intestines were collected for various analyses. Results: The clinical GVHD score in the OPN-KO group was significantly increased compared with the B6 and control groups. We observed a difference in the severity of colonic GVHD between the OPN-KO group and B6 group, but not small intestinal-GVHD between these groups. Interferon-γ, Tumor necrosis factor-α, Interleukin-17A, and Interleukin-18 gene expression in the OPN-KO group was differed between the colon and small intestine. Flow cytometric analysis revealed that the fluorescence intensity of splenic and colonic CD8 T cells expressing Fas Ligand was increased in the OPN-KO group compared with the B6 group. Conclusion: We demonstrated that the importance of OPN in T cells in the onset of acute GI-GVHD involves regulating apoptosis of the intestinal cell via the Fas-Fas Ligand pathway. - Highlights: • A lack of osteopontin in donor cells exacerbated clinical gastrointestinal GVHD. • Donor cells

A Phase I study of gemtuzumab ozogamicin (GO) in combination with busulfan and cyclophosphamide (Bu/Cy) and allogeneic stem cell transplantation in children with poor-risk CD33+ AML: a new targeted immunochemotherapy myeloablative conditioning (MAC) regimen.

PubMed

Satwani, Prakash; Bhatia, Monica; Garvin, James H; George, Diane; Dela Cruz, Filemon; Le Gall, John; Jin, Zhezhen; Schwartz, Joseph; Duffy, Deirdre; van de Ven, Carmella; Foley, Sandra; Hawks, Ria; Morris, Erin; Baxter-Lowe, Lee Ann; Cairo, Mitchell S

2012-02-01

Children with high-risk acute myelogenous leukemia (AML) (induction failure [IF], refractory relapse [RR], third complete remission [CR3]) have dismal outcomes. Over 80% of AML patients express CD33, a target of gemtuzumab ozogamicin (GO). GO is an active drug in childhood AML but has not been studied in a myeloablative conditioning regimen. We sought to determine the safety of GO in combination with busulfan/cyclophosphamide (Bu/Cy) conditioning before allogeneic hematopoietic stem cell transplantation (alloSCT). GO was administered on day -14 at doses of 3.0, 4.5, 6.0, and 7.5 mg/m(2), busulfan on days -7, -6, -5, -4 (12.8-16.0 mg/kg), and cyclophosphamide on days -3 and -2 (60 mg/kg/day). GVHD prophylaxis consisted of tacrolimus and mycophenolate mofetil. We enrolled 12 patients: 8 IF, 3 RR, 1 CR3; median age: 3 years (1-17); median follow-up: 1379 days (939-2305). Nine received umbilical cord blood (UCB), 2 matched unrelated donors (MUDs) and 1 HLA-matched sibling donor: 3 patients each at GO doses of 3.0, 4.5, 6.0, or 7.5 mg/m(2). No dose-limiting toxicities secondary to GO were observed. Day 100 treatment-related mortality (TRM) was 0%. Myeloid and platelet engraftment was observed in 92% and 75% of patients at median day 22 (12-40) and 42 (21-164), respectively. Median day +30 donor chimerism was 99% (85%-100%). The probability of grade II-IV acute graft-versus-host disease (aGVHD) was 42% and chronic GVHD (cGVHD) was 28%. One-year overall survival (OS) and event-free survival (EFS) was 50% (95% confidence interval [CI], 20.8-73.6). GO combined with Bu/Cy regimen followed by alloSCT is well tolerated in children with poor-risk AML. GO at 7.5 mg/m(2) in combination with Bu/Cy is currently being tested in a phase II study. Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Long-term safety and efficacy of autologous platelet lysate drops for treatment of ocular GvHD.

PubMed

Pezzotta, S; Del Fante, C; Scudeller, L; Rossi, G C; Perotti, C; Bianchi, P E; Antoniazzi, E

2017-01-01

Current ocular GvHD (oGvHD) treatments are suboptimal. We investigated the safety and efficacy of long-term continuous treatment with autologous platelet lysate (PL) drops in patients with oGvHD Dry Eye Syndrome (DES) score 2-3 refractory to topical conventional therapy. Ophthalmic evaluation was performed at 6 month intervals. Symptoms were assessed using the Glaucoma Symptom Scale (GSS). Patients were defined 'responders' when showing a reduction at least one grade on National Institutes of Health Eye Score from baseline at the 6 month visit. Thirty-one patients were included, and 16 (51%) completed 36 months of follow-up (range 6.5-72.7). At 6 months all patients were classified as responders: median GSS symptom score decreased from 70 to 41 (33 at 36 months), median GSS function score reduced from 68 to 46 (33 at 36 months) (all P<0.001). Median Tear Break Up Time improved from 3 to 6 s after 6 months and was maintained over time. All signs improved at 6 and 36 months (clinical and statistical significance). No severe adverse events occurred. Long-term treatment with PL drops is secure and effective for oGvHD and can be an efficient therapy option from initial stages of oGvHD to prevent permanent ocular impairment and improving quality of life.

Skin ulcers related to chronic graft-versus-host disease: clinical findings and associated morbidity.

PubMed

Jachiet, M; de Masson, A; Peffault de Latour, R; Rybojad, M; Robin, M; Bourhis, J-H; Xhaard, A; Dhedin, N; Sicre de Fontbrune, F; Suarez, F; Barete, S; Parquet, N; Nguyen, S; Ades, L; Rubio, M-T; Wittnebel, S; Bagot, M; Socié, G; Bouaziz, J-D

2014-07-01

According to the National Institutes of Health classification of chronic graft-versus-host disease (cGVHD), skin ulcers after allogeneic haematopoietic stem-cell transplantation (HSCT) are recorded as having the maximal severity score but published data are scarce. To describe skin ulcers related to cGVHD with an emphasis on clinical findings, associated morbidity, management and evolution. A multicentre retrospective analysis was carried out of patients with a diagnosis of cGVHD skin ulcers. All 25 patients included in the study had sclerotic skin cGVHD and 21 had lichenoid skin lesions associated with the sclerotic skin lesions. Thirteen patients had severe cGVHD without considering the skin, because of the involvement of an extracutaneous organ by cGVHD. The median time from HSCT to the onset of ulcers was 44 months. In addition to scleroderma, initial skin lesions at the site of ulcers were bullous erosive lichen in 21 patients and bullous erosive morphoea in four patients. Fifteen patients had an inaugural oedema. Ulcers were mostly bilateral with a predilection for the lower limbs. They were frequently colonized but few infections occurred. Four patients died during a median follow-up period of 55 months. Chronic graft-versus-host disease skin ulcers occur in patients with sclerodermatous skin cGVHD, are associated with severe cGVHD, often start with bullous lichenoid lesions or bullous morphoea and seem to cause more morbidity than mortality, given the low rate of mortality observed in our series of patients. © 2014 British Association of Dermatologists.

Targeting proteasomes in infectious organisms to combat disease.

PubMed

Bibo-Verdugo, Betsaida; Jiang, Zhenze; Caffrey, Conor R; O'Donoghue, Anthony J

2017-05-01

Proteasomes are multisubunit, energy-dependent, proteolytic complexes that play an essential role in intracellular protein turnover. They are present in eukaryotes, archaea, and in some actinobacteria species. Inhibition of proteasome activity has emerged as a powerful strategy for anticancer therapy and three drugs have been approved for treatment of multiple myeloma. These compounds react covalently with a threonine residue located in the active site of a proteasome subunit to block protein degradation. Proteasomes in pathogenic organisms such as Mycobacterium tuberculosis and Plasmodium falciparum also have a nucleophilic threonine residue in the proteasome active site and are therefore sensitive to these anticancer drugs. This review summarizes efforts to validate the proteasome in pathogenic organisms as a therapeutic target. We describe several strategies that have been used to develop inhibitors with increased potency and selectivity for the pathogen proteasome relative to the human proteasome. In addition, we highlight a cell-based chemical screening approach that identified a potent, allosteric inhibitor of proteasomes found in Leishmania and Trypanosoma species. Finally, we discuss the development of proteasome inhibitors as anti-infective agents. © 2017 Federation of European Biochemical Societies.

Memory T cells: A helpful guard for allogeneic hematopoietic stem cell transplantation without causing graft-versus-host disease.

PubMed

Huang, Wei; Chao, Nelson J

2017-12-01

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (AHSCT) and the major cause of nonrelapse morbidity and mortality of AHSCT. In AHSCT, donor T cells facilitate hematopoietic stem cell (HSC) engraftment, contribute to anti-infection immunity, and mediate graft-versus-leukemia (GVL) responses. However, activated alloreactive T cells also attack recipient cells in vital organs, leading to GVHD. Different T-cell subsets, including naïve T (T N ) cells, memory T (T M ) cells, and regulatory T (T reg ) cells mediate different forms of GVHD and GVL; T N cells mediate severe GVHD, whereas T M cells do not cause GVHD, but preserve T-cell function including GVL. In addition, metabolic reprogramming controls T-cell differentiation and activation in these disease states. This minireview focuses on the role and the related mechanisms of T M cells in AHSCT, and the potential manipulation of T cells in AHSCT. Copyright © 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.

Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation

PubMed Central

Dudley, Mark E.; Carpenter, Robert O.; Kassim, Sadik H.; Rose, Jeremy J.; Telford, William G.; Hakim, Frances T.; Halverson, David C.; Fowler, Daniel H.; Hardy, Nancy M.; Mato, Anthony R.; Hickstein, Dennis D.; Gea-Banacloche, Juan C.; Pavletic, Steven Z.; Sportes, Claude; Maric, Irina; Feldman, Steven A.; Hansen, Brenna G.; Wilder, Jennifer S.; Blacklock-Schuver, Bazetta; Jena, Bipulendu; Bishop, Michael R.; Gress, Ronald E.; Rosenberg, Steven A.

2013-01-01

New treatments are needed for B-cell malignancies persisting after allogeneic hematopoietic stem cell transplantation (alloHSCT). We conducted a clinical trial of allogeneic T cells genetically modified to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. T cells for genetic modification were obtained from each patient’s alloHSCT donor. All patients had malignancy that persisted after alloHSCT and standard donor lymphocyte infusions (DLIs). Patients did not receive chemotherapy prior to the CAR T-cell infusions and were not lymphocyte depleted at the time of the infusions. The 10 treated patients received a single infusion of allogeneic anti-CD19-CAR T cells. Three patients had regressions of their malignancies. One patient with chronic lymphocytic leukemia (CLL) obtained an ongoing complete remission after treatment with allogeneic anti-CD19-CAR T cells, another CLL patient had tumor lysis syndrome as his leukemia dramatically regressed, and a patient with mantle cell lymphoma obtained an ongoing partial remission. None of the 10 patients developed graft-versus-host disease (GVHD). Toxicities included transient hypotension and fever. We detected cells containing the anti-CD19-CAR gene in the blood of 8 of 10 patients. These results show for the first time that donor-derived allogeneic anti-CD19-CAR T cells can cause regression of B-cell malignancies resistant to standard DLIs without causing GVHD. This trial was registered at www.clinicaltrials.gov as #NCT01087294. PMID:24055823

Deletion of Fanca or Fancd2 dysregulates Treg in mice

PubMed Central

Du, Wei; Erden, Ozlem; Wilson, Andrew; Sipple, Jared M.; Schick, Jonathan; Mehta, Parinda; Myers, Kasiani C.; Steinbrecher, Kris A.; Davies, Stella M.

2014-01-01

Fanconi anemia (FA) is a genetic disorder associated with bone marrow (BM) failure and leukemia. Recent studies demonstrate variable immune defects in FA. However, the cause for FA immunodeficiency is unknown. Here we report that deletion of Fanca or Fancd2 dysregulates the suppressive activity of regulatory T cells (Tregs), shown functionally as exacerbation of graft-vs-host disease (GVHD) in mice. Recipient mice of Fanca−/− or Fancd2−/− BM chimeras exhibited severe acute GVHD after allogeneic BM transplantation (BMT). T cells from Fanca−/− or Fancd2−/− mice induced higher GVHD lethality than those from wild-type (WT) littermates. FA Tregs possessed lower proliferative suppression potential compared with WT Tregs, as demonstrated by in vitro proliferation assay and BMT. Analysis of CD25+Foxp3+ Tregs indicated that loss of Fanca or Fancd2 dysregulated Foxp3 target gene expression. Additionally, CD25+Foxp3+ Tregs of Fanca−/− or Fancd2−/− mice were less efficient in suppressing the production of GVHD-associated inflammatory cytokines. Consistently, aberrant NF-κB activity was observed in infiltrated T cells from FA GVHD mice. Conditional deletion of p65 in FA Tregs decreased GVHD mortality. Our study uncovers an essential role for FA proteins in maintaining Treg homeostasis, possibly explaining, at least in part, the immune deficiency reported in some FA patients. PMID:24501220

Deletion of Fanca or Fancd2 dysregulates Treg in mice.

PubMed

Du, Wei; Erden, Ozlem; Wilson, Andrew; Sipple, Jared M; Schick, Jonathan; Mehta, Parinda; Myers, Kasiani C; Steinbrecher, Kris A; Davies, Stella M; Pang, Qishen

2014-03-20

Fanconi anemia (FA) is a genetic disorder associated with bone marrow (BM) failure and leukemia. Recent studies demonstrate variable immune defects in FA. However, the cause for FA immunodeficiency is unknown. Here we report that deletion of Fanca or Fancd2 dysregulates the suppressive activity of regulatory T cells (Tregs), shown functionally as exacerbation of graft-vs-host disease (GVHD) in mice. Recipient mice of Fanca(-/-) or Fancd2(-/-) BM chimeras exhibited severe acute GVHD after allogeneic BM transplantation (BMT). T cells from Fanca(-/-) or Fancd2(-/-) mice induced higher GVHD lethality than those from wild-type (WT) littermates. FA Tregs possessed lower proliferative suppression potential compared with WT Tregs, as demonstrated by in vitro proliferation assay and BMT. Analysis of CD25(+)Foxp3(+) Tregs indicated that loss of Fanca or Fancd2 dysregulated Foxp3 target gene expression. Additionally, CD25(+)Foxp3(+) Tregs of Fanca(-/-) or Fancd2(-/-) mice were less efficient in suppressing the production of GVHD-associated inflammatory cytokines. Consistently, aberrant NF-κB activity was observed in infiltrated T cells from FA GVHD mice. Conditional deletion of p65 in FA Tregs decreased GVHD mortality. Our study uncovers an essential role for FA proteins in maintaining Treg homeostasis, possibly explaining, at least in part, the immune deficiency reported in some FA patients.

A New Method Without Organic Solvent to Targeted Nanodrug for Enhanced Anticancer Efficacy

NASA Astrophysics Data System (ADS)

Wu, Shichao; Yang, Xiangrui; Zou, Mingyuan; Hou, Zhenqing; Yan, Jianghua

2017-06-01

Since the hydrophobic group is always essential to the synthesis of the drug-loaded nanoparticles, a majority of the methods rely heavily on organic solvent, which may not be completely removed and might be a potential threat to the patients. In this study, we completely "green" synthesized 10-hydroxycamptothecine (HCPT) loaded, folate (FA)-modified nanoneedles (HFNDs) for highly efficient cancer therapy with high drug loading, targeting property, and imaging capability. It should be noted that no organic solvent was used in the preparation process. In vitro cell uptake study and the in vivo distribution study showed that the HFNDs, with FA on the surface, revealed an obviously targeting property and entered the HeLa cells easier than the chitosan-HCPT nanoneedles without FA modified (NDs). The cytotoxicity tests illustrated that the HFNDs possessed better killing ability to HeLa cells than the individual drug or the NDs in the same dose, indicating its good anticancer effect. The in vivo anticancer experiment further revealed the pronounced anticancer effects and the lower side effects of the HFNDs. This new method without organic solvent will lead to a promising sustained drug delivery system for cancer diagnosis and treatment.

Target organ damage in hypertensive patients of different ethnic groups.

PubMed

Wolak, Talya; Anfanger, Sharon; Wolak, Arik; Furman, Tsilla; Abuara'ar, Touphic; Biton, Amnon; Pilpel, Dina; Paran, Esther

2007-03-20

Hypertension is associated with involvement of target organs which varies among the different ethnic groups. The multiplicity of the population in Israel offers an opportunity for evaluating target organ damage in hypertensive patients of different ethnic origins. Data were collected from the computerized medical files of hypertensive patients in primary care clinics. The analysis was done on 576 hypertensive patients: 138 Bedouins (Arab residents), 141 Sephardic Jews (immigrants from North Africa and the Middle East), 152 Asian-Indian Jews (immigrants from India) and 145 Ashkenazi Jews (immigrants from Europe and North and South America). In multivariable logistic regressions adjusted for known risk factors and ethnicity, the prevalence of cerebrovascular disease was the highest among the Asian-Indian Jews (OR=3.09, p value=0.009). Renal damage was highest among the Bedouins (OR=4.54, p value<0.0001) and Asian-Indian Jews (OR=2.88, p value=0.005). The differences in the prevalence of renal damage among the various ethnic groups were even more pronounced among patients without diabetes (OR=8.31, p value<0.0001 in Bedouins and OR=7.46, p value=0.001 in Asian-Indian Jews). The prevalence of ischemic heart disease did not differ significantly among the four ethnic groups. The prevalence of cerebrovascular and renal diseases are both significantly associated with ethnic origin of Asian-Indian Jews and Bedouins. However, the multivariate analysis shows that the prevalence of ischemic heart disease is not associated with ethnicity.

Lichenoid Variant of Chronic Cutaneous Graft Versus Host Reaction Post Blood Transfusion: A Rare Event Post Blood Transfusion.

PubMed

Ramakrishnaiah, Pushpa Kodipalya; Lakshman, Archana; Aradhya, Sacchidanand Sarvajnamurthy; Veerabhadrappa, Nataraja Holavanahally

2015-01-01

Chronic graft versus host disease (GVHD) is a less frequently seen disease that occurs post solid organ or bone marrow transplantation. Chronic GVHD occurring post blood transfusion is an even more uncommon disease. It can present either as a lichenoid disease or as a sclerodermatous disease involving multiple systems. In this article, we report a case of chronic graft versus host reaction occurring in skin secondary to blood transfusion.

Influence of intestinal bacterial decontamination using metronidazole and ciprofloxacin or ciprofloxacin alone on the development of acute graft-versus-host disease after marrow transplantation in patients with hematologic malignancies: final results and long-term follow-up of an open-label prospective randomized trial.

PubMed

Beelen, D W; Elmaagacli, A; Müller, K D; Hirche, H; Schaefer, U W

1999-05-15

medication (60% +/- 11%) compared with ciprofloxacin alone (46% +/- 9%). In conclusion, the present study provides evidence that antimicrobial chemotherapy targeted to intestinal anaerobic bacteria in marrow transplant recipients significantly reduces the severity of acute GVHD and supports the theory that the intestinal anaerobic bacterial microflora plays a role in the pathogenesis of acute GVHD after human marrow transplantation.

Inhaled Cadmium Oxide Nanoparticles: Their in Vivo Fate and Effect on Target Organs.

PubMed

Dumkova, Jana; Vrlikova, Lucie; Vecera, Zbynek; Putnova, Barbora; Docekal, Bohumil; Mikuska, Pavel; Fictum, Petr; Hampl, Ales; Buchtova, Marcela

2016-06-03

The increasing amount of heavy metals used in manufacturing equivalently increases hazards of environmental pollution by industrial products such as cadmium oxide (CdO) nanoparticles. Here, we aimed to unravel the CdO nanoparticle destiny upon their entry into lungs by inhalations, with the main focus on the ultrastructural changes that the nanoparticles may cause to tissues of the primary and secondary target organs. We indeed found the CdO nanoparticles to be transported from the lungs into secondary target organs by blood. In lungs, inhaled CdO nanoparticles caused significant alterations in parenchyma tissue including hyperemia, enlarged pulmonary septa, congested capillaries, alveolar emphysema and small areas of atelectasis. Nanoparticles were observed in the cytoplasm of cells lining bronchioles, in the alveolar spaces as well as inside the membranous pneumocytes and in phagosomes of lung macrophages. Nanoparticles even penetrated through the membrane into some organelles including mitochondria and they also accumulated in the cytoplasmic vesicles. In livers, inhalation caused periportal inflammation and local hepatic necrosis. Only minor changes such as diffusely thickened filtration membrane with intramembranous electron dense deposits were observed in kidney. Taken together, inhaled CdO nanoparticles not only accumulated in lungs but they were also transported to other organs causing serious damage at tissue as well as cellular level.

Inhaled Cadmium Oxide Nanoparticles: Their in Vivo Fate and Effect on Target Organs

PubMed Central

Dumkova, Jana; Vrlikova, Lucie; Vecera, Zbynek; Putnova, Barbora; Docekal, Bohumil; Mikuska, Pavel; Fictum, Petr; Hampl, Ales; Buchtova, Marcela

2016-01-01

The increasing amount of heavy metals used in manufacturing equivalently increases hazards of environmental pollution by industrial products such as cadmium oxide (CdO) nanoparticles. Here, we aimed to unravel the CdO nanoparticle destiny upon their entry into lungs by inhalations, with the main focus on the ultrastructural changes that the nanoparticles may cause to tissues of the primary and secondary target organs. We indeed found the CdO nanoparticles to be transported from the lungs into secondary target organs by blood. In lungs, inhaled CdO nanoparticles caused significant alterations in parenchyma tissue including hyperemia, enlarged pulmonary septa, congested capillaries, alveolar emphysema and small areas of atelectasis. Nanoparticles were observed in the cytoplasm of cells lining bronchioles, in the alveolar spaces as well as inside the membranous pneumocytes and in phagosomes of lung macrophages. Nanoparticles even penetrated through the membrane into some organelles including mitochondria and they also accumulated in the cytoplasmic vesicles. In livers, inhalation caused periportal inflammation and local hepatic necrosis. Only minor changes such as diffusely thickened filtration membrane with intramembranous electron dense deposits were observed in kidney. Taken together, inhaled CdO nanoparticles not only accumulated in lungs but they were also transported to other organs causing serious damage at tissue as well as cellular level. PMID:27271611

Pre-transplantation risk factors to develop sclerotic chronic GvHD after allogeneic HSCT: a multicenter retrospective study from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

PubMed

Detrait, M Y; Morisset, S; Peffault de Latour, R; Yakoub-Agha, I; Crocchiolo, R; Tabrizi, R; Bay, J-O; Chevalier, P; Barraco, F; Raus, N; Vigouroux, S; Magro, L; Mohty, M; Milpied, N; Blaise, D; Socié, G; Michallet, M

2015-02-01

Sclerotic chronic GvHD (cGvHD) is one of the most severe complications after allo-hematopoietic stem cell transplantation (HSCT). Risk factors associated with this complication remain not very well defined. With the aim to define a pre-transplantation risk profile, we have conducted a French retrospective analysis in 705 consecutive patients between 2005 and 2010. Analyses to determine pre-transplantation risk factors included as variables: patient and donor age, kind of donor, HLA matching, ABO matching, sex-matching, diagnosis, stem cell source, gender, GvHD prophylaxis and antithymocyte globulin (ATG) in the conditioning regimen. The cumulative incidence of sclerotic cGvHD was 18% (95% CI, 16.6-19.6) 3 years after onset of cGvHD. In univariate analysis, we found a significantly lower number of sclerotic cGvHD form in patients transplanted from cord blood cells (P=0.0021), in patients with a one mismatched donor (P=0.041) and in patients who had received ATG in the conditioning regimen (P=0.002). In multivariate analysis, factors associated with an increased risk of sclerotic cGvHD were young patient age, multiple myeloma and PBSC as the stem cell source. ATG in conditioning regimen and cord blood unit as the stem cell source were associated with a lower risk.

Modulation of Regulatory T Cell Activity by TNF Receptor Type II-Targeting Pharmacological Agents

PubMed Central

Zou, Huimin; Li, Ruixin; Hu, Hao; Hu, Yuanjia; Chen, Xin

2018-01-01

There is now compelling evidence that tumor necrosis factor (TNF)–TNF receptor type II (TNFR2) interaction plays a decisive role in the activation, expansion, and phenotypical stability of suppressive CD4+Foxp3+ regulatory T cells (Tregs). In an effort to translate this basic research finding into a therapeutic benefit, a number of agonistic or antagonistic TNFR2-targeting biological agents with the capacity to activate or inhibit Treg activity have been developed and studied. Recent studies also show that thalidomide analogs, cyclophosphamide, and other small molecules are able to act on TNFR2, resulting in the elimination of TNFR2-expressing Tregs. In contrast, pharmacological agents, such as vitamin D3 and adalimumab, were reported to induce the expansion of Tregs by promoting the interaction of transmembrane TNF (tmTNF) with TNFR2. These studies clearly show that TNFR2-targeting pharmacological agents represent an effective approach to modulating the function of Tregs and thus may be useful in the treatment of major human diseases such as autoimmune disorders, graft-versus-host disease (GVHD), and cancer. In this review, we will summarize and discuss the latest progress in the study of TNFR2-targeting pharmacological agents and their therapeutic potential based on upregulation or downregulation of Treg activity. PMID:29632537

Ikaros-Notch axis in host hematopoietic cells regulates experimental graft-versus-host disease

PubMed Central

Toubai, Tomomi; Sun, Yaping; Tawara, Isao; Friedman, Ann; Liu, Chen; Evers, Rebecca; Nieves, Evelyn; Malter, Chelsea; Chockley, Peter; Maillard, Ivan; Winandy, Susan

2011-01-01

Host hematopoietically derived APCs play a vital role in the initiation of GVH responses. However, the APC autonomous molecular mechanisms that are critical for the induction of GVHD are not known. We report here that the Ikaros-Notch axis in host hematopoietically derived APCs regulates the severity of acute GVHD across multiple clinically relevant murine models of experimental bone marrow transplantation. In the present study, Ikaros deficiency (Ik−/−) limited to host hematopoietically derived APCs enhanced donor T-cell expansion and intensified acute GVHD, as determined by survival and other GVHD-specific parameters. The Ik−/− conventional CD8+ and CD8−CD11c+ dendritic cells (DCs), the most potent APCs, showed no increase in the expression of activation markers or in response to TLR stimulation compared with wild-type controls. However, Ik−/− DCs demonstrated an enhanced stimulation of allogeneic T cells. Deficiency of Ikaros in the conventional CD8+ and CD8−CD11c+ DCs was associated with an increase in Notch signaling, the blockade of which mitigated the enhanced in vitro and in vivo allostimulatory capacity. Therefore, the Ikaros-Notch axis is a novel pathway that modulates DC biology in general, and targeting this pathway in host hematopoietically derived APCs may reduce GVHD. PMID:21471527

Peripherally Administered Nanoparticles Target Monocytic Myeloid Cells, Secondary Lymphoid Organs and Tumors in Mice

PubMed Central

Kourtis, Iraklis C.; Hirosue, Sachiko; de Titta, Alexandre; Kontos, Stephan; Stegmann, Toon; Hubbell, Jeffrey A.; Swartz, Melody A.

2013-01-01

Nanoparticles have been extensively developed for therapeutic and diagnostic applications. While the focus of nanoparticle trafficking in vivo has traditionally been on drug delivery and organ-level biodistribution and clearance, recent work in cancer biology and infectious disease suggests that targeting different cells within a given organ can substantially affect the quality of the immunological response. Here, we examine the cell-level biodistribution kinetics after administering ultrasmall Pluronic-stabilized poly(propylene sulfide) nanoparticles in the mouse. These nanoparticles depend on lymphatic drainage to reach the lymph nodes and blood, and then enter the spleen rather than the liver, where they interact with monocytes, macrophages and myeloid dendritic cells. They were more readily taken up into lymphatics after intradermal (i.d.) compared to intramuscular administration, leading to ∼50% increased bioavailability in blood. When administered i.d., their distribution favored antigen-presenting cells, with especially strong targeting to myeloid cells. In tumor-bearing mice, the monocytic and the polymorphonuclear myeloid-derived suppressor cell compartments were efficiently and preferentially targeted, rendering this nanoparticulate formulation potentially useful for reversing the highly suppressive activity of these cells in the tumor stroma. PMID:23626707

Peripherally administered nanoparticles target monocytic myeloid cells, secondary lymphoid organs and tumors in mice.

PubMed

Kourtis, Iraklis C; Hirosue, Sachiko; de Titta, Alexandre; Kontos, Stephan; Stegmann, Toon; Hubbell, Jeffrey A; Swartz, Melody A

2013-01-01

Nanoparticles have been extensively developed for therapeutic and diagnostic applications. While the focus of nanoparticle trafficking in vivo has traditionally been on drug delivery and organ-level biodistribution and clearance, recent work in cancer biology and infectious disease suggests that targeting different cells within a given organ can substantially affect the quality of the immunological response. Here, we examine the cell-level biodistribution kinetics after administering ultrasmall Pluronic-stabilized poly(propylene sulfide) nanoparticles in the mouse. These nanoparticles depend on lymphatic drainage to reach the lymph nodes and blood, and then enter the spleen rather than the liver, where they interact with monocytes, macrophages and myeloid dendritic cells. They were more readily taken up into lymphatics after intradermal (i.d.) compared to intramuscular administration, leading to ∼50% increased bioavailability in blood. When administered i.d., their distribution favored antigen-presenting cells, with especially strong targeting to myeloid cells. In tumor-bearing mice, the monocytic and the polymorphonuclear myeloid-derived suppressor cell compartments were efficiently and preferentially targeted, rendering this nanoparticulate formulation potentially useful for reversing the highly suppressive activity of these cells in the tumor stroma.

The brain is a target organ after acute exposure to depleted uranium.

PubMed

Lestaevel, P; Houpert, P; Bussy, C; Dhieux, B; Gourmelon, P; Paquet, F

2005-09-01

The health effects of depleted uranium (DU) are mainly caused by its chemical toxicity. Although the kidneys are the main target organs for uranium toxicity, uranium can also reach the brain. In this paper, the central effects of acute exposure to DU were studied in relation to health parameters and the sleep-wake cycle of adult rats. Animals were injected intraperitoneally with 144+/-10 microg DU kg-1 as nitrate. Three days after injection, the amounts of uranium in the kidneys represented 2.6 microg of DU g-1 of tissue, considered as a sub-nephrotoxic dosage. The central effect of uranium could be seen through a decrease in food intake as early as the first day after exposure and shorter paradoxical sleep 3 days after acute DU exposure (-18% of controls). With a lower dosage of DU (70+/-8 microg DU kg-1), no significant effect was observed on the sleep-wake cycle. The present study intends to illustrate the fact that the brain is a target organ, as are the kidneys, after acute exposure to a moderate dosage of DU. The mechanisms by which uranium causes these early neurophysiological perturbations shall be discussed.

SCFSAP controls organ size by targeting PPD proteins for degradation in Arabidopsis thaliana

PubMed Central

Wang, Zhibiao; Li, Na; Jiang, Shan; Gonzalez, Nathalie; Huang, Xiahe; Wang, Yingchun; Inzé, Dirk; Li, Yunhai

2016-01-01

Control of organ size by cell proliferation and growth is a fundamental process, but the mechanisms that determine the final size of organs are largely elusive in plants. We have previously revealed that the ubiquitin receptor DA1 regulates organ size by repressing cell proliferation in Arabidopsis. Here we report that a mutant allele of STERILE APETALA (SAP) suppresses the da1-1 mutant phenotype. We show that SAP is an F-box protein that forms part of a SKP1/Cullin/F-box E3 ubiquitin ligase complex and controls organ size by promoting the proliferation of meristemoid cells. Genetic analyses suggest that SAP may act in the same pathway with PEAPOD1 and PEAPOD2, which are negative regulators of meristemoid proliferation, to control organ size, but does so independently of DA1. Further results reveal that SAP physically associates with PEAPOD1 and PEAPOD2, and targets them for degradation. These findings define a molecular mechanism by which SAP and PEAPOD control organ size. PMID:27048938

Epidermal elafin expression is an indicator of poor prognosis in cutaneous graft-versus-host disease.

PubMed

Brüggen, Marie-Charlotte; Petzelbauer, Peter; Greinix, Hildegard; Contassot, Emmanuel; Jankovic, Dragana; French, Lars; Socié, Gérard; Rabitsch, Werner; Kuzmina, Zoya; Kalhs, Peter; Knobler, Robert; Stingl, Georg; Stary, Georg

2015-04-01

Graft-versus-host disease (GVHD) remains a common and potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation. In the skin, GVHD can present in an acute (aGVHD), chronic lichenoid (clGVHD), or chronic sclerotic form (csGVHD). Measuring peripheral blood levels of the keratinocyte-derived protease inhibitor elafin has recently emerged as a promising tool for the diagnosis of cutaneous aGVHD. We evaluated whether the analysis of elafin expression in skin would allow distinguishing aGVHD from drug hypersensitivity rashes (DHR) and whether cutaneous elafin expression would correlate with disease severity or altered prognosis of aGVHD and clGVHD/csGVHD. Skin biopsies from aGVHD (n=22), clGVHD (n=15), csGVHD (n=7), and DHR (n=10) patients were collected and epidermal elafin expression and its association with diverse clinical/histological parameters were analyzed. Acute GVHD and DHR displayed varying degrees of elafin expression. No elafin was detectable in csGVHD, whereas the molecule was increased in clGVHD as compared with aGVHD. Elafin-high aGVHD/clGVHD lesions presented with epidermal thickening and were associated with poor prognosis-i.e., decreased overall survival in aGVHD and corticosteroid resistance in clGVHD. Although cutaneous elafin does not seem to discriminate aGVHD from DHR lesions, our study strongly suggests an association between cutaneous elafin expression and poor prognosis for patients with cutaneous GVHD.

Factors associated with cardiovascular target organ damage in children after renal transplantation.

PubMed

Borchert-Mörlins, Bianca; Thurn, Daniela; Schmidt, Bernhard M W; Büscher, Anja K; Oh, Jun; Kier, Tanja; Bauer, Elena; Baig, Sabrina; Kanzelmeyer, Nele; Kemper, Markus J; Büscher, Rainer; Melk, Anette

2017-11-01

Cardiovascular disease is the second-most common cause of death in pediatric renal transplant recipients. The aim of this study was to evaluate subclinical cardiovascular target organ damage defined as the presence of arterio- and atherosclerotic lesions and cardiac remodeling and to analyze contributing risk factors in a large cohort of children after renal transplantation (RT). A total of 109 children aged 13.1 ± 3.3 years who had undergone RT at one of three German transplant centers were enrolled in this study. Patients had been transplanted a mean of 5.5 (±4.0) years prior to being enrolled in the study. Anthropometric data, laboratory values and office- and 24-h ambulatory blood pressure monitoring (ABPM) were evaluated. Cardiovascular target organ damage was determined through non-invasive measurements of aortic pulse wave velocity (PWV), carotid intima-media thickness (IMT) and left ventricular mass (LVM). Elevated PWV or IMT values were detected in 22 and 58% of patients, respectively. Left ventricular hypertrophy was found in as many as 43% of patients. The prevalence of uncontrolled or untreated hypertension was 41%, of which 16% of cases were only detected by ABPM measurements. In the multivariable analysis, higher diastolic blood pressure, everolimus intake and lower estimated glomerular filtration rate were independently associated with high PWV. Higher systolic blood pressure and body mass index were associated with elevated LVM. Our results showed an alarming burden of cardiovascular subclinical organ damage in children after RT. Hypertension, obesity, immunosuppressive regimen and renal function emerged as independent risk factors of organ damage. Whereas the latter is not modifiable, the results of our study strongly indicate that the management of children after RT should focus on the control of blood pressure and weight.

Graft-versus-host disease causes failure of donor hematopoiesis and lymphopoiesis in interferon-gamma receptor-deficient hosts.

PubMed

Delisle, Jean-Sébastien; Gaboury, Louis; Bélanger, Marie-Pier; Tassé, Eliane; Yagita, Hideo; Perreault, Claude

2008-09-01

The immunopathologic condition known as graft-versus-host disease (GVHD) results from a type I T-cell process. However, a prototypical type I cytokine, interferon-gamma (IFN-gamma), can protect against several manifestations of GVHD in recipients of major histocompatibility complex (MHC)-mismatched hematopoietic cells. We transplanted hematopoietic cells from C3H.SW donors in wild-type (wt) and IFN-gamma-receptor-deficient (IFN-gammaRKO) MHC-matched C57BL/6 recipients. In IFN-gammaRKO recipients, host cells were unresponsive to IFN-gamma, whereas wt donor cells were exposed to exceptionally high levels of IFN-gamma. From an IFN-gamma perspective, we could therefore evaluate the impact of a loss-of-function on host cells and gain-of-function on donor cells. We found that lack of IFN-gammaR prevented up-regulation of MHC proteins on host cells but did not mitigate damage to most target organs. Two salient phenotypes in IFN-gammaRKO recipients involved donor cells: lymphoid hypoplasia and hematopoietic failure. Lymphopenia was due to FasL-induced apoptosis and decreased cell proliferation. Bone marrow aplasia resulted from a decreased proliferation of hematopoietic stem/progenitor cells that was associated with down-regulation of 2 genes negatively regulated by IFN-gamma: Ccnd1 and Myc. We conclude that IFN-gamma produced by alloreactive T cells may entail a severe graft-versus-graft reaction and could be responsible for cytopenias that are frequently observed in subjects with GVHD.

Non-Target Analyses of organic compounds in ice cores using HPLC-ESI-UHRMS

NASA Astrophysics Data System (ADS)

Zuth, Christoph; Müller-Tautges, Christina; Eichler, Anja; Schwikowski, Margit; Hoffmann, Thorsten

2015-04-01

To study the global climatic and environmental changes it is necessary to know the environmental and especially atmospheric conditions of the past. By analysing climate archives, such as for example ice cores, unique environmental information can be obtained. In contrast to the well-established analysis of inorganic species in ice cores, organic compounds have been analysed in ice cores to a much smaller extent. Because of current analytical limitations it has become commonplace to focus on 'total organic carbon' measurements or specific classes of organic molecules, as no analytical methods exist that can provide a broad characterization of the organic material present[1]. On the one hand, it is important to focus on already known atmospheric markers in ice cores and to quantify, where possible, in order to compare them to current conditions. On the other hand, unfortunately a wealth of information is lost when only a small fraction of the organic material is examined. However, recent developments in mass spectrometry in respect to higher mass resolution and mass accuracy enable a new approach to the analysis of complex environmental samples. The qualitative characterization of the complex mixture of water soluble organic carbon (WSOC) in the ice using high-resolution mass spectrometry allows for novel insights concerning the composition and possible sources of aerosol derived WSOC deposited at glacier sites. By performing a non-target analysis of an ice core from the Swiss Alps using previous enrichment by solid-phase extraction (SPE) and high performance liquid chromatography coupled to electrospray ionization and ultra-high resolution mass spectrometry (HPLC-ESI-UHRMS) 475 elemental formulas distributed onto 659 different peaks were detected. The elemental formulas were classified according to their elemental composition into CHO-, CHON-, CHOS-, CHONS-containing compounds and 'others'. Several methods for the analysis of complex data sets of high resolution

SCF(SAP) controls organ size by targeting PPD proteins for degradation in Arabidopsis thaliana.

PubMed

Wang, Zhibiao; Li, Na; Jiang, Shan; Gonzalez, Nathalie; Huang, Xiahe; Wang, Yingchun; Inzé, Dirk; Li, Yunhai

2016-04-06

Control of organ size by cell proliferation and growth is a fundamental process, but the mechanisms that determine the final size of organs are largely elusive in plants. We have previously revealed that the ubiquitin receptor DA1 regulates organ size by repressing cell proliferation in Arabidopsis. Here we report that a mutant allele of STERILE APETALA (SAP) suppresses the da1-1 mutant phenotype. We show that SAP is an F-box protein that forms part of a SKP1/Cullin/F-box E3 ubiquitin ligase complex and controls organ size by promoting the proliferation of meristemoid cells. Genetic analyses suggest that SAP may act in the same pathway with PEAPOD1 and PEAPOD2, which are negative regulators of meristemoid proliferation, to control organ size, but does so independently of DA1. Further results reveal that SAP physically associates with PEAPOD1 and PEAPOD2, and targets them for degradation. These findings define a molecular mechanism by which SAP and PEAPOD control organ size.

A chemodynamic approach for estimating losses of target organic chemicals from water during sample holding time

USGS Publications Warehouse

Capel, P.D.; Larson, S.J.

1995-01-01

Minimizing the loss of target organic chemicals from environmental water samples between the time of sample collection and isolation is important to the integrity of an investigation. During this sample holding time, there is a potential for analyte loss through volatilization from the water to the headspace, sorption to the walls and cap of the sample bottle; and transformation through biotic and/or abiotic reactions. This paper presents a chemodynamic-based, generalized approach to estimate the most probable loss processes for individual target organic chemicals. The basic premise is that the investigator must know which loss process(es) are important for a particular analyte, based on its chemodynamic properties, when choosing the appropriate method(s) to prevent loss.

[Target and non-target screening of volatile organic compounds in industrial exhaust gas using thermal desorption-gas chromatography-mass spectrometry].

PubMed

Ma, Huilian; Jin, Jing; Li, Yun; Chen, Jiping

2017-10-08

A method of comprehensive screening of the target and non-target volatile organic compounds (VOCs) in industrial exhaust gas using thermal desorption-gas chromatography-mass spectrometry (TD-GC-MS) has been developed. In this paper, two types of solid phase adsorption column were compared, and the Tenex SS TD Tube was selected. The analytes were enriched into the adsorption tube by constant flow sampling, and detected by TD-GC-MS in full scan mode. Target compounds were quantified by internal standard method, and the quantities of non-target compounds were calculated by response coefficient of toluene. The method detection limits (MDLs) for the 24 VOCs were 1.06 to 5.44 ng, and MDLs could also be expressed as 0.004 to 0.018 mg/m 3 assuming that the sampling volume was 300 mL. The average recoveries were in the range of 78.4% to 89.4% with the relative standard deviations (RSDs) of 3.9% to 14.4% ( n =7). The established analytical method was applied for the comprehensive screening of VOCs in a waste incineration power plant in Dalian city. Twenty-nine VOCs were identified. In these compounds, only five VOCs were the target compounds set in advance, which accounted for 26.7% of the total VOCs identified. Therefore, this study further proved the importance of screening non-target compounds in the analysis of VOCs in industrial exhaust gas, and has certain reference significance for the complete determination of VOCs distribution.

ASSESSING POSSIBLE ECOLOGICAL RISKS OF GENETICALLY MODIFIED CROPS: GENE EXPRESSION ASSAYS AND GENETIC MONITORING OF NON-TARGET ORGANISMS

EPA Science Inventory

Widespread planting of genetically modified crops with the Bt transgene pesticide has led to concern over non-target effects of Bt compounds in agroecosystems. While some research suggests that non-target organisms exposed to Bt toxin exhibit reduced fecundity and increased morta...

The Genotype of the Donor for the (GT)n Polymorphism in the Promoter/Enhancer of FOXP3 Is Associated with the Development of Severe Acute GVHD but Does Not Affect the GVL Effect after Myeloablative HLA-Identical Allogeneic Stem Cell Transplantation

PubMed Central

Buces, Elena; Pion, Marjorie; Sánchez-Hernández, Noemí; Martín-Antonio, Beatriz; Guillem, Vicent; Bosch-Vizcaya, Anna; Bento, Leyre; González-Rivera, Milagros; Balsalobre, Pascual; Kwon, Mi; Serrano, David; Gayoso, Jorge; de la Cámara, Rafael; Brunet, Salut; Rojas-Contreras, Rafael; Nieto, José B.; Martínez, Carmen; Gónzalez, Marcos; Espigado, Ildefonso; Vallejo, Juan C.; Sampol, Antonia; Jiménez-Velasco, Antonio; Urbano-Ispizua, Alvaro; Solano, Carlos; Gallardo, David; Díez-Martín, José L.; Buño, Ismael

2015-01-01

The FOXP3 gene encodes for a protein (Foxp3) involved in the development and functional activity of regulatory T cells (CD4+/CD25+/Foxp3+), which exert regulatory and suppressive roles over the immune system. After allogeneic stem cell transplantation, regulatory T cells are known to mitigate graft versus host disease while probably maintaining a graft versus leukemia effect. Short alleles (≤(GT)15) for the (GT)n polymorphism in the promoter/enhancer of FOXP3 are associated with a higher expression of FOXP3, and hypothetically with an increase of regulatory T cell activity. This polymorphism has been related to the development of auto- or alloimmune conditions including type 1 diabetes or graft rejection in renal transplant recipients. However, its impact in the allo-transplant setting has not been analyzed. In the present study, which includes 252 myeloablative HLA-identical allo-transplants, multivariate analysis revealed a lower incidence of grade III-IV acute graft versus host disease (GVHD) in patients transplanted from donors harboring short alleles (OR = 0.26, CI 0.08–0.82, p = 0.021); without affecting chronic GVHD or graft versus leukemia effect, since cumulative incidence of relapse, event free survival and overall survival rates are similar in both groups of patients. PMID:26473355

The Genotype of the Donor for the (GT)n Polymorphism in the Promoter/Enhancer of FOXP3 Is Associated with the Development of Severe Acute GVHD but Does Not Affect the GVL Effect after Myeloablative HLA-Identical Allogeneic Stem Cell Transplantation.

PubMed

Noriega, Víctor; Martínez-Laperche, Carolina; Buces, Elena; Pion, Marjorie; Sánchez-Hernández, Noemí; Martín-Antonio, Beatriz; Guillem, Vicent; Bosch-Vizcaya, Anna; Bento, Leyre; González-Rivera, Milagros; Balsalobre, Pascual; Kwon, Mi; Serrano, David; Gayoso, Jorge; de la Cámara, Rafael; Brunet, Salut; Rojas-Contreras, Rafael; Nieto, José B; Martínez, Carmen; Gónzalez, Marcos; Espigado, Ildefonso; Vallejo, Juan C; Sampol, Antonia; Jiménez-Velasco, Antonio; Urbano-Ispizua, Alvaro; Solano, Carlos; Gallardo, David; Díez-Martín, José L; Buño, Ismael

2015-01-01

The FOXP3 gene encodes for a protein (Foxp3) involved in the development and functional activity of regulatory T cells (CD4+/CD25+/Foxp3+), which exert regulatory and suppressive roles over the immune system. After allogeneic stem cell transplantation, regulatory T cells are known to mitigate graft versus host disease while probably maintaining a graft versus leukemia effect. Short alleles (≤(GT)15) for the (GT)n polymorphism in the promoter/enhancer of FOXP3 are associated with a higher expression of FOXP3, and hypothetically with an increase of regulatory T cell activity. This polymorphism has been related to the development of auto- or alloimmune conditions including type 1 diabetes or graft rejection in renal transplant recipients. However, its impact in the allo-transplant setting has not been analyzed. In the present study, which includes 252 myeloablative HLA-identical allo-transplants, multivariate analysis revealed a lower incidence of grade III-IV acute graft versus host disease (GVHD) in patients transplanted from donors harboring short alleles (OR = 0.26, CI 0.08-0.82, p = 0.021); without affecting chronic GVHD or graft versus leukemia effect, since cumulative incidence of relapse, event free survival and overall survival rates are similar in both groups of patients.

Does the achievement of an intermediate glycemic target reduce organ failure and mortality? A post hoc analysis of the Glucontrol trial.

PubMed

Penning, Sophie; Chase, J Geoffrey; Preiser, Jean-Charles; Pretty, Christopher G; Signal, Matthew; Mélot, Christian; Desaive, Thomas

2014-06-01

This research evaluates the impact of the achievement of an intermediate target glycemic band on the severity of organ failure and mortality. Daily Sequential Organ Failure Assessment (SOFA) score and the cumulative time in a 4.0 to 7.0 mmol/L band (cTIB) were evaluated daily up to 14 days in 704 participants of the multicentre Glucontrol trial (16 centers) that randomized patients to intensive group A (blood glucose [BG] target: 4.4-6.1 mmol/L) or conventional group B (BG target: 7.8-10.0 mmol/L). Sequential Organ Failure Assessment evolution was measured by percentage of patients with SOFA less than or equal to 5 on each day, percentage of individual organ failures, and percentage of organ failure-free days. Conditional and joint probability analysis of SOFA and cTIB 0.5 or more assessed the impact of achieving 4.0 to 7.0 mmol/L target glycemic range on organ failure. Odds ratios (OR) compare the odds risk of death for cTIB 0.5 or more vs cTIB less than 0.5, where a ratio greater than 1.0 indicates an improvement for achieving cTIB 0.5 or more independent of SOFA or glycemic target. Groups A and B were matched for demographic and severity of illness data. Blood glucose differed between groups A and B (P<.05), as expected. There was no difference in the percentage of patients with SOFA less than or equal to 5, individual organ failures, and organ failure-free days between groups A and B over days 1 to 14. However, 20% to 30% of group A patients failed to achieve cTIB 0.5 or more for all days, and significant crossover confounds interpretation. Mortality OR was greater than 1.0 for patients with cTIB 0.5 or more in both groups but much higher for group A on all days. There was no difference in organ failure in the Glucontrol study based on intention to treat to different glycemic targets. Actual outcomes and significant crossover indicate that this result may not be due to the difference in target or treatment. Odds ratios-associated achieving an intermediate 4

Solid organ transplants following hematopoietic stem cell transplant in children.

PubMed

Bunin, Nancy; Guzikowski, Virginia; Rand, Elizabeth R; Goldfarb, Samuel; Baluarte, Jorge; Meyers, Kevin; Olthoff, Kim M

2010-12-01

SOT may be indicated for a select group of pediatric patients who experience permanent organ failure following HSCT. However, there is limited information available about outcomes. We identified eight children at our center who received an SOT following an HSCT. Patients were six months to 18 yr at HSCT. Diseases for which children underwent HSCT included thalassemia, Wiskott-Aldrich syndrome, Shwachman-Diamond/bone marrow failure, sickle cell disease (SCD), erythropoietic porphyria (EP), ALL, chronic granulomatous disease, and neuroblastoma. Time from HSCT to SOT was 13 days to seven yr (median, 27 months. Lung SOT was performed for two patients with BO, kidney transplants for three patients, and liver transplants for three patients (VOD, chronic GVHD). Seven patients are alive with functioning allografts 6-180 months from SOT. Advances in organ procurement, operative technique, immunosuppressant therapy, and infection control may allow SOT for a select group of patients post-HSCT. However, scarcity of donor organs available in a timely fashion continues to be a limiting factor. Children who have undergone HSCT and develop single organ failure should be considered for an SOT if there is a high likelihood of cure of the primary disease. © 2010 John Wiley & Sons A/S.

Sequence homology between HLA-bound cytomegalovirus and human peptides: A potential trigger for alloreactivity

PubMed Central

Koparde, Vishal N.; Jameson-Lee, Maximilian; Elnasseh, Abdelrhman G.; Scalora, Allison F.; Kobulnicky, David J.; Serrano, Myrna G.; Roberts, Catherine H.; Buck, Gregory A.; Neale, Michael C.; Nixon, Daniel E.; Toor, Amir A.

2017-01-01

Human cytomegalovirus (hCMV) reactivation may often coincide with the development of graft-versus-host-disease (GVHD) in stem cell transplantation (SCT). Seventy seven SCT donor-recipient pairs (DRP) (HLA matched unrelated donor (MUD), n = 50; matched related donor (MRD), n = 27) underwent whole exome sequencing to identify single nucleotide polymorphisms (SNPs) generating alloreactive peptide libraries for each DRP (9-mer peptide-HLA complexes); Human CMV CROSS (Cross-Reactive Open Source Sequence) database was compiled from NCBI; HLA class I binding affinity for each DRPs HLA was calculated by NetMHCpan 2.8 and hCMV- derived 9-mers algorithmically compared to the alloreactive peptide-HLA complex libraries. Short consecutive (≥6) amino acid (AA) sequence homology matching hCMV to recipient peptides was considered for HLA-bound-peptide (IC50<500nM) cross reactivity. Of the 70,686 hCMV 9-mers contained within the hCMV CROSS database, an average of 29,658 matched the MRD DRP alloreactive peptides and 52,910 matched MUD DRP peptides (p<0.001). In silico analysis revealed multiple high affinity, immunogenic CMV-Human peptide matches (IC50<500 nM) expressed in GVHD-affected tissue-specific manner. hCMV+GVHD was found in 18 patients, 13 developing hCMV viremia before GVHD onset. Analysis of patients with GVHD identified potential cross reactive peptide expression within affected organs. We propose that hCMV peptide sequence homology with human alloreactive peptides may contribute to the pathophysiology of GVHD. PMID:28800601

Sequence homology between HLA-bound cytomegalovirus and human peptides: A potential trigger for alloreactivity.

PubMed

Hall, Charles E; Koparde, Vishal N; Jameson-Lee, Maximilian; Elnasseh, Abdelrhman G; Scalora, Allison F; Kobulnicky, David J; Serrano, Myrna G; Roberts, Catherine H; Buck, Gregory A; Neale, Michael C; Nixon, Daniel E; Toor, Amir A

2017-01-01

Human cytomegalovirus (hCMV) reactivation may often coincide with the development of graft-versus-host-disease (GVHD) in stem cell transplantation (SCT). Seventy seven SCT donor-recipient pairs (DRP) (HLA matched unrelated donor (MUD), n = 50; matched related donor (MRD), n = 27) underwent whole exome sequencing to identify single nucleotide polymorphisms (SNPs) generating alloreactive peptide libraries for each DRP (9-mer peptide-HLA complexes); Human CMV CROSS (Cross-Reactive Open Source Sequence) database was compiled from NCBI; HLA class I binding affinity for each DRPs HLA was calculated by NetMHCpan 2.8 and hCMV- derived 9-mers algorithmically compared to the alloreactive peptide-HLA complex libraries. Short consecutive (≥6) amino acid (AA) sequence homology matching hCMV to recipient peptides was considered for HLA-bound-peptide (IC50<500nM) cross reactivity. Of the 70,686 hCMV 9-mers contained within the hCMV CROSS database, an average of 29,658 matched the MRD DRP alloreactive peptides and 52,910 matched MUD DRP peptides (p<0.001). In silico analysis revealed multiple high affinity, immunogenic CMV-Human peptide matches (IC50<500 nM) expressed in GVHD-affected tissue-specific manner. hCMV+GVHD was found in 18 patients, 13 developing hCMV viremia before GVHD onset. Analysis of patients with GVHD identified potential cross reactive peptide expression within affected organs. We propose that hCMV peptide sequence homology with human alloreactive peptides may contribute to the pathophysiology of GVHD.

Concurrent Hepatic Tuberculosis and Hepatic Graft-versus-host Disease in an Allogeneic Hematopoietic Stem Cell Transplant Recipient: A Case Report.

PubMed

Zhao, Z; Leow, W Q

2017-09-01

Infection and graft-versus-host disease (GVHD) are among the most common complications after hematopoietic stem cell transplantation (HSCT). With well-known risk factors including allogeneic HSCT and GVHD, tuberculosis (TB) has a higher incidence and shorter survival rate in HSCT recipients than in the general population. A 55-year-old Indonesian female with a history of latent TB was found to have acute myeloid leukemia 3 months after allogeneic HSCT. She presented with fever, abdominal pain, and predominant cholestatic-type liver function tests derangement. Computed tomography scans showed a relatively unremarkable liver. Liver biopsy specimens revealed multiple necrotizing granulomas with numerous acid-fast bacilli shown using Ziehl-Neelsen histochemical stain. No fungal organisms are detected by Grocott's methenamine silver and periodic acid-Schiff stains. There was also mild portal hepatitis with prominent bile duct injury and scattered apoptotic bodies, compatible with GVHD. In addition, the patient was also discovered to have cutaneous and intestinal TB as well as cutaneous and colonic GVHD during investigation. She was started on anti-TB treatment and adjusted immunosuppression scheme accordingly. Unfortunately, our patient died of spontaneous intracranial haemorrhage approximately 2 months after the diagnosis of post-transplantation TB and GVHD. We report a case of concurrent hepatic TB and GVHD in an allogeneic HSCT recipient. Recognition of the dual pathology in the biopsy results aids proper treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Treatment with agonistic DR3 antibody results in expansion of donor Tregs and reduced graft-versus-host disease

PubMed Central

Kim, Byung-Su; Nishikii, Hidekazu; Baker, Jeanette; Pierini, Antonio; Schneidawind, Dominik; Pan, Yuqiong; Beilhack, Andreas; Park, Chung-Gyu

2015-01-01

The paucity of regulatory T cells (Tregs) limits clinical translation to control aberrant immune reactions including graft-versus-host disease (GVHD). Recent studies showed that the agonistic antibody to DR3 (αDR3) expanded CD4+FoxP3+ Tregs in vivo. We investigated whether treating donor mice with a single dose of αDR3 could alleviate acute GVHD in a MHC-mismatched bone marrow transplantation model. αDR3 induced selective proliferation of functional Tregs. CD4+ T cells isolated from αDR3-treated mice contained higher numbers of Tregs and were less proliferative to allogeneic stimuli. In vivo GVHD studies confirmed that Tregs from αDR3-treated donors expanded robustly and higher frequencies of Tregs within donor CD4+ T cells were maintained, resulting in improved survival. Conventional T cells derived from αDR3-treated donors showed reduced activation and proliferation. Serum levels of proinflammatory cytokines (IFNγ, IL-1β, and TNFα) and infiltration of donor T cells into GVHD target tissues (gastrointestinal tract and liver) were decreased. T cells from αDR3-treated donors retained graft-vs-tumor (GVT) effects. In conclusion, a single dose of αDR3 alleviates acute GVHD while preserving GVT effects by selectively expanding and maintaining donor Tregs. This novel strategy will facilitate the clinical application of Treg-based therapies. PMID:26063163

Target Organ Metabolism, Toxicity, and Mechanisms of Trichloroethylene and Perchloroethylene: Key Similarities, Differences, and Data Gaps

PubMed Central

Cichocki, Joseph A.; Guyton, Kathryn Z.; Guha, Neela; Chiu, Weihsueh A.

2016-01-01

Trichloroethylene (TCE) and perchloroethylene or tetrachloroethylene (PCE) are high–production volume chemicals with numerous industrial applications. As a consequence of their widespread use, these chemicals are ubiquitous environmental contaminants to which the general population is commonly exposed. It is widely assumed that TCE and PCE are toxicologically similar; both are simple olefins with three (TCE) or four (PCE) chlorines. Nonetheless, despite decades of research on the adverse health effects of TCE or PCE, few studies have directly compared these two toxicants. Although the metabolic pathways are qualitatively similar, quantitative differences in the flux and yield of metabolites exist. Recent human health assessments have uncovered some overlap in target organs that are affected by exposure to TCE or PCE, and divergent species- and sex-specificity with regard to cancer and noncancer hazards. The objective of this minireview is to highlight key similarities, differences, and data gaps in target organ metabolism and mechanism of toxicity. The main anticipated outcome of this review is to encourage research to 1) directly compare the responses to TCE and PCE using more sensitive biochemical techniques and robust statistical comparisons; 2) more closely examine interindividual variability in the relationship between toxicokinetics and toxicodynamics for TCE and PCE; 3) elucidate the effect of coexposure to these two toxicants; and 4) explore new mechanisms for target organ toxicity associated with TCE and/or PCE exposure. PMID:27511820

Can eHealth tools enable health organizations to reach their target audience?

PubMed

Zbib, Ahmad; Hodgson, Corinne; Calderwood, Sarah

2011-01-01

Data from the health risk assessment operated by the Heart and Stroke Foundation found users were more likely to be female; married; have completed post secondary education; and report hypertension, stroke, or being overweight or obese. In developing and operating eHealth tools for health promotion, organizations should compare users to their target population(s). eHealth tools may not be optimal for reaching some higher-risk sub-groups, and a range of social marketing approaches may be required.

Enantioselective Effects of Chiral Pesticides on their Primary Targets and Secondary Targets.

PubMed

Yang, Ye; Zhang, Jianyun; Yao, Yijun

2017-01-01

Enantioselectivity has been well recognized in the environmental fate and effects of chiral pesticides. Enantiospecific action of the optical enantiomers on the biological molecules establishes the mechanistic basis for the enantioselective toxicity of chiral pesticides to both target and non-target organisms. We undertook a structured search of bibliographic databases for research literature concerning the enantioselective effects of chiral pesticides, including insecticides, herbicides and fungicides, on biomolecules in various species by using some key words. The results of the relevant literatures were reviewed in the text and summarized in tables. Pesticides generally exert their activity on the target organisms via disrupting the primary target biomolecules. In non-target species, effects of pesticides on the secondary targets distinguished from the primary ones make great contribution to their toxicity. Recent investigations have provided convincing evidence of enantioselective toxicity of chiral pesticides to both target and non-target species which is recognized to result from their enantiospecific action on the primary or secondary targets in organisms. This review confirms that chiral pesticides have enantiospecific effects on both primary and secondary target biomolecules in organisms. Future studies regarding toxicological effects of chiral pesticides should focus on the relationship between the enantiomeric difference in the compound-biomolecules interaction and the enantioselectivity in their toxicity.

The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals.

PubMed

Ehret, Georg B; Ferreira, Teresa; Chasman, Daniel I; Jackson, Anne U; Schmidt, Ellen M; Johnson, Toby; Thorleifsson, Gudmar; Luan, Jian'an; Donnelly, Lousie A; Kanoni, Stavroula; Petersen, Ann-Kristin; Pihur, Vasyl; Strawbridge, Rona J; Shungin, Dmitry; Hughes, Maria F; Meirelles, Osorio; Kaakinen, Marika; Bouatia-Naji, Nabila; Kristiansson, Kati; Shah, Sonia; Kleber, Marcus E; Guo, Xiuqing; Lyytikäinen, Leo-Pekka; Fava, Cristiano; Eriksson, Niclas; Nolte, Ilja M; Magnusson, Patrik K; Salfati, Elias L; Rallidis, Loukianos S; Theusch, Elizabeth; Smith, Andrew J P; Folkersen, Lasse; Witkowska, Kate; Pers, Tune H; Joehanes, Roby; Kim, Stuart K; Lataniotis, Lazaros; Jansen, Rick; Johnson, Andrew D; Warren, Helen; Kim, Young Jin; Zhao, Wei; Wu, Ying; Tayo, Bamidele O; Bochud, Murielle; Absher, Devin; Adair, Linda S; Amin, Najaf; Arking, Dan E; Axelsson, Tomas; Baldassarre, Damiano; Balkau, Beverley; Bandinelli, Stefania; Barnes, Michael R; Barroso, Inês; Bevan, Stephen; Bis, Joshua C; Bjornsdottir, Gyda; Boehnke, Michael; Boerwinkle, Eric; Bonnycastle, Lori L; Boomsma, Dorret I; Bornstein, Stefan R; Brown, Morris J; Burnier, Michel; Cabrera, Claudia P; Chambers, John C; Chang, I-Shou; Cheng, Ching-Yu; Chines, Peter S; Chung, Ren-Hua; Collins, Francis S; Connell, John M; Döring, Angela; Dallongeville, Jean; Danesh, John; de Faire, Ulf; Delgado, Graciela; Dominiczak, Anna F; Doney, Alex S F; Drenos, Fotios; Edkins, Sarah; Eicher, John D; Elosua, Roberto; Enroth, Stefan; Erdmann, Jeanette; Eriksson, Per; Esko, Tonu; Evangelou, Evangelos; Evans, Alun; Fall, Tove; Farrall, Martin; Felix, Janine F; Ferrières, Jean; Ferrucci, Luigi; Fornage, Myriam; Forrester, Terrence; Franceschini, Nora; Duran, Oscar H Franco; Franco-Cereceda, Anders; Fraser, Ross M; Ganesh, Santhi K; Gao, He; Gertow, Karl; Gianfagna, Francesco; Gigante, Bruna; Giulianini, Franco; Goel, Anuj; Goodall, Alison H; Goodarzi, Mark O; Gorski, Mathias; Gräßler, Jürgen; Groves, Christopher; Gudnason, Vilmundur; Gyllensten, Ulf; Hallmans, Göran; Hartikainen, Anna-Liisa; Hassinen, Maija; Havulinna, Aki S; Hayward, Caroline; Hercberg, Serge; Herzig, Karl-Heinz; Hicks, Andrew A; Hingorani, Aroon D; Hirschhorn, Joel N; Hofman, Albert; Holmen, Jostein; Holmen, Oddgeir Lingaas; Hottenga, Jouke-Jan; Howard, Phil; Hsiung, Chao A; Hunt, Steven C; Ikram, M Arfan; Illig, Thomas; Iribarren, Carlos; Jensen, Richard A; Kähönen, Mika; Kang, Hyun; Kathiresan, Sekar; Keating, Brendan J; Khaw, Kay-Tee; Kim, Yun Kyoung; Kim, Eric; Kivimaki, Mika; Klopp, Norman; Kolovou, Genovefa; Komulainen, Pirjo; Kooner, Jaspal S; Kosova, Gulum; Krauss, Ronald M; Kuh, Diana; Kutalik, Zoltan; Kuusisto, Johanna; Kvaløy, Kirsti; Lakka, Timo A; Lee, Nanette R; Lee, I-Te; Lee, Wen-Jane; Levy, Daniel; Li, Xiaohui; Liang, Kae-Woei; Lin, Honghuang; Lin, Li; Lindström, Jaana; Lobbens, Stéphane; Männistö, Satu; Müller, Gabriele; Müller-Nurasyid, Martina; Mach, François; Markus, Hugh S; Marouli, Eirini; McCarthy, Mark I; McKenzie, Colin A; Meneton, Pierre; Menni, Cristina; Metspalu, Andres; Mijatovic, Vladan; Moilanen, Leena; Montasser, May E; Morris, Andrew D; Morrison, Alanna C; Mulas, Antonella; Nagaraja, Ramaiah; Narisu, Narisu; Nikus, Kjell; O'Donnell, Christopher J; O'Reilly, Paul F; Ong, Ken K; Paccaud, Fred; Palmer, Cameron D; Parsa, Afshin; Pedersen, Nancy L; Penninx, Brenda W; Perola, Markus; Peters, Annette; Poulter, Neil; Pramstaller, Peter P; Psaty, Bruce M; Quertermous, Thomas; Rao, Dabeeru C; Rasheed, Asif; Rayner, N William N W R; Renström, Frida; Rettig, Rainer; Rice, Kenneth M; Roberts, Robert; Rose, Lynda M; Rossouw, Jacques; Samani, Nilesh J; Sanna, Serena; Saramies, Jouko; Schunkert, Heribert; Sebert, Sylvain; Sheu, Wayne H-H; Shin, Young-Ah; Sim, Xueling; Smit, Johannes H; Smith, Albert V; Sosa, Maria X; Spector, Tim D; Stančáková, Alena; Stanton, Alice; Stirrups, Kathleen E; Stringham, Heather M; Sundstrom, Johan; Swift, Amy J; Syvänen, Ann-Christine; Tai, E-Shyong; Tanaka, Toshiko; Tarasov, Kirill V; Teumer, Alexander; Thorsteinsdottir, Unnur; Tobin, Martin D; Tremoli, Elena; Uitterlinden, Andre G; Uusitupa, Matti; Vaez, Ahmad; Vaidya, Dhananjay; van Duijn, Cornelia M; van Iperen, Erik P A; Vasan, Ramachandran S; Verwoert, Germaine C; Virtamo, Jarmo; Vitart, Veronique; Voight, Benjamin F; Vollenweider, Peter; Wagner, Aline; Wain, Louise V; Wareham, Nicholas J; Watkins, Hugh; Weder, Alan B; Westra, Harm-Jan; Wilks, Rainford; Wilsgaard, Tom; Wilson, James F; Wong, Tien Y; Yang, Tsun-Po; Yao, Jie; Yengo, Loic; Zhang, Weihua; Zhao, Jing Hua; Zhu, Xiaofeng; Bovet, Pascal; Cooper, Richard S; Mohlke, Karen L; Saleheen, Danish; Lee, Jong-Young; Elliott, Paul; Gierman, Hinco J; Willer, Cristen J; Franke, Lude; Hovingh, G Kees; Taylor, Kent D; Dedoussis, George; Sever, Peter; Wong, Andrew; Lind, Lars; Assimes, Themistocles L; Njølstad, Inger; Schwarz, Peter Eh; Langenberg, Claudia; Snieder, Harold; Caulfield, Mark J; Melander, Olle; Laakso, Markku; Saltevo, Juha; Rauramaa, Rainer; Tuomilehto, Jaakko; Ingelsson, Erik; Lehtimäki, Terho; Hveem, Kristian; Palmas, Walter; März, Winfried; Kumari, Meena; Salomaa, Veikko; Chen, Yii-Der I; Rotter, Jerome I; Froguel, Philippe; Jarvelin, Marjo-Riitta; Lakatta, Edward G; Kuulasmaa, Kari; Franks, Paul W; Hamsten, Anders; Wichmann, H-Erich; Palmer, Colin N A; Stefansson, Kari; Ridker, Paul M; Loos, Ruth J F; Chakravarti, Aravinda; Deloukas, Panos; Morris, Andrew P; Newton-Cheh, Christopher; Munroe, Patricia B

2016-10-01

To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.

The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

PubMed Central

Chasman, Daniel I.; Jackson, Anne U.; Schmidt, Ellen M.; Johnson, Toby; Thorleifsson, Gudmar; Luan, Jian'an; Donnelly, Lousie A.; Kanoni, Stavroula; Petersen, Ann-Kristin; Pihur, Vasyl; Strawbridge, Rona J.; Shungin, Dmitry; Hughes, Maria F.; Meirelles, Osorio; Kaakinen, Marika; Bouatia-Naji, Nabila; Kristiansson, Kati; Shah, Sonia; Kleber, Marcus E.; Guo, Xiuqing; Lyytikäinen, Leo-Pekka; Fava, Cristiano; Eriksson, Niclas; Nolte, Ilja M.; Magnusson, Patrik K.; Salfati, Elias L.; Rallidis, Loukianos S.; Theusch, Elizabeth; Smith, Andrew J.P.; Folkersen, Lasse; Witkowska, Kate; Pers, Tune H.; Joehanes, Roby; Kim, Stuart K.; Lataniotis, Lazaros; Jansen, Rick; Johnson, Andrew D.; Warren, Helen; Kim, Young Jin; Zhao, Wei; Wu, Ying; Tayo, Bamidele O.; Bochud, Murielle; Absher, Devin; Adair, Linda S.; Amin, Najaf; Arking, Dan E.; Axelsson, Tomas; Baldassarre, Damiano; Balkau, Beverley; Bandinelli, Stefania; Barnes, Michael R.; Barroso, Inês; Bevan, Stephen; Bis, Joshua C.; Bjornsdottir, Gyda; Boehnke, Michael; Boerwinkle, Eric; Bonnycastle, Lori L.; Boomsma, Dorret I.; Bornstein, Stefan R.; Brown, Morris J.; Burnier, Michel; Cabrera, Claudia P.; Chambers, John C.; Chang, I-Shou; Cheng, Ching-Yu; Chines, Peter S.; Chung, Ren-Hua; Collins, Francis S.; Connell, John M.; Döring, Angela; Dallongeville, Jean; Danesh, John; de Faire, Ulf; Delgado, Graciela; Dominiczak, Anna F.; Doney, Alex S.F.; Drenos, Fotios; Edkins, Sarah; Eicher, John D.; Elosua, Roberto; Enroth, Stefan; Erdmann, Jeanette; Eriksson, Per; Esko, Tonu; Evangelou, Evangelos; Evans, Alun; Fall, Tove; Farrall, Martin; Felix, Janine F.; Ferrières, Jean; Ferrucci, Luigi; Fornage, Myriam; Forrester, Terrence; Franceschini, Nora; Duran, Oscar H. Franco; Franco-Cereceda, Anders; Fraser, Ross M.; Ganesh, Santhi K.; Gao, He; Gertow, Karl; Gianfagna, Francesco; Gigante, Bruna; Giulianini, Franco; Goel, Anuj; Goodall, Alison H.; Goodarzi, Mark O.; Gorski, Mathias; Gräßler, Jürgen; Groves, Christopher; Gudnason, Vilmundur; Gyllensten, Ulf; Hallmans, Göran; Hartikainen, Anna-Liisa; Hassinen, Maija; Havulinna, Aki S.; Hayward, Caroline; Hercberg, Serge; Herzig, Karl-Heinz; Hicks, Andrew A.; Hingorani, Aroon D.; Hirschhorn, Joel N.; Hofman, Albert; Holmen, Jostein; Holmen, Oddgeir Lingaas; Hottenga, Jouke-Jan; Howard, Phil; Hsiung, Chao A.; Hunt, Steven C.; Ikram, M. Arfan; Illig, Thomas; Iribarren, Carlos; Jensen, Richard A.; Kähönen, Mika; Kang, Hyun; Kathiresan, Sekar; Keating, Brendan J.; Khaw, Kay-Tee; Kim, Yun Kyoung; Kim, Eric; Kivimaki, Mika; Klopp, Norman; Kolovou, Genovefa; Komulainen, Pirjo; Kooner, Jaspal S.; Kosova, Gulum; Krauss, Ronald M.; Kuh, Diana; Kutalik, Zoltan; Kuusisto, Johanna; Kvaløy, Kirsti; Lakka, Timo A; Lee, Nanette R.; Lee, I-Te; Lee, Wen-Jane; Levy, Daniel; Li, Xiaohui; Liang, Kae-Woei; Lin, Honghuang; Lin, Li; Lindström, Jaana; Lobbens, Stéphane; Männistö, Satu; Müller, Gabriele; Müller-Nurasyid, Martina; Mach, François; Markus, Hugh S.; Marouli, Eirini; McCarthy, Mark I.; McKenzie, Colin A.; Meneton, Pierre; Menni, Cristina; Metspalu, Andres; Mijatovic, Vladan; Moilanen, Leena; Montasser, May E.; Morris, Andrew D.; Morrison, Alanna C.; Mulas, Antonella; Nagaraja, Ramaiah; Narisu, Narisu; Nikus, Kjell; O'Donnell, Christopher J.; O'Reilly, Paul F.; Ong, Ken K.; Paccaud, Fred; Palmer, Cameron D.; Parsa, Afshin; Pedersen, Nancy L.; Penninx, Brenda W.; Perola, Markus; Peters, Annette; Poulter, Neil; Pramstaller, Peter P.; Psaty, Bruce M.; Quertermous, Thomas; Rao, Dabeeru C.; Rasheed, Asif; Rayner, N William N.W.R.; Renström, Frida; Rettig, Rainer; Rice, Kenneth M.; Roberts, Robert; Rose, Lynda M.; Rossouw, Jacques; Samani, Nilesh J.; Sanna, Serena; Saramies, Jouko; Schunkert, Heribert; Sebert, Sylvain; Sheu, Wayne H.-H.; Shin, Young-Ah; Sim, Xueling; Smit, Johannes H.; Smith, Albert V.; Sosa, Maria X.; Spector, Tim D.; Stančáková, Alena; Stanton, Alice; Stirrups, Kathleen E.; Stringham, Heather M.; Sundstrom, Johan; Swift, Amy J.; Syvänen, Ann-Christine; Tai, E-Shyong; Tanaka, Toshiko; Tarasov, Kirill V.; Teumer, Alexander; Thorsteinsdottir, Unnur; Tobin, Martin D.; Tremoli, Elena; Uitterlinden, Andre G.; Uusitupa, Matti; Vaez, Ahmad; Vaidya, Dhananjay; van Duijn, Cornelia M.; van Iperen, Erik P.A.; Vasan, Ramachandran S.; Verwoert, Germaine C.; Virtamo, Jarmo; Vitart, Veronique; Voight, Benjamin F.; Vollenweider, Peter; Wagner, Aline; Wain, Louise V.; Wareham, Nicholas J.; Watkins, Hugh; Weder, Alan B.; Westra, Harm-Jan; Wilks, Rainford; Wilsgaard, Tom; Wilson, James F.; Wong, Tien Y.; Yang, Tsun-Po; Yao, Jie; Yengo, Loic; Zhang, Weihua; Zhao, Jing Hua; Zhu, Xiaofeng; Bovet, Pascal; Cooper, Richard S.; Mohlke, Karen L.; Saleheen, Danish; Lee, Jong-Young; Elliott, Paul; Gierman, Hinco J.; Willer, Cristen J.; Franke, Lude; Hovingh, G Kees; Taylor, Kent D.; Dedoussis, George; Sever, Peter; Wong, Andrew; Lind, Lars; Assimes, Themistocles L.; Njølstad, Inger; Schwarz, Peter EH.; Langenberg, Claudia; Snieder, Harold; Caulfield, Mark J.; Melander, Olle; Laakso, Markku; Saltevo, Juha; Rauramaa, Rainer; Tuomilehto, Jaakko; Ingelsson, Erik; Lehtimäki, Terho; Hveem, Kristian; Palmas, Walter; März, Winfried; Kumari, Meena; Salomaa, Veikko; Chen, Yii-Der I.; Rotter, Jerome I.; Froguel, Philippe; Jarvelin, Marjo-Riitta; Lakatta, Edward G.; Kuulasmaa, Kari; Franks, Paul W.; Hamsten, Anders; Wichmann, H.-Erich; Palmer, Colin N.A.; Stefansson, Kari; Ridker, Paul M; Loos, Ruth J.F.; Chakravarti, Aravinda; Deloukas, Panos; Morris, Andrew P.; Newton-Cheh, Christopher; Munroe, Patricia B.

2016-01-01

To dissect the genetic architecture of blood pressure and assess effects on target-organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure loci, of which 17 were novel and 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our findings expand current knowledge of blood pressure pathways and highlight tissues beyond the classic renal system in blood pressure regulation. PMID:27618452

Targeting nursing homes under the Quality Improvement Organization program's 9th statement of work.

PubMed

Stevenson, David G; Mor, Vincent

2009-09-01

In the Quality Improvement Organization (QIO) program's latest Statement of Work, the Centers for Medicare and Medicaid Services (CMS) is targeting its nursing home activities toward facilities that perform poorly on two quality measures-pressure ulcers and restraint use. The designation of target facilities is a shift in strategy for CMS and a direct response to criticism that QIO program resources were not being targeted effectively to facilities or clinical areas that most needed improvement. Using administrative data, this article analyzes implications of using narrowly defined criteria to identify facilities that need improvement, particularly in light of considerable evidence showing that nursing home quality is multidimensional and may change over time. The analyses show that one in four facilities is targeted for improvement nationally but that approximately half of some states' facilities are targeted while other states have almost none targeted. The analyses also convey deeper limitations to using threshold values on individual measures to identify poorly performing homes. Target facilities can be among the top performers on a range of other quality measures, and their performance on targeted measures themselves may change over time. The implication of these features is that a very different group of facilities would have been chosen had the QIO program targeted other measures or examined performance at a different point in time. Ultimately, CMS has chosen a blunt instrument to identify poorly performing nursing homes, and supplemental strategies-such as soliciting input from state survey agencies and more closely aligning quality improvement and quality assurance efforts-should be considered to address potential limitations.

Extracorporeal photopheresis for graft-versus-host disease: the role of patient, transplant, and classification criteria and hematologic values on outcome-results from a large single-center study.

PubMed

Berger, Massimo; Albiani, Roberto; Sini, Bruno; Fagioli, Franca

2015-04-01

Extracorporeal photopheresis (ECP) has been shown as active therapy for graft-versus-host disease (GVHD). The aim was to ascertain the role of ECP in 71 patients with steroid-refractory or -dependent acute and chronic GVHD (aGVHD and cGVHD) with special focus on hematologic variables and GVHD staging classification. A total of 34 patients were treated for aGVHD and 37 for cGVHD. The overall response rate (ORR) for aGVHD was 65% and the complete aGVHD-free survival was 50% (95% confidence interval [CI], 36%-70%). The ORR for cGVHD response was 81% while the complete cGVHD-free survival was 50% (95% CI, 34%-73%). The aGVHD-free survival was associated with aGVHD grading (Grade II 81%, Grade III 33%, and Grade IV 0%, p ≤ 0.00) and the absence of visceral involvement (77% vs. 33%, p = 0.03). The cGVHD-free survival was associated with the female sex (67% vs. 25%, p = 0.01) and with the limited form according to the Seattle classification (67% vs. 20%, p = 0.003). No role for hematologic values or apheresis cell count was found, except for the cGVHD ORR (p = 0.037). Transplant-related mortality and overall survival were associated with ECP response 0% versus 54% (p = 0.0001) and 77% versus 45% (p = 0.03) for aGVHD patients and 7% versus 14% (p = 0.02) and 73% versus 20% (p = 0.0003) for cGVHD patients, respectively. While confirming a higher probability of GVHD responses for early GVHD, our study shows no role of hematologic values or apheresis cell count on GVHD response. © 2014 The Authors. Transfusion published by Wiley Periodicals, Inc. on behalf of AABB.

Significantly worse survival of patients with NIH-defined chronic graft-versus-host disease and thrombocytopenia or progressive onset type: results of a prospective study.

PubMed

Kuzmina, Z; Eder, S; Böhm, A; Pernicka, E; Vormittag, L; Kalhs, P; Petkov, V; Stary, G; Nepp, J; Knobler, R; Just, U; Krenn, K; Worel, N; Greinix, H T

2012-04-01

Chronic graft-versus-host disease (GVHD) remains a serious complication after allogeneic hematopoietic stem cell transplantation (HCT). In 2005 the National Institutes of Health (NIH) established new criteria for chronic GVHD based on retrospective data and expert recommendations. We prospectively evaluated the incidence of NIH-defined chronic GVHD and its prognostic impact in 178 consecutive patients. The cumulative incidence of chronic GVHD at 3 years was 64, 48 and 16% for chronic classic GVHD and overlap syndrome. Prior acute GVHD and myeloablative conditioning were significantly associated with increased risk of chronic GVHD. Three-year survival (overall survival (OS)) for late-acute GVHD, chronic classic and overlap chronic GVHD when assigned on day 100 were 69, 83 and 73%. OS was significantly worse for patients with platelet counts below 100 g/l at onset of chronic GVHD (35% versus 86%, P<0.0001) and progressive as compared with de novo and quiescent onset of chronic GVHD (54.5% versus 89.5% versus 84%, P = 0.022 and 0.001). Peak severity of chronic GVHD had no impact on non-relapse mortality (NRM) and OS. Recurrent acute GVHD, platelet counts below 100 g/l at diagnosis of chronic GVHD, progressive onset of chronic GVHD and advanced disease stage prior to HCT were significantly associated with increased NRM. This prospective analysis provides for the first-time data on the incidence rates of NIH-defined chronic GVHD categories and identified risk factors for the occurrence of chronic GVHD. A prognostic value of thrombocytopenia and progressive onset type of chronic GVHD for survival after HCT was observed in NIH-defined chronic GVHD.

EFFECT OF NON-TARGET ORGANICS ON ORGANIC CHEMICAL TRANSPORT

EPA Science Inventory

To improve our standard of living, man has synthesized organic compounds for use in products considered essential for life. These compounds are having and will continue to have a significant impact on the terrestrial environment. Understanding organic chemical transport through s...

Mismatched HLA-DRB3 Can Induce a Potent Immune Response After HLA 10/10 Matched Stem Cell Transplantation.

PubMed

van Balen, Peter; van Luxemburg-Heijs, Simone A P; van de Meent, Marian; van Bergen, Cornelis A M; Halkes, Constantijn J M; Jedema, Inge; Falkenburg, J H Frederik

2017-12-01

Donors for allogeneic stem cell transplantation are preferentially matched with patients for HLA-A, -B, -C, and -DRB1. Mismatches between donor and patient in these alleles are associated with an increased risk of graft-versus-host disease (GVHD). In contrast, HLA-DRB3, 4 and 5, HLA-DQ and HLA-DP are usually assumed to be low expression loci with limited relevance, although mismatches in HLA-DQ and HLA-DP can result in alloimmune responses. Mismatches in HLA-DRB3, 4, and 5 are usually not taken into account in donor selection. Conversion of chimerism in the presence of GVHD after CD4 donor lymphocyte infusion was observed in a patient, HLA 10/10 matched, but mismatched for HLA-DRB3 and HLA-DPB1 compared with the donor. Alloreactive CD4 T cells were isolated from peripheral blood after CD4 donor lymphocyte infusion and recognition of donor-derived target cells transduced with the mismatched patient variant HLA-DRB3 and HLA-DPB1 molecule was tested. A dominant polyclonal CD4 T cell response against patient's mismatched HLA-DRB3 molecule was found in addition to an immune response against patient's mismatched HLA-DPB1 molecule. CD4 T cells specific for these HLA class II molecules recognized both hematopoietic target cells as well as GVHD target cells. In contrast to the assumption that mismatches in HLA-DRB3, 4, and 5 are not of immunogenic significance after HLA 10/10 matched allogeneic stem cell transplantation, we show that in this matched setting not only mismatches in HLA-DPB1, but also mismatches in HLA-DRB3 may induce a polyclonal allo-immune response associated with conversion of chimerism and severe GVHD.

Consensus on performing skin biopsies, laboratory workup, evaluation of tissue samples and reporting of the results in patients with suspected cutaneous graft-versus-host disease.

PubMed

Hillen, U; Häusermann, P; Massi, D; Janin, A; Wolff, D; Lawitschka, A; Greinix, H; Meyer, R; Ziemer, M

2015-05-01

Histopathological diagnosis including selection of lesions, the determination of the best point of time for biopsy and workup is not trivial in cutaneous graft-versus-host disease (GvHD). To develop interdisciplinary recommendations on performing, the laboratory work up and reporting of the results of skin biopsies in patients with suspected cutaneous GvHD. A working group consisting of dermatopathologists, dermatologists, transplant-physicians and transplant-pathologists prepared recommendations for performing skin biopsies, laboratory workup and evaluation of tissue samples, and reporting of the results in patients with cutaneous GvHD. After achieving a consensus within the working group, a survey that comprised the core issues of the recommendations was electronically sent out to 72 alloHSCT centres within Germany, Austria, and Switzerland and their Departments of Pathology. The answers were discussed in a Consensus Conference and final recommendations were established. Twenty-five centres responded to the clinical and 17 centres to the histopathological survey. Questions addressed to the clinicians comprised the indication for skin biopsy in chronic GvHD (cGvHD) and acute GvHD (aGvHD) and the appropriate point of time for skin biopsy. Eighty-eight per cent agreed that the skin biopsy is generally indicated in patients with suspected cGvHD lacking diagnostic features. In contrast, with suspected aGvHD, only 62% of respondents felt that skin biopsy was necessary even if GvHD had not been confirmed in another organ. Although restricted due to the fact that immunosuppression is often applied in an emergency setting most centres supported skin biopsies before initiation of topical or systemic immunosuppression. The majority of pathologists agreed that in non-sclerotic GvHD a punch biopsy is adequate, whereas in sclerotic GvHD a scalpel biopsy is preferred. While a consensus on the need for biopsies in cGvHD was reached the value of skin biopsies in aGvHD and

Target Organ Metabolism, Toxicity, and Mechanisms of Trichloroethylene and Perchloroethylene: Key Similarities, Differences, and Data Gaps.

PubMed

Cichocki, Joseph A; Guyton, Kathryn Z; Guha, Neela; Chiu, Weihsueh A; Rusyn, Ivan; Lash, Lawrence H

2016-10-01

Trichloroethylene (TCE) and perchloroethylene or tetrachloroethylene (PCE) are high-production volume chemicals with numerous industrial applications. As a consequence of their widespread use, these chemicals are ubiquitous environmental contaminants to which the general population is commonly exposed. It is widely assumed that TCE and PCE are toxicologically similar; both are simple olefins with three (TCE) or four (PCE) chlorines. Nonetheless, despite decades of research on the adverse health effects of TCE or PCE, few studies have directly compared these two toxicants. Although the metabolic pathways are qualitatively similar, quantitative differences in the flux and yield of metabolites exist. Recent human health assessments have uncovered some overlap in target organs that are affected by exposure to TCE or PCE, and divergent species- and sex-specificity with regard to cancer and noncancer hazards. The objective of this minireview is to highlight key similarities, differences, and data gaps in target organ metabolism and mechanism of toxicity. The main anticipated outcome of this review is to encourage research to 1) directly compare the responses to TCE and PCE using more sensitive biochemical techniques and robust statistical comparisons; 2) more closely examine interindividual variability in the relationship between toxicokinetics and toxicodynamics for TCE and PCE; 3) elucidate the effect of coexposure to these two toxicants; and 4) explore new mechanisms for target organ toxicity associated with TCE and/or PCE exposure. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Tracking targeted bimodal nanovaccines: immune responses and routing in cells, tissue, and whole organism.

PubMed

Cruz, Luis J; Tacken, Paul J; Zeelenberg, Ingrid S; Srinivas, Mangala; Bonetto, Fernando; Weigelin, Bettina; Eich, Christina; de Vries, I Jolanda; Figdor, Carl G

2014-12-01

Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs), involved in the induction of immunity and currently exploited for antitumor immunotherapies. An optimized noninvasive imaging modality capable of determining and quantifying DC-targeted nanoparticle (NP) trajectories could provide valuable information regarding therapeutic vaccine outcome. Here, targeted poly(d,l-lactide-co-glycolide) nanoparticles (PLGA NPs) recognizing DC receptors were equipped with superparamagnetic iron oxide particles (SPIO) or gold nanoparticles with fluorescently labeled antigen. The fluorescent label allowed for rapid analysis and quantification of DC-specific uptake of targeted PLGA NPs in comparison to uptake by other cells. Transmission electron microscopy (TEM) showed that a fraction of the encapsulated antigen reached the lysosomal compartment of DCs, where SPIO and gold were already partially released. However, part of the PLGA NPs localized within the cytoplasm, as confirmed by confocal microscopy. DCs targeted with NPs carrying SPIO or fluorescent antigen were detected within lymph nodes as early as 1 h after injection by magnetic resonance imaging (MRI). Despite the fact that targeting did not markedly affect PLGA NP biodistribution on organism and tissue level, it increased delivery of NPs to DCs residing in peripheral lymph nodes and resulted in enhanced T cell proliferation. In conclusion, two imaging agents within a single carrier allows tracking of targeted PLGA NPs at the subcellular, cellular, and organismal levels, thereby facilitating the rational design of in vivo targeted vaccination strategies.

Synthetic lipid nanoparticles targeting steroid organs.

PubMed

Mérian, Juliette; Boisgard, Raphaël; Decleves, Xavier; Thezé, Benoît; Texier, Isabelle; Tavitian, Bertrand

2013-11-01

Lipidots are original nanoparticulate lipid delivery vectors for drugs and contrast agents made from materials generally regarded as safe. Here, we characterized the in vivo stability, biodistribution, and pharmacokinetics of lipidots. Lipidots 55 nm in diameter and coated with a phospholipid/poly(ethyleneglycol) surfactant shell were triply labeled with (3)H-cholesteryl-hexadecyl-ether, cholesteryl-(14)C-oleate, and the 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine infrared fluorescent dye and injected intravenously into immunocompetent Friend virus B-type mice. The pharmacokinetics and biodistribution of lipidots were analyzed quantitatively in serial samples of blood and tissue and with in vivo optical imaging and were refined by microscopic examination of selected target tissues. The plasmatic half-life of lipidots was approximately 30 min. Radioactive and fluorescent tracers displayed a similar nanoparticle-driven biodistribution, indicative of the lipidots' integrity during the first hours after injection. Lipidots distributed in the liver and, surprisingly, in the steroid-rich organs adrenals and ovaries, but not in the spleen. This tropism was confirmed at the microscopic level by histologic detection of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine. Nanoparticle loading with cholesterol derivatives increased accumulation in ovaries in a dose-dependent manner. This previously unreported distribution pattern is specific to lipidots and attributed to their nanometric size and composition, conferring on them a lipoproteinlike behavior. The affinity of lipidots for steroid hormone-rich areas is of interest to address drugs and contrast agents to lipoprotein-receptor-overexpressing cancer cells found in hormone-dependent tumors.

ST2 blockade reduces sST2-producing T cells while maintaining protective mST2-expressing T cells during graft-versus-host disease

PubMed Central

Zhang, Jilu; Ramadan, Abdulraouf M.; Griesenauer, Brad; Li, Wei; Turner, Matthew J.; Liu, Chen; Kapur, Reuben; Hanenberg, Helmut; Blazar, Bruce R.; Tawara, Isao; Paczesny, Sophie

2015-01-01

Graft-versus-host disease (GVHD) remains a devastating complication after allogeneic hematopoietic cell transplantation (HCT). We previously identified high plasma soluble suppression of tumorigenicity 2 (sST2) as a biomarker of the development of GVHD and death. sST2 sequesters interleukin (IL)-33, limiting its availability to T cells expressing membrane-bound ST2 (mST2) [Th2 cells and ST2+FoxP3+regulatory T cells]. Here, we report that blockade of sST2 in the peri-transplant period with a neutralizing monoclonal antibody (anti-ST2 mAb) reduced GVHD severity and mortality. We identified intestinal stromal cells and T cells as major sources of sST2 during GVHD. ST2 blockade decreased systemic interferon-γ, IL-17, and IL-23 but increased IL-10 and IL-33 plasma levels. ST2 blockade also reduced sST2 production by IL-17–producing T cells while maintaining protective mST2-expressing T cells, increasing the frequency of intestinal myeloid-derived suppressor cells, and decreasing frequency of intestinal CD103 dendritic cells. Finally, ST2 blockade preserved graft-versus-leukemia activity in a model of GFP+MLL-AF9 acute myeloid leukemia. Our findings suggest that ST2 is a therapeutic target for severe GVHD, and that the ST2/IL-33 pathway could be investigated in other T-cell mediated immune disorders with loss of tolerance. PMID:26446957

[Prevalence of target organ damage in patients treated for primary arterial hypertension: Comparison between men and women. ESSENTIELLE study].

PubMed

Boivin, J-M; Koch, C; Vigié, L; Meppiel, L

2015-06-01

To compare the percentages of men and women treated for primary arterial hypertension presenting with at least one target organ damage; to identify factors associated with target organ damage and/or blood pressure control. Observational, transverse study carried out between March 2012 and July 2013 on a representative sample of 2666 outpatients (including 1343 men) consulting general practitioners (n=469) or cardiologists (n=250) in routine follow-up. Characteristics "men vs. women" were: mean age (62.6 ± 11.6 vs. 57.4 ± 14.7 years; P<0.0001); ≥ 60 years (61.1% vs. 43.9%; P<0.0001); waist circumference (98.9 ± 12.2 vs. 89.4 ± 14.3 cm; P<0.0001); SBP (146.5 ± 16.1 vs. 145.8 ± 17.0 mmHg; NS); DBP (85.1 ± 10.3 vs. 84.2 ± 10.4; P=0,03). Target organ damage was more frequent in men (37.6% vs. 22.9%; P<0.0001), whether it was subclinical (20.4% vs. 13.6%; P<0.0001) or documented (26.3% vs. 13.5%; P<0.0001); some patients presented with both types of damages. Men developed more often microalbuminuria (6.5% vs. 4.3%; P=0.01) and LVH (16.3% vs. 10.5%; P<0.0001); some patients presented with both types of subclinical injuries. Target organ damage was more common in men without regular physical activity than in those exercising regularly (42.1% vs. 32.5%; P=0.0004). Regular exercises had no effect in women (24.1% vs. 21.3%). For both sexes, other factors associated with target organ damage were: age ≥ 60 years, myocardial infarction/sudden death in family history, LDL-cholesterol ≥ 1.60 g/L, HDL-cholesterol ≤ 0.40 g/L. Stroke before 45 years in family history was a predictive factor in women. Hypertension was controlled in one third of patients without difference between sexes. In women, hypertension was less often controlled in case of excessive alcohol consumption compared to normal alcohol intake (17.9% vs. 36.1%; P=0.0007); this factor had no effect in men (28.1% vs. 32.6%). Other factors associated with poor blood pressure control were: BMI (P=0.002), LDL

Female genital tract graft-versus-host disease: incidence, risk factors and recommendations for management.

PubMed

Zantomio, D; Grigg, A P; MacGregor, L; Panek-Hudson, Y; Szer, J; Ayton, R

2006-10-01

Female genital tract graft-versus-host disease (GVHD) is an under-recognized complication of allogeneic stem cell transplantation impacting on quality of life. We describe a prospective surveillance programme for female genital GVHD to better characterize incidence, risk factors and clinical features and the impact of a structured intervention policy. A retrospective audit was conducted on the medical records of all female transplant recipients surviving at least 6 months at a single centre over a 5-year period. Patients commenced topical vaginal oestrogen early post transplant with hormone replacement as appropriate for age, prior menopausal status and co-morbidities. A genital tract management programme included regular gynaecological review and self-maintenance of vaginal capacity by dilator or intercourse. The incidence of genital GVHD was 35% (95% confidence interval (CI) (25, 50%)) at 1 year and 49% (95% CI (36, 63%)) at 2 years. Topical therapy was effective in most cases; no patient required surgical intervention to divide vaginal adhesions. The main risk factor was stem cell source with peripheral blood progenitor cells posing a higher risk than marrow (hazard ratio=3.07 (1.22, 7.73), P=0.017). Extensive GVHD in other organs was a common association. We conclude that female genital GVHD is common, and early detection and commencement of topical immunosuppression with dilator use appears to be highly effective at preventing progression.

Enhanced guide-RNA design and targeting analysis for precise CRISPR genome editing of single and consortia of industrially relevant and non-model organisms.

PubMed

Mendoza, Brian J; Trinh, Cong T

2018-01-01

Genetic diversity of non-model organisms offers a repertoire of unique phenotypic features for exploration and cultivation for synthetic biology and metabolic engineering applications. To realize this enormous potential, it is critical to have an efficient genome editing tool for rapid strain engineering of these organisms to perform novel programmed functions. To accommodate the use of CRISPR/Cas systems for genome editing across organisms, we have developed a novel method, named CRISPR Associated Software for Pathway Engineering and Research (CASPER), for identifying on- and off-targets with enhanced predictability coupled with an analysis of non-unique (repeated) targets to assist in editing any organism with various endonucleases. Utilizing CASPER, we demonstrated a modest 2.4% and significant 30.2% improvement (F-test, P < 0.05) over the conventional methods for predicting on- and off-target activities, respectively. Further we used CASPER to develop novel applications in genome editing: multitargeting analysis (i.e. simultaneous multiple-site modification on a target genome with a sole guide-RNA requirement) and multispecies population analysis (i.e. guide-RNA design for genome editing across a consortium of organisms). Our analysis on a selection of industrially relevant organisms revealed a number of non-unique target sites associated with genes and transposable elements that can be used as potential sites for multitargeting. The analysis also identified shared and unshared targets that enable genome editing of single or multiple genomes in a consortium of interest. We envision CASPER as a useful platform to enhance the precise CRISPR genome editing for metabolic engineering and synthetic biology applications. https://github.com/TrinhLab/CASPER. ctrinh@utk.edu. Supplementary data are available at Bioinformatics online. © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Construction of ultrasonic nanobubbles carrying CAIX polypeptides to target carcinoma cells derived from various organs.

PubMed

Zhu, Lianhua; Guo, Yanli; Wang, Luofu; Fan, Xiaozhou; Xiong, Xingyu; Fang, Kejing; Xu, Dan

2017-09-29

. Targeted nanobubbles carrying CAIX polypeptides can specifically enhance ultrasound imaging in CAIX-positive transplanted tumor tissues and could potentially be used in early diagnosis of a variety of solid tumors derived from various organs.

IL-2 promotes early Treg reconstitution after allogeneic hematopoietic cell transplantation.

PubMed

Betts, Brian C; Pidala, Joseph; Kim, Jongphil; Mishra, Asmita; Nishihori, Taiga; Perez, Lia; Ochoa-Bayona, Jose Leonel; Khimani, Farhad; Walton, Kelly; Bookout, Ryan; Nieder, Michael; Khaira, Divis K; Davila, Marco; Alsina, Melissa; Field, Teresa; Ayala, Ernesto; Locke, Frederick L; Riches, Marcie; Kharfan-Dabaja, Mohamed; Fernandez, Hugo; Anasetti, Claudio

2017-05-01

Graft- versus -host disease (GvHD) remains a major cause of transplant-related mortality. Interleukin-2 (IL-2) plus sirolimus (SIR) synergistically reduces acute GvHD in rodents and promotes regulatory T cells. This phase II trial tested the hypothesis that IL-2 would facilitate STAT5 phosphorylation in donor T cells, expand regulatory T cells, and ameliorate GvHD. Between 16 th April 2014 and 19 th December 2015, 20 patients received IL-2 (200,000 IU/m 2 thrice weekly, days 0 to +90) with SIR (5-14 ng/mL) and tacrolimus (TAC) (3-7 ng/mL) after HLA-matched related or unrelated allogeneic hematopoietic cell transplantation (HCT). The study was designed to capture an increase in regulatory T cells from 16.0% to more than 23.2% at day +30. IL-2/SIR/TAC significantly increased regulatory T cells at day +30 compared to our published data with SIR/TAC (23.8% vs. 16.0%, P =0.0016; 0.052 k/uL vs. 0.037 k/uL, P =0.0163), achieving the primary study end point. However, adding IL-2 to SIR/TAC led to a fall in regulatory T cells by day +90 and did not reduce acute or chronic GvHD. Patients who discontinued IL-2 before day +100 showed a suggested trend toward less grade II-IV acute GvHD (16.7% vs. 50%, P =0.1475). We surmise that the reported accumulation of IL-2 receptors in circulation over time may neutralize IL-2, lead to progressive loss of regulatory T cells, and offset its clinical efficacy. The amount of phospho-STAT3 + CD4 + T cells correlated with donor T-cell activation and acute GvHD incidence despite early T-cell STAT5 phosphorylation by IL-2. Optimizing IL-2 dosing and overcoming cytokine sequestration by soluble IL-2 receptor may sustain lasting regulatory T cells after transplantation. However, an approach to target STAT3 is needed to enhance GvHD prevention. ( clinicaltrials.gov identifier: 01927120 ). Copyright© Ferrata Storti Foundation.

Differential Effect of MyD88 Signal in Donor T Cells on Graft-versus-Leukemia Effect and Graft-versus-Host Disease after Experimental Allogeneic Stem Cell Transplantation.

PubMed

Lim, Ji-Young; Ryu, Da-Bin; Lee, Sung-Eun; Park, Gyeongsin; Choi, Eun Young; Min, Chang-Ki

2015-11-01

Despite the presence of toll like receptor (TLR) expression in conventional TCRαβ T cells, the direct role of TLR signaling via myeloid differentiation factor 88 (MyD88) within T lymphocytes on graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect after allogeneic stem cell transplantation (allo-SCT) remains unknown. In the allo-SCT model of C57BL/6 (H-2(b)) → B6D2F1 (H-2(b/d)), recipients received transplants of wild type (WT) T-cell-depleted (TCD) bone marrow (BM) and splenic T cells from either WT or MyD88 deficient (MyD88KO) donors. Host-type (H-2(d)) P815 mastocytoma or L1210 leukemia cells were injected either subcutaneously or intravenously to generate a GVHD/GVL model. Allogeneic recipients of MyD88KO T cells demonstrated a greater tumor growth without attenuation of GVHD severity. Moreover, GVHD-induced GVL effect, caused by increasing the conditioning intensity was also not observed in the recipients of MyD88KO T cells. In vitro, the absence of MyD88 in T cells resulted in defective cytolytic activity to tumor targets with reduced ability to produce IFN-γ or granzyme B, which are known to critical for the GVL effect. However, donor T cell expansion with effector and memory T-cell differentiation were more enhanced in GVHD hosts of MyD88KO T cells. Recipients of MyD88KO T cells experienced greater expansion of Foxp3- and IL4-expressing T cells with reduced INF-γ producing T cells in the spleen and tumor-draining lymph nodes early after transplantation. Taken together, these results highlight a differential role for MyD88 deficiency on donor T-cells, with decreased GVL effect without attenuation of the GVHD severity after experimental allo-SCT.

Biosafety research for non-target organism risk assessment of RNAi-based GE plants

PubMed Central

Roberts, Andrew F.; Devos, Yann; Lemgo, Godwin N. Y.; Zhou, Xuguo

2015-01-01

RNA interference, or RNAi, refers to a set of biological processes that make use of conserved cellular machinery to silence genes. Although there are several variations in the source and mechanism, they are all triggered by double stranded RNA (dsRNA) which is processed by a protein complex into small, single stranded RNA, referred to as small interfering RNAs (siRNA) with complementarity to sequences in genes targeted for silencing. The use of the RNAi mechanism to develop new traits in plants has fueled a discussion about the environmental safety of the technology for these applications, and this was the subject of a symposium session at the 13th ISBGMO in Cape Town, South Africa. This paper continues that discussion by proposing research areas that may be beneficial for future environmental risk assessments of RNAi-based genetically modified plants, with a particular focus on non-target organism assessment. PMID:26594220

Diverse T-cell responses characterize the different manifestations of cutaneous graft-versus-host disease.

PubMed

Brüggen, Marie-Charlotte; Klein, Irene; Greinix, Hildegard; Bauer, Wolfgang; Kuzmina, Zoya; Rabitsch, Werner; Kalhs, Peter; Petzelbauer, Peter; Knobler, Robert; Stingl, Georg; Stary, Georg

2014-01-09

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HCT) and can present in an acute (aGVHD), a chronic lichenoid (clGVHD), and a chronic sclerotic form (csGVHD). It is unclear whether similar or different pathomechanisms lead to these distinct clinical presentations. To address this issue, we collected lesional skin biopsies from aGVHD (n = 25), clGVHD (n = 17), and csGVHD (n = 7) patients as well as serial nonlesional biopsies from HCT recipients (prior to or post-HCT) (n = 14) and subjected them to phenotypic and functional analyses. Our results revealed striking differences between aGVHD and clGVHD. In aGVHD, we found a clear predominance of T helper (Th)2 cytokines/chemokines and, surprisingly, of interleukin (IL)-22 messenger RNA as well as an increase of IL-22-producing CD4(+) T cells. Thymic stromal lymphopoietin, a cytokine skewing the immune response toward a Th2 direction, was elevated at day 20 to 30 post-HCT in the skin of patients who later developed aGVHD. In sharp contrast to aGVHD, the immune response occurring in clGVHD showed a mixed Th1/Th17 signature with upregulated Th1/Th17 cytokine/chemokine transcripts and elevated numbers of interferon-γ- and IL-17-producing CD8(+) T cells. Our findings shed new light on the T-cell responses involved in the different manifestations of cutaneous GVHD and identify molecular signatures indicating the development of the disease.

Attractive Toxic Sugar Bait (ATSB) For Control of Mosquitoes and Its Impact on Non-Target Organisms: A Review

PubMed Central

Fiorenzano, Jodi M.; Koehler, Philip G.; Xue, Rui-De

2017-01-01

Mosquito abatement programs contend with mosquito-borne diseases, insecticidal resistance, and environmental impacts to non-target organisms. However, chemical resources are limited to a few chemical classes with similar modes of action, which has led to insecticide resistance in mosquito populations. To develop a new tool for mosquito abatement programs that control mosquitoes while combating the issues of insecticidal resistance, and has low impacts of non-target organisms, novel methods of mosquito control, such as attractive toxic sugar baits (ATSBs), are being developed. Whereas insect baiting to dissuade a behavior, or induce mortality, is not a novel concept, as it was first introduced in writings from 77 AD, mosquito baiting through toxic sugar baits (TSBs) had been quickly developing over the last 60 years. This review addresses the current body of research of ATSB by providing an overview of active ingredients (toxins) include in TSBs, attractants combined in ATSB, lethal effects on mosquito adults and larvae, impact on non-target insects, and prospects for the use of ATSB. PMID:28394284

Attractive Toxic Sugar Bait (ATSB) For Control of Mosquitoes and Its Impact on Non-Target Organisms: A Review.

PubMed

Fiorenzano, Jodi M; Koehler, Philip G; Xue, Rui-De

2017-04-10

Mosquito abatement programs contend with mosquito-borne diseases, insecticidal resistance, and environmental impacts to non-target organisms. However, chemical resources are limited to a few chemical classes with similar modes of action, which has led to insecticide resistance in mosquito populations. To develop a new tool for mosquito abatement programs that control mosquitoes while combating the issues of insecticidal resistance, and has low impacts of non-target organisms, novel methods of mosquito control, such as attractive toxic sugar baits (ATSBs), are being developed. Whereas insect baiting to dissuade a behavior, or induce mortality, is not a novel concept, as it was first introduced in writings from 77 AD, mosquito baiting through toxic sugar baits (TSBs) had been quickly developing over the last 60 years. This review addresses the current body of research of ATSB by providing an overview of active ingredients (toxins) include in TSBs, attractants combined in ATSB, lethal effects on mosquito adults and larvae, impact on non-target insects, and prospects for the use of ATSB.

Pathogenicity Tests on Nine Mosquito Species and Several Non-target Organisms with Strelkovimermis spiculatus (Nemata Mermithidae).

PubMed

Becnel, J J; Johnson, M A

1998-12-01

Nine species of mosquitoes and several species of non-target aquatic organisms were tested for susceptibility to the mernaithid nematode, Strelkovimermis spiculatus. All species of Anopheles, Aedes, Culex, and Toxorhynchites exposed to S. spiculatus were susceptible. Of the nine mosquito species tested, C. pipiens quinquefasciatus had the greatest tolerance to initial invasion and the highest percent infection of those that survived. High levels of infection were also achieved with Aedes taeniorhynchus and A. albopictus, but these mosquitoes were significantly less tolerant to parasitism than C. pipiens quinquefasciatus. Strelkovimermis spiculatus did not infect or develop in any of the non-target hosts tested.

The mitochondria-targeted antioxidant MitoQ protects against organ damage in a lipopolysaccharide-peptidoglycan model of sepsis.

PubMed

Lowes, Damon A; Thottakam, Bensita M V; Webster, Nigel R; Murphy, Michael P; Galley, Helen F

2008-12-01

Sepsis is characterised by a systemic dysregulated inflammatory response and oxidative stress, often leading to organ failure and death. Development of organ dysfunction associated with sepsis is now accepted to be due at least in part to oxidative damage to mitochondria. MitoQ is an antioxidant selectively targeted to mitochondria that protects mitochondria from oxidative damage and which has been shown to decrease mitochondrial damage in animal models of oxidative stress. We hypothesised that if oxidative damage to mitochondria does play a significant role in sepsis-induced organ failure, then MitoQ should modulate inflammatory responses, reduce mitochondrial oxidative damage, and thereby ameliorate organ damage. To assess this, we investigated the effects of MitoQ in vitro in an endothelial cell model of sepsis and in vivo in a rat model of sepsis. In vitro MitoQ decreased oxidative stress and protected mitochondria from damage as indicated by a lower rate of reactive oxygen species formation (P=0.01) and by maintenance of the mitochondrial membrane potential (P<0.005). MitoQ also suppressed proinflammatory cytokine release from the cells (P<0.05) while the production of the anti-inflammatory cytokine interleukin-10 was increased by MitoQ (P<0.001). In a lipopolysaccharide-peptidoglycan rat model of the organ dysfunction that occurs during sepsis, MitoQ treatment resulted in lower levels of biochemical markers of acute liver and renal dysfunction (P<0.05), and mitochondrial membrane potential was augmented (P<0.01) in most organs. These findings suggest that the use of mitochondria-targeted antioxidants such as MitoQ may be beneficial in sepsis.

Membrane organization of virus and target cell plays a role in HIV entry.

PubMed

Dumas, Fabrice; Preira, Pascal; Salomé, Laurence

2014-12-01

The initial steps of the Human Immunodeficiency Virus (HIV) replication cycle play a crucial role that arbitrates viral tropism and infection efficiency. Before the release of its genome into the host cell cytoplasm, viruses operate a complex sequence of events that take place at the plasma membrane of the target cell. The first step is the binding of the HIV protein envelope (Env) to the cellular receptor CD4. This triggers conformational changes of the gp120 viral protein that allow its interaction with a co-receptor that can be either CCR5 or CXCR4, defining the tropism of the virus entering the cell. This sequential interaction finally drives the fusion of the viral and host cell membrane or to the endocytosis of the viruses. Here, we discuss how the membrane composition and organization of both the virus and the target cell can affect these steps and thus influence the capability of the viruses to infect cells. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Graft-Versus-Host-Disease

MedlinePlus

... after transplant. There are 2 types of GVHD: Acute GVHD: Usually happens in the early weeks and ... transplant. Some transplant recipients don’t have any acute GVHD. If you have any symptoms of GVHD , ...

An efficient and robust MRI-guided radiotherapy planning approach for targeting abdominal organs and tumours in the mouse

PubMed Central

Bird, Luke; Tullis, Iain D. C.; Newman, Robert G.; Corroyer-Dulmont, Aurelien; Falzone, Nadia; Azad, Abul; Vallis, Katherine A.; Sansom, Owen J.; Muschel, Ruth J.; Vojnovic, Borivoj; Hill, Mark A.; Fokas, Emmanouil; Smart, Sean C.

2017-01-01

Introduction Preclinical CT-guided radiotherapy platforms are increasingly used but the CT images are characterized by poor soft tissue contrast. The aim of this study was to develop a robust and accurate method of MRI-guided radiotherapy (MR-IGRT) delivery to abdominal targets in the mouse. Methods A multimodality cradle was developed for providing subject immobilisation and its performance was evaluated. Whilst CT was still used for dose calculations, target identification was based on MRI. Each step of the radiotherapy planning procedure was validated initially in vitro using BANG gel dosimeters. Subsequently, MR-IGRT of normal adrenal glands with a size-matched collimated beam was performed. Additionally, the SK-N-SH neuroblastoma xenograft model and the transgenic KPC model of pancreatic ductal adenocarcinoma were used to demonstrate the applicability of our methods for the accurate delivery of radiation to CT-invisible abdominal tumours. Results The BANG gel phantoms demonstrated a targeting efficiency error of 0.56 ± 0.18 mm. The in vivo stability tests of body motion during MR-IGRT and the associated cradle transfer showed that the residual body movements are within this MR-IGRT targeting error. Accurate MR-IGRT of the normal adrenal glands with a size-matched collimated beam was confirmed by γH2AX staining. Regression in tumour volume was observed almost immediately post MR-IGRT in the neuroblastoma model, further demonstrating accuracy of x-ray delivery. Finally, MR-IGRT in the KPC model facilitated precise contouring and comparison of different treatment plans and radiotherapy dose distributions not only to the intra-abdominal tumour but also to the organs at risk. Conclusion This is, to our knowledge, the first study to demonstrate preclinical MR-IGRT in intra-abdominal organs. The proposed MR-IGRT method presents a state-of-the-art solution to enabling robust, accurate and efficient targeting of extracranial organs in the mouse and can operate with a

Trace organic chemical pollutants from the lake waters of San Pablo City, Philippines by targeted and non-targeted analysis.

PubMed

Dimzon, Ian Ken D; Morata, Ann Selma; Müller, Janine; Yanela, Roy Kristian; Lebertz, Stephan; Weil, Heike; Perez, Teresita R; Müller, Jutta; Dayrit, Fabian M; Knepper, Thomas P

2018-10-15

More than half of the freshwater lakes in the Philippines are small with surface areas of <2 km 2 . The dynamics in these lakes are different from those in the bigger lakes. This study was conducted to determine the organic pollutants and their sources in three of the seven lakes of San Pablo City in Laguna, Philippines: lakes Palakpakin, Sampaloc, and Pandin. Gas Chromatography-Mass Spectrometry (GC-MS) and Liquid Chromatography - Tandem Mass Spectrometry (LC-MS/MS) were used in the targeted and non-targeted analysis of the lake water samples. The three lakes are all volcanic crater lakes but are exposed to different anthropogenic activities, which includes domestic activities, livelihood (farming and aquaculture) and eco-tourism. Due to the presence of rice fields and fruit plantations, chlorpyrifos was detected in the three lakes while other pesticides like cypermethrin, picolinafen and quinoxyfen were additionally found in Lake Sampaloc, which is the biggest of the three lakes and located within the urbanized section of the city. Traces of different surfactants (linear alkylbenzene sulfonates, secondary alkyl sulfonates, alkyl sulfates, alkyl ether sulfates), biocide benzalkonium chloride, insect repellent diethyltoluamide, antibiotics (sulfadiazine and sulfamethoxazole), hypertension drug telmisartan, phosphate-based fire retardants, and artificial sweeteners (acesulfame, cyclamate, saccharin and sucralose) were detected in lakes Sampaloc and Palakpakin. The same surfactants, artificial sweeteners, insect repellant and phosphate-based fire retardants were also found in Lake Pandin, which is mainly used for eco-tourism activities like swimming and boating. The results of this study suggest that the organic pollutants present in the small lakes can be linked to the various human activities in the immediate lake environment. Because small lakes are more prone to environmental stresses, human activities in the said lakes must be regulated to ensure sustainable

Expanded target-chemical analysis reveals extensive mixed-organic-contaminant exposure in USA streams

USGS Publications Warehouse

Bradley, Paul M.; Journey, Celeste A.; Romanok, Kristin; Barber, Larry B.; Buxton, Herbert T.; Foreman, William T.; Furlong, Edward T.; Glassmeyer, Susan T.; Hladik, Michelle L.; Iwanowicz, Luke R.; Jones, Daniel K.; Kolpin, Dana W.; Kuivila, Kathryn M.; Loftin, Keith A.; Mills, Marc A.; Meyer, Michael T.; Orlando, James L.; Reilly, Timothy J.; Smalling, Kelly L.; Villeneuve, Daniel L.

2017-01-01

Surface water from 38 streams nationwide was assessed using 14 target-organic methods (719 compounds). Designed-bioactive anthropogenic contaminants (biocides, pharmaceuticals) comprised 57% of 406 organics detected at least once. The 10 most-frequently detected anthropogenic-organics included eight pesticides (desulfinylfipronil, AMPA, chlorpyrifos, dieldrin, metolachlor, atrazine, CIAT, glyphosate) and two pharmaceuticals (caffeine, metformin) with detection frequencies ranging 66–84% of all sites. Detected contaminant concentrations varied from less than 1 ng L–1 to greater than 10 μg L–1, with 77 and 278 having median detected concentrations greater than 100 ng L–1 and 10 ng L–1, respectively. Cumulative detections and concentrations ranged 4–161 compounds (median 70) and 8.5–102 847 ng L–1, respectively, and correlated significantly with wastewater discharge, watershed development, and toxic release inventory metrics. Log10 concentrations of widely monitored HHCB, triclosan, and carbamazepine explained 71–82% of the variability in the total number of compounds detected (linear regression; p-values: < 0.001–0.012), providing a statistical inference tool for unmonitored contaminants. Due to multiple modes of action, high bioactivity, biorecalcitrance, and direct environment application (pesticides), designed-bioactive organics (median 41 per site at μg L–1 cumulative concentrations) in developed watersheds present aquatic health concerns, given their acknowledged potential for sublethal effects to sensitive species and lifecycle stages at low ng L–1.

Preventive effect of ultraviolet radiation on murine chronic sclerodermatous graft-versus-host disease.

PubMed

Mermet, Isabelle; Kleinclauss, François; Marandin, Aliette; Guérrini, Jean Sébastien; Angonin, Régis; Tiberghien, Pierre; Saas, Philippe; Aubin, François

2007-12-27

Although previous studies have demonstrated the efficient modulatory effects of ultraviolet radiation B (UVB) on cutaneous graft-versus-host disease (GVHD), most animal research on GVHD has been performed in murine models of acute GVHD. Here, we studied the preventive effect of UVB radiation on the occurrence of chronic sclerodermatous (Scl) GVHD in a murine model. Scl GVHD was induced by transplanting lethally irradiated BALB/c mice with B10.D2 bone marrow and spleen cells. Recipient mice were exposed to UVB before or after bone marrow and spleen cell infusion. Histological and clinical evaluation of GVHD was performed, in association with the characterization of epidermal Langerhans cells. UVB irradiation of recipients after, and more remarkably before, transplantation induced a decrease of Scl GVHD severity associated with epidermal Langerhans cells depletion. We conclude that UVB irradiation of recipient before or after transplantation has a preventive effect on cutaneous Scl GVHD and may represent an effective strategy for prevention of Scl GVHD.

A multifunctional metal-organic framework based tumor targeting drug delivery system for cancer therapy

NASA Astrophysics Data System (ADS)

Wang, Xiao-Gang; Dong, Zhi-Yue; Cheng, Hong; Wan, Shuang-Shuang; Chen, Wei-Hai; Zou, Mei-Zhen; Huo, Jia-Wei; Deng, He-Xiang; Zhang, Xian-Zheng

2015-09-01

Drug delivery systems (DDSs) with biocompatibility and precise drug delivery are eagerly needed to overcome the paradox in chemotherapy that high drug doses are required to compensate for the poor biodistribution of drugs with frequent dose-related side effects. In this work, we reported a metal-organic framework (MOF) based tumor targeting DDS developed by a one-pot, and organic solvent-free ``green'' post-synthetic surface modification procedure, starting from the nanoscale MOF MIL-101. Owing to the multifunctional surface coating, premature drug release from this DDS was prevented. Due to the pH responsive benzoic imine bond and the redox responsive disulfide bond at the modified surface, this DDS exhibited tumor acid environment enhanced cellular uptake and intracellular reducing environment triggered drug release. In vitro and in vivo results showed that DOX loaded into this DDS exhibited effective cancer cell inhibition with much reduced side effects.Drug delivery systems (DDSs) with biocompatibility and precise drug delivery are eagerly needed to overcome the paradox in chemotherapy that high drug doses are required to compensate for the poor biodistribution of drugs with frequent dose-related side effects. In this work, we reported a metal-organic framework (MOF) based tumor targeting DDS developed by a one-pot, and organic solvent-free ``green'' post-synthetic surface modification procedure, starting from the nanoscale MOF MIL-101. Owing to the multifunctional surface coating, premature drug release from this DDS was prevented. Due to the pH responsive benzoic imine bond and the redox responsive disulfide bond at the modified surface, this DDS exhibited tumor acid environment enhanced cellular uptake and intracellular reducing environment triggered drug release. In vitro and in vivo results showed that DOX loaded into this DDS exhibited effective cancer cell inhibition with much reduced side effects. Electronic supplementary information (ESI) available

Platelet-lysate-expanded mesenchymal stromal cells as a salvage therapy for severe resistant graft-versus-host disease in a pediatric population.

PubMed

Lucchini, Giovanna; Introna, Martino; Dander, Erica; Rovelli, Attilio; Balduzzi, Adriana; Bonanomi, Sonia; Salvadè, Agnese; Capelli, Chiara; Belotti, Daniela; Gaipa, Giuseppe; Perseghin, Paolo; Vinci, Paola; Lanino, Edoardo; Chiusolo, Patrizia; Orofino, Maria Grazia; Marktel, Sarah; Golay, Jose; Rambaldi, Alessandro; Biondi, Andrea; D'Amico, Giovanna; Biagi, Ettore

2010-09-01

Despite advances in graft-versus-host-disease (GVHD) treatment, it is estimated that overall survival (OS) at 2 years for hematopoietic cell transplantation (HCT) recipients who experience steroid-resistant GVHD is 10%. Among recent therapeutic approaches for GVHD treatment, mesenchymal stromal cells (MSCs) hold a key position. We describe a multicenter experience of 11 pediatric patients diagnosed with acute or chronic GVHD (aGVHD, cGVHD) treated for compassionate use with GMP-grade unrelated HLA-disparate donors' bone marrow-derived MSCs, expanded in platelet-lysate (PL)-containing medium. Eleven patients (aged 4-15 years) received intravenous (i.v.) MSCs for aGVHD or cGVHD, which was resistant to multiple lines of immunosuppression. The median dose was 1.2 x 10(6)/kg (range: 0.7-3.7 x 10(6)/kg). No acute side effects were observed, and no late side effects were reported at a median follow-up of 8 months (range: 4-18 months). Overall response was obtained in 71.4% of patients, with complete response in 23.8% of cases. None of our patients presented GVHD progression upon MSC administration, but 4 patients presented GVHD recurrence 2 to 5 months after infusion. Two patients developed chronic limited GVHD. This study underlines the safety of PL-expanded MSC use in children. MSC efficacy seems to be greater in aGVHD than in cGVHD, even after failure of multiple lines of immunosuppression. Copyright (c) 2010 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Colorimetric detection of genetically modified organisms based on exonuclease III-assisted target recycling and hemin/G-quadruplex DNAzyme amplification.

PubMed

Zhang, Decai; Wang, Weijia; Dong, Qian; Huang, Yunxiu; Wen, Dongmei; Mu, Yuejing; Yuan, Yong

2017-12-21

An isothermal colorimetric method is described for amplified detection of the CaMV 35S promoter sequence in genetically modified organism (GMO). It is based on (a) target DNA-triggered unlabeled molecular beacon (UMB) termini binding, and (b) exonuclease III (Exo III)-assisted target recycling, and (c) hemin/G-quadruplex (DNAzyme) based signal amplification. The specific binding of target to the G-quadruplex sequence-locked UMB triggers the digestion of Exo III. This, in turn, releases an active G-quadruplex segment and target DNA for successive hybridization and cleavage. The Exo III impellent recycling of targets produces numerous G-quadruplex sequences. These further associate with hemin to form DNAzymes and hence will catalyze H 2 O 2 -mediated oxidation of the chromogenic enzyme substrate ABTS 2- causing the formation of a green colored product. This finding enables a sensitive colorimetric determination of GMO DNA (at an analytical wavelength of 420 nm) at concentrations as low as 0.23 nM. By taking advantage of isothermal incubation, this method does not require sophisticated equipment or complicated syntheses. Analyses can be performed within 90 min. The method also discriminates single base mismatches. In our perception, it has a wide scope in that it may be applied to the detection of many other GMOs. Graphical abstract An isothermal and sensitive colorimetric method is described for amplified detection of CaMV 35S promoter sequence in genetically modified organism (GMO). It is based on target DNA-triggered molecular beacon (UMB) termini-binding and exonuclease III assisted target recycling, and on hemin/G-quadruplex (DNAzyme) signal amplification.

Chemical structure determines target organ carcinogenesis in rats

PubMed Central

Carrasquer, C. A.; Malik, N.; States, G.; Qamar, S.; Cunningham, S.L.; Cunningham, A.R.

2012-01-01

SAR models were developed for 12 rat tumour sites using data derived from the Carcinogenic Potency Database. Essentially, the models fall into two categories: Target Site Carcinogen – Non-Carcinogen (TSC-NC) and Target Site Carcinogen – Non-Target Site Carcinogen (TSC-NTSC). The TSC-NC models were composed of active chemicals that were carcinogenic to a specific target site and inactive ones that were whole animal non-carcinogens. On the other hand, the TSC-NTSC models used an inactive category also composed of carcinogens but to any/all other sites but the target site. Leave one out validations produced an overall average concordance value for all 12 models of 0.77 for the TSC-NC models and 0.73 for the TSC-NTSC models. Overall, these findings suggest that while the TSC-NC models are able to distinguish between carcinogens and non-carcinogens, the TSC-NTSC models are identifying structural attributes that associate carcinogens to specific tumour sites. Since the TSC-NTSC models are composed of active and inactive compounds that are genotoxic and non-genotoxic carcinogens, the TSC-NTSC models may be capable of deciphering non-genotoxic mechanisms of carcinogenesis. Together, models of this type may also prove useful in anticancer drug development since they essentially contain chemicals moieties that target specific tumour site. PMID:23066888

Multi-target determination of organic ultraviolet absorbents in organism tissues by ultrasonic assisted extraction and ultra-high performance liquid chromatography-tandem mass spectrometry.

PubMed

Peng, Xianzhi; Jin, Jiabin; Wang, Chunwei; Ou, Weihui; Tang, Caiming

2015-03-06

A sensitive and reliable method was developed for multi-target determination of 13 most widely used organic ultraviolet (UV) absorbents (including UV filters and UV stabilizers) in aquatic organism tissues. The organic UV absorbents were extracted using ultrasonic-assisted extraction, purified via gel permeation chromatography coupled with silica gel column chromatography, and determined by ultra-high performance liquid chromatography-tandem mass spectrometry. Recoveries of the UV absorbents from organism tissues mostly ranged from 70% to 120% from fish filet with satisfactory reproducibility. Method quantification limits were 0.003-1.0ngg(-1) dry weight (dw) except for 2-ethylhexyl 4-methoxycinnamate. This method has been applied to analysis of the UV absorbents in wild and farmed aquatic organisms collected from the Pearl River Estuary, South China. 2-Hydroxy-4-methoxybenzophenone and UV-P were frequently detected in both wild and farmed marine organisms at low ngg(-1)dw. 3-(4-Methylbenzylidene)camphor and most of the benzotriazole UV stabilizers were also frequently detected in maricultured fish. Octocrylene and 2-ethylhexyl 4-methoxycinnamate were not detected in any sample. This work lays basis for in-depth study about bioaccumulation and biomagnification of the UV absorbents in marine environment. Copyright © 2015 Elsevier B.V. All rights reserved.

Predictors for Permanent Discontinuation of Systemic Immunosuppression in Severely Affected Chronic Graft-Versus-Host Disease Patients.

PubMed

Curtis, Lauren M; Pirsl, Filip; Steinberg, Seth M; Mitchell, Sandra A; Baird, Kristin; Cowen, Edward W; Mays, Jacqueline; Buxbaum, Nataliya P; Pichard, Dominique C; Im, Annie; Avila, Daniele; Taylor, Tiffani; Fowler, Daniel H; Gress, Ronald E; Pavletic, Steven Z

2017-11-01

Predicting the duration of systemic therapy in patients with chronic graft-versus-host disease (cGVHD) is of critical clinical importance when counseling patients and for treatment planning. cGVHD characteristics associated with this outcome have not been studied in severely affected patients. The National Institutes of Health (NIH) cGVHD scoring provides a standardized set of organ severity measures that could represent clinically useful and reproducible predictive characteristics. We analyzed 227 previously treated patients most with moderate (n = 54) or severe (n = 170) cGVHD defined by NIH criteria who were prospectively enrolled in a natural history protocol (NCT00092235). Patients received a median of 4 prior systemic therapy regimens and were seen at the NIH for a single time-point visit and were then monitored for survival and ability to discontinue cGVHD systemic therapy. With a median follow-up of 71.1 months, the cumulative incidence of systemic therapy discontinuation was 9.5% (95% confidence interval, 6.0% to 13.9%) at 2 years and 27.7% (95% confidence interval, 20.9% to 34.8%) by 5 years after the initial visit. Factors associated with a higher incidence of immunosuppression discontinuation included lower NIH global severity (P = .019) and lung (P = .030) scores and less extensive deep sclerosis (<37% body surface area, P = .024). Lower patient- and clinician-reported 0 to 10 severity NIH scores and noncyclosporine prophylaxis regimens were also associated with higher incidence of immunosuppression discontinuation (P <.05). In conclusion, we found low success rates for immune suppression discontinuation in previously treated patients who were severely affected with cGVHD. NIH scoring and clinical measures provide new standardized disease-specific tools to predict discontinuation of systemic therapy. Published by Elsevier Inc.

Carotid and aortic stiffness in essential hypertension and their relation with target organ damage: the CATOD study

PubMed Central

Bruno, Rosa Maria; Cartoni, Giulia; Stea, Francesco; Armenia, Sabina; Bianchini, Elisabetta; Buralli, Simona; Giannarelli, Chiara; Taddei, Stefano; Ghiadoni, Lorenzo

2017-01-01

Objective The objective of the study is to investigate in the hypertensive population the possible differential association between increased aortic and/or carotid stiffness and organ damage in multiple districts, such as the kidney, the vessels, and the heart. Methods In 314 essential hypertensive patients, carotid–femoral pulse wave velocity (cfPWV, by applanation tonometry) and carotid stiffness (from ultrasound images analysis), together with left ventricular hypertrophy, carotid intima–media thickness, urinary albumin–creatinin ratio, and glomerular filtration rate were measured. Increased cfPWV and carotid stiffness were defined according to either international reference values or the 90th percentile of a local control group (110 age and sex-matched healthy individuals). Results When considering the 90th percentile of a local control group, increased cfPWV was associated with reduced glomerular filtration rate, either when carotid stiffness was increased [odds ratio (OR) 13.27 (confidence limits (CL) 95% 3.86–45.58)] or not [OR 7.39 (CL95% 2.25–24.28)], whereas increased carotid stiffness was associated with left ventricular hypertrophy, either when cfPWV was increased [OR 2.86 (CL95% 1.15–7.09)] or not [OR 2.81 (CL95% 1.13–6.97)]. No association between increased cfPWV or carotid stiffness and target organ damage was found when cutoffs obtained by international reference values were used. The concomitance of both increased cfPWV and carotid stiffness did not have an additive effect on organ damage. Conclusion Aortic and carotid stiffness are differentially associated with target organ damage in hypertensive patients. Regional arterial stiffness as assessed by cfPWV is associated with renal organ damage and local carotid stiffness with cardiac organ damage. PMID:27841779

Pretransplant comorbidities predict severity of acute graft-versus-host disease and subsequent mortality

PubMed Central

Martin, Paul J.; Storb, Rainer F.; Bhatia, Smita; Maziarz, Richard T.; Pulsipher, Michael A.; Maris, Michael B.; Davis, Christopher; Deeg, H. Joachim; Lee, Stephanie J.; Maloney, David G.; Sandmaier, Brenda M.; Appelbaum, Frederick R.; Gooley, Theodore A.

2014-01-01

Whether the hematopoietic cell transplantation comorbidity index (HCT-CI) can provide prognostic information about development of acute graft-versus-host disease (GVHD) and subsequent mortality is unknown. Five institutions contributed information on 2985 patients given human leukocyte antigen-matched grafts to address this question. Proportional hazards models were used to estimate the hazards of acute GVHD and post-GVHD mortality after adjustment for known risk variables. Higher HCT-CI scores predicted increased risk of grades 3 to 4 acute GVHD (P < .0001 and c-statistic of 0.64), and tests of interaction suggested that this association was consistent among different conditioning intensities, donor types, and stem cell sources. Probabilities of grades 3 to 4 GVHD were 13%, 18%, and 24% for HCT-CI risk groups of 0, 1 to 4, and ≥5. The HCT-CI was statistically significantly associated with mortality rates following diagnosis of grade 2 (hazard ratio [HR] = 1.24; P < .0001) or grades 3 to 4 acute GVHD (HR = 1.19; P < .0001). Patients with HCT-CI scores of ≥3 who developed grades 3 to 4 acute GVHD had a 2.63-fold higher risk of mortality than those with scores of 0 to 2 and did not develop acute GVHD. Thus, pretransplant comorbidities are associated with the development and severity of acute GVHD and with post-GVHD mortality. The HCT-CI could be useful in designing trials for GVHD prevention and could inform expectations for GVHD treatment trials. PMID:24797298

Relationship between increased arterial stiffness and other markers of target organ damage.

PubMed

Rodilla, Enrique; Costa, José Antonio; Pérez-Lahiguera, Francisco; González, Carmen; Pascual, José María

2010-04-24

The purpose of the present study was to assess the relationship of arterial stiffness with other markers of target organ damage, and the clinical factors related to it. Cross-sectional study that included 208 (115 men) never treated hypertensive, non-diabetic patients (mean age, 49+/-12 years). In addition to a full clinical study, 24h ambulatory blood pressure (BP), and determination of left ventricular hypertrophy (LVH) and microalbuminuria were performed. Clinical arterial stiffness was assessed by carotid-femoral pulse wave velocity (PWV) obtained with applanation tonometry (SphygmoCor-System). PWV was 8.3 (7.3-9.9)m/s (median, interquartile range). Stepwise regression analysis revealed that age (beta=0.086, p<0.001), 24-h pulse pressure (beta=0.058, p<0.001), and low-density lipoprotein (LDL) cholesterol (beta=0.009, p<0.013) were independent determinants of PWV. PWV>12m/s (indicating target organ lesion) was present in only 16 (7.7%) patients, less frequent than LVH (28% of the patients) and microalbuminuria (16%). However, of the 16 patients with elevated PWV, 10 (62%) had neither LVH or microalbuminuria. In a logistic multivariate regression analysis the factors related to elevated PWV were age > or =45 in man and > or =55 in women (OR: 23.8, 95% CI: 2.7-195.5; p=0.004), LDL cholesterol > or =160mg/dl (OR: 10.6, 95% CI: 2.6-42.7; p=0.001) and increased 24-h pulse pressure > or =55mmHg (OR: 3.9, 95% CI: 1.2-12.9; p=0.03). In untreated middle age hypertensives arterial stiffness assessed by PWV is less frequent than LVH or microalbuminuria. PWV is mainly related to age, LDL cholesterol, and pulse pressure values. 2009 Elsevier España, S.L. All rights reserved.

Single nucleotide polymorphism of CC chemokine ligand 5 promoter gene in recipients may predict the risk of chronic graft-versus-host disease and its severity after allogeneic transplantation.

PubMed

Kim, Dong Hwan; Jung, Hee Du; Lee, Nan Young; Sohn, Sang Kyun

2007-10-15

Leukocyte trafficking, regulated by chemokine ligands and their receptors, involves in the pathogenesis of graft-versus-host disease (GVHD) including CC ligand 5 (CCL5) or CC receptor 5 (CCR5). The current study analyzed the association of acute or chronic GVHD (cGVHD) with the CCR5/CCL5 gene single nucleotide polymorphisms (SNPs) of recipients and donors. We evaluated the SNPs of CCL5 promoter gene at position -28 (rs1800825)/-403 (rs2107538) and CCR5 gene at 59029 (rs1799987) in 72 recipients and donors using polymerase chain reaction/RFLP (Restriction Fragment Length Polymorphism) methods. With a median follow up of 924 days for survivors (range 48-2,360 days), the CG genotype of CCL5 gene at position -28 in recipients was significantly associated with a higher incidence of cGVHD (P=0.004), extensive cGVHD (P=0.038 by Seattle's criteria), and severe grade of cGVHD at presentation (P=0.017 by prognostic grading by Apkek et al.) compared to CC genotype. In terms of haplotype analysis, the recipients with AG haplotype of CCL5 gene also showed a higher incidence of cGVHD (P=0.003), extensive cGVHD (P=0.023), and more severe grade of cGVHD (P=0.020). However, there was no association of CCL5/CCR5 SNPs with acute GVHD. The donors' genotype of CCL5/CCR5 was not associated with the risk of cGVHD. The CCL5 promoter gene polymorphism of recipients was associated with the risk of cGVHD and its severity. The current study suggested an involvement of CCL5 in leukocyte trafficking for the development of cGVHD.

Impacts of graft-versus-host disease on outcomes after allogeneic hematopoietic stem cell transplantation for chronic myelomonocytic leukemia: A nationwide retrospective study.

PubMed

Itonaga, Hidehiro; Iwanaga, Masako; Aoki, Kazunari; Aoki, Jun; Ishiyama, Ken; Ishikawa, Takayuki; Sakura, Toru; Fukuda, Takahiro; Najima, Yuho; Yujiri, Toshiaki; Mori, Takehiko; Kurokawa, Mineo; Nawa, Yuichiro; Uchida, Naoyuki; Morishita, Yoshihisa; Hashimoto, Hisako; Eto, Tetsuya; Hirokawa, Makoto; Morishima, Yasuo; Nagamura-Inoue, Tokiko; Atsuta, Yoshiko; Miyazaki, Yasushi

2016-02-01

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a therapeutic option that may lead to improved outcomes in patients with chronic myelomonocytic leukemia (CMML). However, few studies have examined the impact of the grade of graft-versus-host disease (GVHD) on post-transplant outcomes for CMML. We retrospectively analyzed the outcomes of 141 patients with CMML who underwent allo-HSCT between 1987 and 2010, and achieved neutrophil engraftment. The effects of acute GVHD (aGVHD) or chronic GVHD (cGVHD) on overall survival (OS), leukemia-associated mortality (LAM), and transplant-related mortality were evaluated by hazards regression models, in which the onset date of aGVHD or cGVHD was treated as a time-dependent covariate. Grade I aGVHD was associated with better OS and lower LAM (P=0.042, P=0.033, respectively) than no GVHD in univariate analyses, but not in the multivariate analyses. The multivariate analyses demonstrated that extensive cGVHD significantly associated with better OS (Hazard Ratio [HR] 0.35 [95% confidence intervals (CI), 0.16-0.74]; P=0.007) and lower LAM (HR 0.36 [95% CI, 0.14-0.92]; P=0.033) in patients who were not in complete remission at transplantation. In conclusion, the occurrence of cGVHD may be an important factor affecting the outcomes of CMML patients who received transplantation. Copyright © 2015 Elsevier Ltd. All rights reserved.

[Musculoskeletal system as a target organ of a frailty processes].

PubMed

Zlobina, I A; Krivtsunov, A N; Bogat, S V; Prashchayeu, K I

Pathology of the musculoskeletal system is widespread in the population and is one of the most common diseases of patients in older age groups. The most significant of them are osteoporosis, osteoarthritis and sarcopenia. All three components separately, of course, lead to lower quality of life. In our work we show the mechanisms of interference of these states at each other, and their combined impact on the musculoskeletal system as a target organ processes senile asthenia. Osteoarthritis, osteoporosis, and sarcopenia, and especially their combination lead to hypomobility. Hypomobility under the influence of external factors is one of the leading syndromes potentiating aggravation processes senile asthenia. Thus, the mechanism of re-entry is triggered, and a vicious circle leading to fatal medical-social and social consequences. It is shown that changes in the musculoskeletal system should be considered as a single aging within senile asthenia, and all used and newly created medical and social rehabilitation and prevention programs should be integrated in nature.

Development and validation of a 48-target analytical method for high-throughput monitoring of genetically modified organisms.

PubMed

Li, Xiaofei; Wu, Yuhua; Li, Jun; Li, Yunjing; Long, Likun; Li, Feiwu; Wu, Gang

2015-01-05

The rapid increase in the number of genetically modified (GM) varieties has led to a demand for high-throughput methods to detect genetically modified organisms (GMOs). We describe a new dynamic array-based high throughput method to simultaneously detect 48 targets in 48 samples on a Fludigm system. The test targets included species-specific genes, common screening elements, most of the Chinese-approved GM events, and several unapproved events. The 48 TaqMan assays successfully amplified products from both single-event samples and complex samples with a GMO DNA amount of 0.05 ng, and displayed high specificity. To improve the sensitivity of detection, a preamplification step for 48 pooled targets was added to enrich the amount of template before performing dynamic chip assays. This dynamic chip-based method allowed the synchronous high-throughput detection of multiple targets in multiple samples. Thus, it represents an efficient, qualitative method for GMO multi-detection.

Development and Validation of A 48-Target Analytical Method for High-throughput Monitoring of Genetically Modified Organisms

PubMed Central

Li, Xiaofei; Wu, Yuhua; Li, Jun; Li, Yunjing; Long, Likun; Li, Feiwu; Wu, Gang

2015-01-01

The rapid increase in the number of genetically modified (GM) varieties has led to a demand for high-throughput methods to detect genetically modified organisms (GMOs). We describe a new dynamic array-based high throughput method to simultaneously detect 48 targets in 48 samples on a Fludigm system. The test targets included species-specific genes, common screening elements, most of the Chinese-approved GM events, and several unapproved events. The 48 TaqMan assays successfully amplified products from both single-event samples and complex samples with a GMO DNA amount of 0.05 ng, and displayed high specificity. To improve the sensitivity of detection, a preamplification step for 48 pooled targets was added to enrich the amount of template before performing dynamic chip assays. This dynamic chip-based method allowed the synchronous high-throughput detection of multiple targets in multiple samples. Thus, it represents an efficient, qualitative method for GMO multi-detection. PMID:25556930

Improved prediction of peptide detectability for targeted proteomics using a rank-based algorithm and organism-specific data.

PubMed

Qeli, Ermir; Omasits, Ulrich; Goetze, Sandra; Stekhoven, Daniel J; Frey, Juerg E; Basler, Konrad; Wollscheid, Bernd; Brunner, Erich; Ahrens, Christian H

2014-08-28

The in silico prediction of the best-observable "proteotypic" peptides in mass spectrometry-based workflows is a challenging problem. Being able to accurately predict such peptides would enable the informed selection of proteotypic peptides for targeted quantification of previously observed and non-observed proteins for any organism, with a significant impact for clinical proteomics and systems biology studies. Current prediction algorithms rely on physicochemical parameters in combination with positive and negative training sets to identify those peptide properties that most profoundly affect their general detectability. Here we present PeptideRank, an approach that uses learning to rank algorithm for peptide detectability prediction from shotgun proteomics data, and that eliminates the need to select a negative dataset for the training step. A large number of different peptide properties are used to train ranking models in order to predict a ranking of the best-observable peptides within a protein. Empirical evaluation with rank accuracy metrics showed that PeptideRank complements existing prediction algorithms. Our results indicate that the best performance is achieved when it is trained on organism-specific shotgun proteomics data, and that PeptideRank is most accurate for short to medium-sized and abundant proteins, without any loss in prediction accuracy for the important class of membrane proteins. Targeted proteomics approaches have been gaining a lot of momentum and hold immense potential for systems biology studies and clinical proteomics. However, since only very few complete proteomes have been reported to date, for a considerable fraction of a proteome there is no experimental proteomics evidence that would allow to guide the selection of the best-suited proteotypic peptides (PTPs), i.e. peptides that are specific to a given proteoform and that are repeatedly observed in a mass spectrometer. We describe a novel, rank-based approach for the prediction

Risk assessment of Bt crops on the non-target plant-associated insects and soil organisms.

PubMed

Yaqoob, Amina; Shahid, Ahmad Ali; Samiullah, Tahir Rehman; Rao, Abdul Qayyum; Khan, Muhammad Azmat Ullah; Tahir, Sana; Mirza, Safdar Ali; Husnain, Tayyab

2016-06-01

Transgenic plants containing Bacillus thuringiensis (Bt) genes are being cultivated worldwide to express toxic insecticidal proteins. However, the commercial utilisation of Bt crops greatly highlights biosafety issues worldwide. Therefore, assessing the risks caused by genetically modified crops prior to their commercial cultivation is a critical issue to be addressed. In agricultural biotechnology, the goal of safety assessment is not just to identify the safety of a genetically modified (GM) plant, rather to demonstrate its impact on the ecosystem. Various experimental studies have been made worldwide during the last 20 years to investigate the risks and fears associated with non-target organisms (NTOs). The NTOs include beneficial insects, natural pest controllers, rhizobacteria, growth promoting microbes, pollinators, soil dwellers, aquatic and terrestrial vertebrates, mammals and humans. To highlight all the possible risks associated with different GM events, information has been gathered from a total of 76 articles, regarding non-target plant and soil inhabiting organisms, and summarised in the form of the current review article. No significant harmful impact has been reported in any case study related to approved GM events, although critical risk assessments are still needed before commercialisation of these crops. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Pathogen reduction by ultraviolet C light effectively inactivates human white blood cells in platelet products.

PubMed

Pohler, Petra; Müller, Meike; Winkler, Carla; Schaudien, Dirk; Sewald, Katherina; Müller, Thomas H; Seltsam, Axel

2015-02-01

Residual white blood cells (WBCs) in cellular blood components induce a variety of adverse immune events, including nonhemolytic febrile transfusion reactions, alloimmunization to HLA antigens, and transfusion-associated graft-versus-host disease (TA-GVHD). Pathogen reduction (PR) methods such as the ultraviolet C (UVC) light-based THERAFLEX UV-Platelets system were developed to reduce the risk of transfusion-transmitted infection. As UVC light targets nucleic acids, it interferes with the replication of both pathogens and WBCs. This preclinical study aimed to evaluate the ability of UVC light to inactivate contaminating WBCs in platelet concentrates (PCs). The in vitro and in vivo function of WBCs from UVC-treated PCs was compared to that of WBCs from gamma-irradiated and untreated PCs by measuring cell viability, proliferation, cytokine secretion, antigen presentation in vitro, and xenogeneic GVHD responses in a humanized mouse model. UVC light was at least as effective as gamma irradiation in preventing GVHD in the mouse model. It was more effective in suppressing T-cell proliferation (>5-log reduction in the limiting dilution assay), cytokine secretion, and antigen presentation than gamma irradiation. The THERAFLEX UV-Platelets (MacoPharma) PR system can substitute gamma irradiation for TA-GVHD prophylaxis in platelet (PLT) transfusion. Moreover, UVC treatment achieves suppression of antigen presentation and inhibition of cytokine accumulation during storage of PCs, which has potential benefits for transfusion recipients. © 2014 AABB.

Depletion of host CCR7(+) dendritic cells prevented donor T cell tissue tropism in anti-CD3-conditioned recipients.

PubMed

He, Wei; Racine, Jeremy J; Johnston, Heather F; Li, Xiaofan; Li, Nainong; Cassady, Kaniel; Liu, Can; Deng, Ruishu; Martin, Paul; Forman, Stephen; Zeng, Defu

2014-07-01

We reported previously that anti-CD3 mAb treatment before hematopoietic cell transplantation (HCT) prevented graft-versus-host disease (GVHD) and preserved graft-versus-leukemia (GVL) effects in mice. These effects were associated with downregulated donor T cell expression of tissue-specific homing and chemokine receptors, marked reduction of donor T cell migration into GVHD target tissues, and deletion of CD103(+) dendritic cells (DCs) in mesenteric lymph nodes (MLN). MLN CD103(+) DCs and peripheral lymph node (PLN) DCs include CCR7(+) and CCR7(-) subsets, but the role of these DC subsets in regulating donor T cell expression of homing and chemokine receptors remain unclear. Here, we show that recipient CCR7(+), but not CCR7(-), DCs in MLN induced donor T cell expression of gut-specific homing and chemokine receptors in a retinoid acid-dependent manner. CCR7 regulated activated DC migration from tissue to draining lymph node, but it was not required for the ability of DCs to induce donor T cell expression of tissue-specific homing and chemokine receptors. Finally, anti-CD3 treatment depleted CCR7(+) but not CCR7(-) DCs by inducing sequential expansion and apoptosis of CCR7(+) DCs in MLN and PLN. Apoptosis of CCR7(+) DCs was associated with DC upregulation of Fas expression and natural killer cell but not T, B, or dendritic cell upregulation of FasL expression in the lymph nodes. These results suggest that depletion of CCR7(+) host-type DCs, with subsequent inhibition of donor T cell migration into GVHD target tissues, can be an effective approach in prevention of acute GVHD and preservation of GVL effects. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Non-target organism effects tests on Vip3A and their application to the ecological risk assessment for cultivation of MIR162 maize.

PubMed

Raybould, Alan; Vlachos, Demetra

2011-06-01

Transgenic crops producing insecticidal proteins from Bacillus thuringiensis (Bt) provide economic, environmental and health benefits by maintaining or increasing crop yields with fewer applications of insecticide. To sustain these benefits, it is important to delay the evolution of insect resistance to the proteins, and to ensure that the proteins do not harm non-target organisms, particularly those that may control secondary pests that would otherwise flourish because of reduced insecticide applications. Vip3A is a Bt vegetative insecticidal protein that is active against lepidopterous pests. It has a different mode of action from other proteins for control of Lepidoptera in current Bt crops, and when combined with these proteins, it should help to delay the evolution of pest resistance to Bt crops. This paper presents data on the effects of Vip3A on non-target organisms, and an ecological risk assessment of MIR162 maize, which expresses Vip3Aa20. Laboratory studies indicate few adverse effects of Vip3A to non-target organisms: 11 of 12 species tested showed no adverse effects when exposed to high concentrations of Vip3A relative to estimated exposures resulting from cultivation of MIR162 maize. Daphnia magna exposed to Vip3Aa20 were unaffected in terms of survival or fecundity, but grew slightly more slowly than unexposed controls. The data indicate that cultivation of MIR162 maize poses negligible risk to non-target organisms, and that crops producing Vip3A are unlikely to adversely affect biological control organisms such that benefits from reduced insecticide applications are lost.

STAT3 signaling in CD4+ T cells is critical for the pathogenesis of chronic sclerodermatous graft-versus-host disease in a murine model.

PubMed

Radojcic, Vedran; Pletneva, Maria A; Yen, Hung-Rong; Ivcevic, Sanja; Panoskaltsis-Mortari, Angela; Gilliam, Anita C; Drake, Charles G; Blazar, Bruce R; Luznik, Leo

2010-01-15

Donor CD4+ T cells are thought to be essential for inducing delayed host tissue injury in chronic graft-versus-host disease (GVHD). However, the relative contributions of distinct effector CD4+ T cell subpopulations and the molecular pathways influencing their generation are not known. We investigated the role of the STAT3 pathway in a murine model of chronic sclerodermatous GVHD. This pathway integrates multiple signaling events during the differentiation of naive CD4+ T cells and impacts their homeostasis. We report that chimeras receiving an allograft containing STAT3-ablated donor CD4+ T cells do not develop classic clinical and pathological manifestations of alloimmune tissue injury. Analysis of chimeras showed that abrogation of STAT3 signaling reduced the in vivo expansion of donor-derived CD4+ T cells and their accumulation in GVHD target tissues without abolishing antihost alloreactivity. STAT3 ablation did not significantly affect Th1 differentiation while enhancing CD4+CD25+Foxp3+ T cell reconstitution through thymus-dependent and -independent pathways. Transient depletion of CD25+ T cells in chimeras receiving STAT3-deficient T cells resulted in delayed development of alloimmune gut and liver injury. This delayed de novo GVHD was associated with the emergence of donor hematopoietic stem cell-derived Th1 and Th17 cells. These results suggest that STAT3 signaling in graft CD4+ T cells links the alloimmune tissue injury of donor graft T cells and the emergence of donor hematopoietic stem cell-derived pathogenic effector cells and that both populations contribute, albeit in different ways, to the genesis of chronic GVHD after allogenic bone marrow transplantation in a murine model.

Dexamethasone palmitate ameliorates macrophages-rich graft-versus-host disease by inhibiting macrophage functions.

PubMed

Nishiwaki, Satoshi; Nakayama, Takayuki; Murata, Makoto; Nishida, Tetsuya; Terakura, Seitaro; Saito, Shigeki; Kato, Tomonori; Mizuno, Hiroki; Imahashi, Nobuhiko; Seto, Aika; Ozawa, Yukiyasu; Miyamura, Koichi; Ito, Masafumi; Takeshita, Kyosuke; Kato, Hidefumi; Toyokuni, Shinya; Nagao, Keisuke; Ueda, Ryuzo; Naoe, Tomoki

2014-01-01

Macrophage infiltration of skin GVHD lesions correlates directly with disease severity, but the mechanisms underlying this relationship remain unclear and GVHD with many macrophages is a therapeutic challenge. Here, we characterize the macrophages involved in GVHD and report that dexamethasone palmitate (DP), a liposteroid, can ameliorate such GVHD by inhibiting macrophage functions. We found that host-derived macrophages could exacerbate GVHD in a mouse model through expression of higher levels of pro-inflammatory TNF-α and IFN-γ, and lower levels of anti-inflammatory IL-10 than resident macrophages in mice without GVHD. DP significantly decreased the viability and migration capacity of primary mouse macrophages compared to conventional dexamethasone in vitro. DP treatment on day 7 and day 14 decreased macrophage number, and attenuated GVHD score and subsequent mortality in a murine model. This is the first study to provide evidence that therapy for GVHD should be changed on the basis of infiltrating cell type.

α-Mannan induces Th17-mediated pulmonary graft-versus-host disease in mice.

PubMed

Uryu, Hidetaka; Hashimoto, Daigo; Kato, Koji; Hayase, Eiko; Matsuoka, Satomi; Ogasawara, Reiki; Takahashi, Shuichiro; Maeda, Yoshinobu; Iwasaki, Hiromi; Miyamoto, Toshihiro; Saijo, Shinobu; Iwakura, Yoichiro; Hill, Geoffrey R; Akashi, Koichi; Teshima, Takanori

2015-05-07

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for various hematopoietic disorders. Graft-versus-host disease (GVHD) and infections are the major obstacles of HSCT, and their close relationship has been suggested. Although roles of bacterial and viral infections in the pathophysiology of GVHD are well described, impacts of fungal infection on GVHD remain to be elucidated. In mouse models of GVHD, injection of α-mannan (Mn), a major component of fungal cell wall, or heat-killed Candida albicans exacerbated GVHD, particularly in the lung. Mn-induced donor T-cell polarization toward Th17 and lung-specific chemokine environment in GVHD led to accumulation of Th17 cells in the lung. The detrimental effects of Mn on GVHD depended on donor IL-17A production and host C-type lectin receptor Dectin-2. These results suggest a previously unrecognized link between pulmonary GVHD and fungal infection after allogeneic HSCT. © 2015 by The American Society of Hematology.

Graft-versus-Host Disease Treatment: Predictors of Survival

PubMed Central

Levine, John E.; Logan, Brent; Wu, Juan; Alousi, Amin M.; Ho, Vincent; Bolaños-Meade, Javier; Weisdorf, Daniel

2010-01-01

Acute graft-versus-host disease (aGVHD) following allogeneic hematopoietic cell transplant (HCT) is the major reason for non-relapse mortality and thus is a major determinant of long term survival. Clinical trials of new aGVHD treatments are needed in order to identify approaches that will ultimately improve upon HCT survival. At present it is not clear how quickly response to GVHD treatment needs to be established in order to reliably categorize patients at high risk for death or to promptly identify those who might benefit from alternate treatment. Therefore, we analyzed time to response from onset of aGVHD treatment in 180 patients who were enrolled on a national, randomized, phase II aGVHD treatment clinical trial whose initial treatment of GVHD consisted of high dose steroids plus a second immunosuppressive agent. The aim of this analysis was to determine whether time to aGVHD treatment response predicts patient outcomes, especially survival. We used response at 14, 28 and 56 days from initiation of aGVHD treatment to categorize patients for non-relapse mortality and survival. Multivariate analyses and specificity/sensitivity analyses identified that day 28 response (complete or partial response) best categorized patients by non-relapse mortality and survival at 9 months from start of aGVHD treatment. If verified as a reliable predictor of late outcomes following other aGVHD treatment approaches, day 28 response should serve as a standard early endpoint for future trials of aGVHD therapy. PMID:20541024

Phase I Trial of Brentuximab Vedotin for Steroid-Refractory Chronic Graft-Versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation.

PubMed

DeFilipp, Zachariah; Li, Shuli; Kempner, Maria E; Brown, Jami; Del Rio, Candice; Valles, Betsy; Hunnewell, Chrisa; Saylor, Meredith; Vanderklish, Julie; Dey, Bimalangshu R; El-Jawahri, Areej; McAfee, Steven L; Spitzer, Thomas R; Chen, Yi-Bin

2018-05-11

We conducted a phase I study of brentuximab vedotin (BV), an antibody-drug conjugate targeting CD30, for the treatment of steroid-refractory chronic graft-versus-host disease (cGVHD). A modified 3+3 study design was used with the primary endpoint to determine the maximum tolerated dose (MTD) of BV in this population. Escalating doses of BV were planned, starting with 0.6 mg/kg q3weeks (dose level 0) and increasing by 0.3 mg/kg per dose level. BV was administered in 21-day cycles for up to 16 cycles of therapy. Nineteen patients were enrolled on the study, with 2 withdrawing consent prior to dosing. The median number of cycles of therapy was 4 (range, 1-16). Reasons for stopping therapy prematurely included toxicities (n=9), patient decision (n=3), lack of response (n=2), and death (n=1). There were 2 DLTs observed: PRES (cohort 4, grade 3) and sepsis (cohort 4, grade 4). The MTD was not reached as the trial was prematurely closed due to toxicity. Seven patients (41%) developed grade 3 or 4 adverse events that were attributed to therapy, including 4 patients who developed moderate or severe peripheral neuropathy that led to cessation of treatment in each case. According to NIH cGVHD Response Criteria, 8 patients (47%) experienced a partial response while 9 patients (53%) had a lack of response. There were no complete responses observed. Eleven patients (65%) were able to decrease their systemic corticosteroid dose by ≥50% by 6 months after initiation of BV, including 3 patients who were able to stop corticosteroids completely. The median soluble CD30 level prior to therapy was 61.5 ng/mL (range, 7.8-474.9), however, we did not observe any association between soluble CD30 level and cGVHD severity at enrollment or clinical responses to BV. In conclusion, BV may have activity in treatment of steroid-refractory cGVHD, yet its use is limited by treatment-emergent toxicities, including peripheral neuropathy. Continued efforts to investigate targeted approaches to cGVHD

Effect of malachite green toxicity on non target soil organisms.

PubMed

Gopinathan, R; Kanhere, J; Banerjee, J

2015-02-01

Although malachite green (MG), is banned in Europe and US for its carcinogenic and teratogenic effect, the dye being cheap, is persistently used in various countries for fish farming, silk, dye, leather and textile industries. Current research, however, fails to elucidate adequate knowledge concerning the effects of MG in our ecosystem. In the present investigation, for the first time, an attempt has been made to study the effects of MG on soil biota by testing Bacillus subtilis, Azotobacter chroococcum, Saccharomyces cerevisiae, Penicillium roqueforti, Eisenia fetida and seeds of three crop plants of different families. Various tests were conducted for determining cytotoxicity, genotoxicity, acute toxicity, morphological and germination effect. Our data confirmed MG toxicity on fungi and bacteria (gram positive and gram negative organisms) showing elevated level of ROS. Genotoxicity caused in the microorganisms was detected by DNA polymorphism and fragmentation. Also, scanning electron microscopy data suggests that the inhibitory effect of MG to these beneficial microbes in the ecosystem might be due to pore formation in the cell and its eventual disruption. Filter paper and artificial soil test conducted on earthworms demonstrated a LC 50 of 2.6 mg cm(-2) and 1.45 mg kg(-1) respectively with severe morphological damage. However, seed germination of Mung bean, Wheat and Mustard was found to be unaffected in presence of MG up to 100 mL(-1) concentration. Thus, understanding MG toxicity in non target soil organisms and emphasis on its toxicological effects would potentially explicate its role as an environmental contaminant. Copyright © 2014 Elsevier Ltd. All rights reserved.

Dendritic cell chimerism in oral mucosa of transplanted patients affected by graft-versus-host disease.

PubMed

Pérez, Claudio A; Rabanales, Ramón; Rojas-Alcayaga, Gonzalo; Larrondo, Milton; Escobar, Alejandro F; López, Mercedes N; Salazar-Onfray, Flavio; Alfaro, Jorge I; González, Fermín E

2016-02-01

Graft-versus-host disease (GVHD) is one of the main complications after haematopoietic stem cell transplantation. Clinical features of GVHD include either an acute (aGVHD) or a chronic (cGVHD) condition that affects locations such as the oral mucosa. While the involvement of the host's dendritic cells (DCs) has been demonstrated in aGVHD, the origin (donor/host) and mechanisms underlying oral cGVHD have not been completely elucidated. In this study, we intend to determine the origin of DCs present in mucosal tissue biopsies from the oral cavity of transplanted patients affected by cGVHD. We purified DCs, from oral biopsies of three patients with cGVHD, through immunobeads and subsequently performed DNA extraction. The origin of the obtained DCs was determined by PCR amplification of 13 informative short tandem repeat (STR) alleles. We also characterised the DCs phenotype and the inflammatory infiltrate from biopsies of two patients by immunohistochemistry. Clinical and histological features of the biopsies were concordant with oral cGVHD. We identified CD11c-, CD207- and CD1a-positive cells in the epithelium and beneath the basal layer. Purification of DCs from the mucosa of patients affected by post-transplantation cGVHD was >95%. PCR-STR data analysis of DCs DNA showed that 100% of analysed cells were of donor origin in all of the evaluated patients. Our results demonstrate that resident DCs isolated from the oral tissue of allotransplanted patients affected by cGVHD are originated from the donor. Further research will clarify the role of DCs in the development and/or severity of oral cGVHD. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Therapeutics for Graft-versus-Host Disease: From Conventional Therapies to Novel Virotherapeutic Strategies.

PubMed

Villa, Nancy Y; Rahman, Masmudur M; McFadden, Grant; Cogle, Christopher R

2016-03-22

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has a curative potential for many hematologic malignancies and blood diseases. However, the success of allo-HSCT is limited by graft-versus-host disease (GVHD), an immunological syndrome that involves inflammation and tissue damage mediated by donor lymphocytes. Despite immune suppression, GVHD is highly incident even after allo-HSCT using human leukocyte antigen (HLA)-matched donors. Therefore, alternative and more effective therapies are needed to prevent or control GVHD while preserving the beneficial graft-versus-cancer (GVC) effects against residual disease. Among novel therapeutics for GVHD, oncolytic viruses such as myxoma virus (MYXV) are receiving increased attention due to their dual role in controlling GVHD while preserving or augmenting GVC. This review focuses on the molecular basis of GVHD, as well as state-of-the-art advances in developing novel therapies to prevent or control GVHD while minimizing impact on GVC. Recent literature regarding conventional and the emerging therapies are summarized, with special emphasis on virotherapy to prevent GVHD. Recent advances using preclinical models with oncolytic viruses such as MYXV to ameliorate the deleterious consequences of GVHD, while maintaining or improving the anti-cancer benefits of GVC will be reviewed.

Expanded Target-Chemical Analysis Reveals Extensive Mixed-Organic-Contaminant Exposure in U.S. Streams.

PubMed

Bradley, Paul M; Journey, Celeste A; Romanok, Kristin M; Barber, Larry B; Buxton, Herbert T; Foreman, William T; Furlong, Edward T; Glassmeyer, Susan T; Hladik, Michelle L; Iwanowicz, Luke R; Jones, Daniel K; Kolpin, Dana W; Kuivila, Kathryn M; Loftin, Keith A; Mills, Marc A; Meyer, Michael T; Orlando, James L; Reilly, Timothy J; Smalling, Kelly L; Villeneuve, Daniel L

2017-05-02

Surface water from 38 streams nationwide was assessed using 14 target-organic methods (719 compounds). Designed-bioactive anthropogenic contaminants (biocides, pharmaceuticals) comprised 57% of 406 organics detected at least once. The 10 most-frequently detected anthropogenic-organics included eight pesticides (desulfinylfipronil, AMPA, chlorpyrifos, dieldrin, metolachlor, atrazine, CIAT, glyphosate) and two pharmaceuticals (caffeine, metformin) with detection frequencies ranging 66-84% of all sites. Detected contaminant concentrations varied from less than 1 ng L -1 to greater than 10 μg L -1 , with 77 and 278 having median detected concentrations greater than 100 ng L -1 and 10 ng L -1 , respectively. Cumulative detections and concentrations ranged 4-161 compounds (median 70) and 8.5-102 847 ng L -1 , respectively, and correlated significantly with wastewater discharge, watershed development, and toxic release inventory metrics. Log 10 concentrations of widely monitored HHCB, triclosan, and carbamazepine explained 71-82% of the variability in the total number of compounds detected (linear regression; p-values: < 0.001-0.012), providing a statistical inference tool for unmonitored contaminants. Due to multiple modes of action, high bioactivity, biorecalcitrance, and direct environment application (pesticides), designed-bioactive organics (median 41 per site at μg L -1 cumulative concentrations) in developed watersheds present aquatic health concerns, given their acknowledged potential for sublethal effects to sensitive species and lifecycle stages at low ng L -1 .

Therapeutic effects of hydrogen on chronic graft-versus-host disease.

PubMed

Qian, Liren; Liu, Xiaopeng; Shen, Jianliang; Zhao, Defeng; Yin, Wenjie

2017-10-01

The incidence of chronic graft-versus-host disease (cGVHD) is rising recent years, which has been the leading cause of non-transplantation mortality post allogenetic hematopoietic stem cell transplantation (HSCT). Imbalance of inflammatory cytokines and fibrosis plays critical roles in the pathogenesis of cGVHD. Recent studies showed that molecular hydrogen has anti-inflammatory, antioxidant, anti-fibrosis effects. Therefore, we hypothesized that molecular hydrogen may have therapeutic effects on cGVHD. To determine whether hydrogen could protect mice from cGVHD in an MHC-incompatible murine bone marrow transplantation (BMT) model, survival rates of mice were calculated, and skin lesions were also evaluated after BMT. This article demonstrated that administration of hydrogen-rich saline increased survival rate of cGVHD mice. Administration of hydrogen-rich saline after transplantation also reduced skin lesions of cGVHD mice. Previously, we reported the therapeutic effects of hydrogen on acute GVHD. However, there was no report on the therapeutic effects of hydrogen on cGVHD mice. It is suggested that hydrogen has a potential as an effective and safe therapeutic agent on cGVHD. This study will provide new ideas on the treatment of cGVHD and has important theoretical values. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Preclinical Testing of Antihuman CD28 Fab' Antibody in a Novel Nonhuman Primate Small Animal Rodent Model of Xenogenic Graft-Versus-Host Disease.

PubMed

Hippen, Keli L; Watkins, Benjamin; Tkachev, Victor; Lemire, Amanda M; Lehnen, Charles; Riddle, Megan J; Singh, Karnail; Panoskaltsis-Mortari, Angela; Vanhove, Bernard; Tolar, Jakub; Kean, Leslie S; Blazar, Bruce R

2016-12-01

Graft-versus-host disease (GVHD) is a severe complication of hematopoietic stem cell transplantation. Current therapies to prevent alloreactive T cell activation largely cause generalized immunosuppression and may result in adverse drug, antileukemia and antipathogen responses. Recently, several immunomodulatory therapeutics have been developed that show efficacy in maintaining antileukemia responses while inhibiting GVHD in murine models. To analyze efficacy and better understand immunological tolerance, escape mechanisms, and side effects of clinical reagents, testing of species cross-reactive human agents in large animal GVHD models is critical. We have previously developed and refined a nonhuman primate (NHP) large animal GVHD model. However, this model is not readily amenable to semi-high throughput screening of candidate clinical reagents. Here, we report a novel, optimized NHP xenogeneic GVHD (xeno-GVHD) small animal model that recapitulates many aspects of NHP and human GVHD. This model was validated using a clinically available blocking, monovalent anti-CD28 antibody (FR104) whose effects in a human xeno-GVHD rodent model are known. Because human-reactive reagents may not be fully cross-reactive or effective in vivo on NHP immune cells, this NHP xeno-GVHD model provides immunological insights and direct testing on NHP-induced GVHD before committing to the intensive NHP studies that are being increasingly used for detailed evaluation of new immune therapeutic strategies before human trials.

Antibiotic-Induced Depletion of Anti-inflammatory Clostridia Is Associated with the Development of Graft-versus-Host Disease in Pediatric Stem Cell Transplantation Patients.

PubMed

Simms-Waldrip, Tiffany R; Sunkersett, Gauri; Coughlin, Laura A; Savani, Milan R; Arana, Carlos; Kim, Jiwoong; Kim, Minsoo; Zhan, Xiaowei; Greenberg, David E; Xie, Yang; Davies, Stella M; Koh, Andrew Y

2017-05-01

Adult stem cell transplantation (SCT) patients with graft-versus-host-disease (GVHD) exhibit significant disruptions in gut microbial communities. These changes are associated with higher overall mortality and appear to be driven by specific antibiotic therapies. It is unclear whether pediatric SCT patients who develop GVHD exhibit similar antibiotic-induced gut microbiota community changes. Here, we show that pediatric SCT patients (from Children's Medical Center Dallas, n = 8, and Cincinnati Children's Hospital, n = 7) who developed GVHD showed a significant decline, up to 10-log fold, in gut anti-inflammatory Clostridia (AIC) compared with those without GVHD. In fact, the development of GVHD is significantly associated with this AIC decline and with cumulative antibiotic exposure, particularly antibiotics effective against anaerobic bacteria (P = .003, Firth logistic regression analysis). Using metagenomic shotgun sequencing analysis, we were able to identify specific commensal bacterial species, including AIC, that were significantly depleted in GVHD patients. We then used a preclinical GVHD model to verify our clinical observations. Clindamycin depleted AIC and exacerbated GVHD in mice, whereas oral AIC supplementation increased gut AIC levels and mitigated GVHD in mice. Together, these data suggest that an antibiotic-induced AIC depletion in the gut microbiota is associated with the development of GVHD in pediatric SCT patients. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Maternal microchimerism in biliary atresia

PubMed Central

Muraji, Toshihiro

2014-01-01

The etiology of biliary atresia (BA) is unknown; however, the liver histology is similar to that observed in immune-mediated hepatic disorders. Liver fibrosis in BA progresses even after bile drainage has been achieved by the Kasai operation. Maternal microchimerism has been purported to play a part in the pathogenesis of BA as well as certain autoimmune diseases. However, the role of maternal cells has not yet been determined in BA. Specifically, it is unknown whether these maternal cells function as maternal effector T lymphocytes, or targets or bystanders. We currently hypothesize that the first hit is due to GvHD interaction by engrafted maternal effector T lymphocytes. Furthermore, we suggest that the secondary effects that are manifested by progressive cirrhosis are caused either by maternal chimeric effector T lymphocytes (e.g., GvHD interaction) or targets (e.g., HvGD interaction). Based on our hypothesis, mixed lymphocyte reactions between patients and their mothers might shed light on the etiopathogenesis and prognostic indicators. PMID:24670921

Serum Vitamin A Levels May Affect the Severity of Ocular Graft-versus-Host Disease.

PubMed

Tong, Jiefeng; Hu, Renjian; Zhao, Yingying; Xu, Yang; Zhao, Xiaoying; Jin, Xiuming

2017-01-01

Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established therapeutic option for a range of inherited and acquired hematological disorders. However, graft-versus-host disease (GVHD) remains the leading cause of non-relapse mortality in allogeneic HSCT recipients. Ocular involvement occurs in up to 80% of chronic GVHD patients. In our cases, the diagnosis of vitamin A deficiency was suspected for GVHD patients. Serum vitamin A measurements were conducted to confirm clinical suspicions. Our study revealed significant decrease in serum levels of vitamin A in chronic liver GVHD patients. Although there have been many studies evaluating ocular manifestations in patients with GVHD, the present study is, to our knowledge, the first to study the relationship between vitamin A and ocular manifestations of GVHD in humans. Our data suggest that vitamin A deficiency affects the severity of ocular GVHD in adults.

Joint and fascial chronic graft-vs-host disease: correlations with clinical and laboratory parameters

PubMed Central

Vukić, Tamara; Smith, Sean Robinson; Ljubas Kelečić, Dina; Desnica, Lana; Prenc, Ema; Pulanić, Dražen; Vrhovac, Radovan; Nemet, Damir; Pavletic, Steven Z.

2016-01-01

Aim To determine if there are correlations between joint and fascial chronic graft-vs-host disease (cGVHD) with clinical findings, laboratory parameters, and measures of functional capacity. Methods 29 patients were diagnosed with cGVHD based on National Institutes of Health (NIH) Consensus Criteria at the University Hospital Centre Zagreb from October 2013 to October 2015. Physical examination, including functional measures such as 2-minute walk test and hand grip strength, as well as laboratory tests were performed. The relationship between these evaluations and the severity of joint and fascial cGVHD was tested by logistical regression analysis. Results 12 of 29 patients (41.3%) had joint and fascial cGVHD diagnosed according to NIH Consensus Criteria. There was a significant positive correlation of joint and fascial cGVHD and skin cGVHD (P < 0.001), serum C3 complement level (P = 0.045), and leukocytes (P = 0.032). There was a significant negative correlation between 2-minute walk test (P = 0.016), percentage of cytotoxic T cells CD3+/CD8+ (P = 0.022), serum albumin (P = 0.047), and Karnofsky score (P < 0.001). Binary logistic regression model found that a significant predictor for joint and fascial cGVHD was cGVHD skin involvement (odds ratio, 7.79; 95 confidence interval 1.87-32.56; P = 0.005). Conclusion Joint and fascial cGVHD manifestations correlated with multiple laboratory measurements, clinical features, and cGVHD skin involvement, which was a significant predictor for joint and fascial cGVHD. PMID:27374828

Endoscopic and Histological Findings Are Predicted by Fecal Calprotectin in Acute Intestinal Graft-Versus-Host-Disease.

PubMed

Adam, Birgit; Koldehoff, Michael; Ditschkowski, Markus; Gromke, Tanja; Hlinka, Michal; Trenschel, Rudolf; Kordeals, Lambros; Steckel, Nina K; Beelen, Dietrich W; Liebregts, Tobias

2016-07-01

Gastrointestinal graft-versus-host-disease (GI-GVHD) is a major cause of nonrelapse mortality after hematopoietic stem cell transplantation (HSCT) necessitating endoscopic examinations and biopsies for diagnosis. Fecal calprotectin (CPT) has been widely used in gastrointestinal inflammation, but comprehensive data in GI-GVHD are lacking. We aimed to identify an association of CPT with endoscopic findings, mucosal damage and symptoms for diagnosing and monitoring acute GI-GVHD. Symptoms were prospectively evaluated in 110 consecutive HSCT recipients by standardized questionnaires and Bristol Stool Scale (BSS). CPT was assayed by ELISA. Symptom assessment and CPT were performed weekly and with onset of first symptoms. GVHD was diagnosed according to the Glucksberg criteria and by endoscopic biopsies. Patients with GI-GVHD received standard high-dose corticosteroid therapy and follow-up CPT, and symptom evaluation was performed after 28 days. Patients not responding to steroid treatment were re-evaluated by colonoscopy. GI-GVHD was diagnosed in 40 patients. Twelve patients with GI symptoms and CMV colitis and 24 patients with isolated skin GVHD were included as control subjects. CPT was significantly higher in GI-GVHD compared to skin GVHD and CMV colitis. Endoscopic findings, histological grading, abdominal cramps, diarrhea, urgency and BSS correlated with CPT. At follow-up, CPT correlated with abdominal cramps, diarrhea, urgency and BSS. In steroid refractory patients, CPT level was still significantly associated with severity of mucosal damage. CPT predicts endoscopic and histological findings in GI-GVHD and correlates with lower GI symptoms. It enables to discriminate GVHD from CMV colitis and to monitor therapeutic success.

Simultaneous cytofluorometric measurement of phagocytosis, burst production and killing of human phagocytes using Candida albicans and Staphylococcus aureus as target organisms.

PubMed

Salih, H R; Husfeld, L; Adam, D

2000-05-01

Polymorphonuclear leukocytes (PMN) play a central role in the elimination of most extracellular pathogens, and an impairment of their functions predisposes an individual towards local and systemic bacterial and fungal infections. Here we describe a rapid and easy-to-perform cytofluorometric assay for investigation of PMN activity using Candida albicans and Staphylococcus aureus as target organisms. Phagocytes were stained with anti-CD13-RPE antibody, and microorganisms were stained with calcein-AM. Oxidative burst production was measured by oxidation of dihydroethidium. The percentage of killed target organisms after ingestion was determined by staining with ethidium-homodimer-1 after lysis of human cells. The dyes and procedures used in this method were chosen after comparison of different stains and cell preparation techniques described in previous assays. Concerning phagocytosis, the percentages of active phagocytes and of ingested microorganisms were determined. Furthermore, the method allowed measurement of the resulting percentage of PMNs producing respiratory burst, and of the percentage of killed microorganisms. We minimized artifactual changes, which might have been the reason for the difficulties and conflicting results of other cytofluorometric methods. The described method provides a new whole blood cytofluorometric assay, which combines rapid and simple handling with high reproducibility of results obtained by investigation of PMN activity using Candida albicans and Staphylococcus aureus as target organisms.

Surrogate species selection for assessing potential adverse environmental impacts of genetically engineered insect-resistant plants on non-target organisms.

PubMed

Carstens, Keri; Cayabyab, Bonifacio; De Schrijver, Adinda; Gadaleta, Patricia G; Hellmich, Richard L; Romeis, Jörg; Storer, Nicholas; Valicente, Fernando H; Wach, Michael

2014-01-01

Most regulatory authorities require that developers of genetically engineered insect-resistant (GEIR) crops evaluate the potential for these crops to have adverse impacts on valued non-target organisms (NTOs), i.e., organisms not intended to be controlled by the trait. In many cases, impacts to NTOs are assessed using surrogate species, and it is critical that the data derived from surrogates accurately predict any adverse impacts likely to be observed from the use of the crop in the agricultural context. The key is to select surrogate species that best represent the valued NTOs in the location where the crop is going to be introduced, but this selection process poses numerous challenges for the developers of GE crops who will perform the tests, as well as for the ecologists and regulators who will interpret the test results. These issues were the subject of a conference "Surrogate Species Selection for Assessing Potential Adverse Environmental Impacts of Genetically Engineered Plants on Non-Target Organisms" convened by the Center for Environmental Risk Assessment, ILSI Research Foundation. This report summarizes the proceedings of the conference, including the presentations, discussions and the points of consensus agreed to by the participants.

Blood and Marrow Transplant Clinical Trials Network Report on the Development of Novel Endpoints and Selection of Promising Approaches for Graft-versus-Host Disease Prevention Trials.

PubMed

Pasquini, Marcelo C; Logan, Brent; Jones, Richard J; Alousi, Amin M; Appelbaum, Frederick R; Bolaños-Meade, Javier; Flowers, Mary E D; Giralt, Sergio; Horowitz, Mary M; Jacobsohn, David; Koreth, John; Levine, John E; Luznik, Leo; Maziarz, Richard; Mendizabal, Adam; Pavletic, Steven; Perales, Miguel-Angel; Porter, David; Reshef, Ran; Weisdorf, Daniel; Antin, Joseph H

2018-06-01

Graft-versus-host disease (GVHD) is a common complication after hematopoietic cell transplantation (HCT) and associated with significant morbidity and mortality. Preventing GVHD without chronic therapy or increasing relapse is a desired goal. Here we report a benchmark analysis to evaluate the performance of 6 GVHD prevention strategies tested at single institutions compared with a large multicenter outcomes database as a control. Each intervention was compared with the control for the incidence of acute and chronic GVHD and overall survival and against novel composite endpoints: acute and chronic GVHD, relapse-free survival (GRFS), and chronic GVHD, relapse-free survival (CRFS). Modeling GRFS and CRFS using the benchmark analysis further informed the design of 2 clinical trials testing GVHD prophylaxis interventions. This study demonstrates the potential benefit of using an outcomes database to select promising interventions for multicenter clinical trials and proposes novel composite endpoints for use in GVHD prevention trials. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Treatment of oral mucosal manifestations of chronic graft-versus-host disease: dexamethasone vs. budesonide.

PubMed

Zadik, Yehuda; Elad, Sharon; Shapira, Anat; Shapira, Michael Y

2017-02-01

The oral mucosa is commonly involved in chronic graft-versus-host disease (cGVHD). Oral mucosal cGVHD markedly affect individual's daily function and wellbeing. In some cases, it might become a life threating complication. Areas covered: This article describes the rationale for treatment, method of topical application in the oral cavity, evidence supporting the topical administration of dexamethasone and budesonide for oral cGVHD, and their adverse effects. Expert opinion: Evidence supports the use of topical dexamethasone and budesonide for treatment of oral cGVHD. Topical corticosteroid choice for oral cGVHD, takes into consideration the potency, bioavailability, preferred concentration, and possible adverse effects. Budesonide's pharmacological characteristics mark it as a preferable topical agent for oral cGVHD.

Office and 24-hour heart rate and target organ damage in hypertensive patients

PubMed Central

2012-01-01

Background We investigated the association between heart rate and its variability with the parameters that assess vascular, renal and cardiac target organ damage. Methods A cross-sectional study was performed including a consecutive sample of 360 hypertensive patients without heart rate lowering drugs (aged 56 ± 11 years, 64.2% male). Heart rate (HR) and its standard deviation (HRV) in clinical and 24-hour ambulatory monitoring were evaluated. Renal damage was assessed by glomerular filtration rate and albumin/creatinine ratio; vascular damage by carotid intima-media thickness and ankle/brachial index; and cardiac damage by the Cornell voltage-duration product and left ventricular mass index. Results There was a positive correlation between ambulatory, but not clinical, heart rate and its standard deviation with glomerular filtration rate, and a negative correlation with carotid intima-media thickness, and night/day ratio of systolic and diastolic blood pressure. There was no correlation with albumin/creatinine ratio, ankle/brachial index, Cornell voltage-duration product or left ventricular mass index. In the multiple linear regression analysis, after adjusting for age, the association of glomerular filtration rate and intima-media thickness with ambulatory heart rate and its standard deviation was lost. According to the logistic regression analysis, the predictors of any target organ damage were age (OR = 1.034 and 1.033) and night/day systolic blood pressure ratio (OR = 1.425 and 1.512). Neither 24 HR nor 24 HRV reached statistical significance. Conclusions High ambulatory heart rate and its variability, but not clinical HR, are associated with decreased carotid intima-media thickness and a higher glomerular filtration rate, although this is lost after adjusting for age. Trial Registration ClinicalTrials.gov: NCT01325064 PMID:22439900

Application of the target lipid model and passive samplers to characterize the toxicity of bioavailable organics in oil sands process-affected water.

PubMed

Redman, Aaron D; Parkerton, Thomas F; Butler, Josh David; Letinski, Daniel J; Frank, Richard A; Hewitt, L Mark; Bartlett, Adrienne J; Gillis, Patricia Leigh; Marentette, Julie R; Parrott, Joanne L; Hughes, Sarah A; Guest, Rodney; Bekele, Asfaw; Zhang, Kun; Morandi, Garrett; Wiseman, Steve B; Giesy, John P

2018-06-14

Oil sand operations in Alberta, Canada will eventually include returning treated process-affected waters to the environment. Organic constituents in oil sand process-affected water (OSPW) represent complex mixtures of nonionic and ionic (e.g. naphthenic acids) compounds, and compositions can vary spatially and temporally, which has impeded development of water quality benchmarks. To address this challenge, it was hypothesized that solid phase microextraction fibers coated with polydimethylsiloxane (PDMS) could be used as a biomimetic extraction (BE) to measure bioavailable organics in OSPW. Organic constituents of OSPW were assumed to contribute additively to toxicity, and partitioning to PDMS was assumed to be predictive of accumulation in target lipids, which were the presumed site of action. This method was tested using toxicity data for individual model compounds, defined mixtures, and organic mixtures extracted from OSPW. Toxicity was correlated with BE data, which supports the use of this method in hazard assessments of acute lethality to aquatic organisms. A species sensitivity distribution (SSD), based on target lipid model and BE values, was similar to SSDs based on residues in tissues for both nonionic and ionic organics. BE was shown to be an analytical tool that accounts for bioaccumulation of organic compound mixtures from which toxicity can be predicted, with the potential to aid in the development of water quality guidelines.

Toxicity of the bionematicide 1,4-naphthoquinone on non-target soil organisms.

PubMed

Chelinho, S; Maleita, C M N; Francisco, R; Braga, M E M; da Cunha, M J M; Abrantes, I; de Sousa, H C; Morais, P V; Sousa, J P

2017-08-01

The main goal of the present study was to evaluate the ecotoxicological effects of 1,4-naphthoquinone (1,4-NTQ), a natural-origin compound presenting nematicidal activity, that can be obtained from walnut husk, in plants and soil invertebrates, including non-target soil nematode communities. This research was part of an ongoing project that aims to develop environmentally-friendly nematicides obtained from agricultural residues. The battery of ISO tests included emergence and growth of corn (Zea mays) and rape (Brassica napus); avoidance with the earthworm Eisenia andrei and the collembolan Folsomia candida; and reproduction with the previous species plus the enchytraeid Enchytraeus crypticus. A novel soil nematode community assay was also performed. ISO tests and nematode assays were conducted using a natural uncontaminated soil that was spiked with a range of 1,4-NTQ concentrations. Toxicity of 1,4-NTQ was found for all test-species and the most sensitive were F. candida and E. andrei. After 7 days of exposure to 1,4-NTQ, nematode abundance decreased along the concentration gradient, and a partial recovery was observed after 14 days (1,4-NTQ <48 mg kg -1 soil). The number of nematode families consistently decreased in both periods. Overall, results indicate that a 1,4-NTQ concentration of <20 mg kg -1 could be environmentally safe but preliminary data suggest that it might be ineffective for the target-nematodes, root-knot nematodes, Meloidogyne spp., and root-lesion nematodes, Pratylenchus spp. In addition, if higher dosages of 1,4-NTQ bionematicide are necessary, the potential recovery of non-target organisms under real field scenarios also needs to be assessed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Ambulatory and home blood pressure monitoring in children and adolescents: diagnosis of hypertension and assessment of target-organ damage.

PubMed

Karpettas, Nikos; Nasothimiou, Efthimia; Kollias, Anastasios; Vazeou, Adriani; Stergiou, George S

2013-04-01

The prevalence of elevated blood pressure in children and adolescents is more common than previously believed and often represents the early onset of essential hypertension, particularly in adolescents. The definition of hypertension in children is based on distribution criteria and normalcy tables that provide blood pressure percentiles for each measurement method (office, ambulatory and home) according to the individual's age, gender and body size. Owing to the white coat and masked hypertension phenomena, ambulatory blood pressure monitoring is indispensable for the diagnosis of hypertension in children. Home blood pressure monitoring in children has been less well studied, and at present, treatment decisions should not be based solely on such measurements. Hypertension-induced preclinical target-organ damage (mainly echocardiographic left ventricular hypertrophy) is not uncommon in children and should be evaluated in all hypertensive children. Other indices of target-organ damage, such as carotid intima-media thickness, pulse wave velocity and microalbuminuria, remain under investigation in pediatric hypertension.

Non-target screening analyses of organic contaminants in river systems as a base for monitoring measures

NASA Astrophysics Data System (ADS)

Schwarzbauer, J.

2009-04-01

Organic contaminants discharged to the aquatic environment exhibit a high diversity with respect to their molecular structures and the resulting physico-chemical properties. The chemical analysis of anthropogenic contamination in river systems is still an important feature, especially with respect to (i) the identification and structure elucidation of novel contaminants, (ii) to the characterisation of their environmental behaviour and (iii) to their risk for natural systems. A huge proportion of riverine contamination is caused by low-molecular weight organic compounds, like pesticides plasticizers, pharmaceuticals, personal care products, technical additives etc. Some of them, like PCB or PAH have already been investigated thoroughly and, consequently, their behaviour in aqueous systems is very well described. Although analyses on organic substances in river water traditionally focused on selected pollutants, in particular on common priority pollutants which are monitored routinely, the occurrence of further contaminants, e.g. pharmaceuticals, personal care products or chelating agents has received increasing attention within the last decade. Accompanied, screening analyses revealing an enormous diversity of low-molecular weight organic contaminants in waste water effluents and river water become more and more noticed. Since many of these substances have been rarely noticed so far, it will be an important task for the future to study their occurrence and fate in natural environments. Further on, it should be a main issue of environmental studies to provide a comprehensive view on the state of pollution of river water, in particular with respect to lipophilic low molecular weight organic contaminants. However, such non-target-screening analyses has been performed only rarely in the past. Hence, we applied extended non-target screening analyses on longitudinal sections of the rivers Rhine, Rur and Lippe (Germany) on the base of GC/MS analyses. The investigations

Tolerance and chimerism.

PubMed

Kolb, Hans-Jochem; Guenther, Wolfgang; Gyurkocza, Boglarka; Hoetzl, Florian; Simoes, Belinda; Falk, Christine; Schleuning, Michael; Ledderose, Georg

2003-05-15

Stem-cell transplantation from human leukocyte antigen (HLA)-haploidentical family members carries a high risk of rejection and graft-versus-host disease (GVHD) if donor and recipient differ by more than one HLA antigen. The authors have developed treatment protocols from studies in dog leukocyte antigen-haploidentical dogs that prevent rejection and modify GVHD to the extent that patients with aggressive hematologic neoplasia can be treated with success. Principal improvements have been achieved in the use of cyclophosphamide and total-body irradiation for conditioning and T-cell depletion for prevention of GVHD. More recently, the combination of marrow and CD6-depleted mobilized donor blood cells (MDBC) has been introduced for HLA-haploidentical transplantation on the basis that CD6-depleted MDBC contain immunoregulatory cells besides stem cells and natural killer cells. Clinical results are reported on 36 patients with high-risk hematologic neoplasia. The results encourage the use of HLA-haploidentical stem-cell transplantation at an earlier stage of the disease. This method could also be of use for tolerance induction in organ transplantation.

Increased Level of IFN-γ and IL-4 Spot-Forming Cells on ELISPOT Assay as Biomarkers for Acute Graft-Versus-Host Disease and Concurrent Infections

PubMed Central

Hirayama, Masahiro; Azuma, Eiichi; Komada, Yoshihiro

2012-01-01

Acute graft-versus-host disease (aGVHD) remains a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Infections may coexist and in certain circumstances aggravate aGVHD. It was described that type 1 as well as type 2 cytokines are important mediators of aGVHD. We measured spot-forming cells (SFCs) for interferon (IFN)-γ, interleukin (IL)-4, IL-10, and IL-17 in unstimulated peripheral blood from 80 patients with hematological disorders who underwent allogeneic hematopoietic stem cell transplantation by using the enzyme-linked immunospot (ELISPOT) assay that reflects the ongoing in vivo immune status. A serial monitoring showed that both type 1 and type 2 cytokine SFCs were correlated with aGVHD activity. The numbers of IFN-γ and IL-4 SFCs in patients with grade II-IV aGVHD were significantly higher than those in patients with grade 0 and/or I aGVHD. Elevation of IFN-γ and IL-4 SFCs was significantly correlated with the severity of aGVHD, but not with infection itself, e.g., cytomegalovirus infection. Cytokine SFCs are clinically relevant biomarkers for the diagnostic and therapeutic evaluation of aGVHD and concurrent infection. PMID:24710414

Defining the Role of BTLA in Breast Cancer Immunosurveillance and Selective Targeting of the BTLA-HVEM-LIGHT Costimulatory System

DTIC Science & Technology

2010-05-01

receptor superfamily, member 14 ( herpesvirus entry mediator) (Tnfrsf14), mRNA. 1 atggaacctc tcccaggatg ggggtcggca ccctggagcc...reverse disease, suggesting its mechanism occurs early after aHSCT. Anti-BTLA treatment prevented GVHD independently of herpesvirus entry mediator...2663-2674 (2007). 29. Nelson, C. A. et al., Structural determinants of herpesvirus entry mediator recognition by murine B and T lymphocyte

Occurrence of graft-versus-host disease increases mortality after umbilical cord blood transplantation for acute myeloid leukaemia: a report from Eurocord and the ALWP of the EBMT.

PubMed

Baron, F; Ruggeri, A; Beohou, E; Labopin, M; Mohty, M; Sanz, J; Vigouroux, S; Furst, S; Bosi, A; Chevallier, P; Cornelissen, J J; Michallet, M; Sierra, J; Karakasis, D; Savani, B N; Gluckman, E; Nagler, A

2018-02-01

The efficacy of umbilical cord blood transplantation (UCBT) as treatment for acute myeloid leukaemia (AML) relies on immune-mediated graft-versus-leukaemia effects. Previous studies have suggested a strong association between graft-versus-host disease (GVHD) occurrence and graft-versus-leukaemia effects after allogeneic hematopoietic cell transplantation. Here, we evaluated the kinetics of relapse rate in correlation with GVHD occurrence after UCBT. The kinetics of relapse rate over time in correlation to GVHD occurrence were assessed by calculating the relapse rate per patient-year within sequential 90-day intervals. The impact of GVHD on relapse and mortality was further studied in multivariate Cox models handling GVHD as a time-dependent covariate. The study included data from 1068 patients given single (n = 567) or double (n = 501) UCBT. The proportion of patients with grade II, III and IV acute GVHD was 20%, 7% and 4%, respectively. At 2 years, the cumulative incidence of chronic GVHD was 42%, the cumulative incidence of relapse was 32%, and overall survival was 32% as well. Relapse rates declined gradually over time during the first 30 months after transplantation. There was a possible suggestion that grade II-IV acute (HR = 0.8, P = 0.1) and chronic (HR = 0.65, P = 0.1) GVHD decreased relapse risk. However, grade II-IV acute GVHD significantly increased early (the first 18 months after UCBT) mortality (HR = 1.3, P = 0.02), whilst chronic GVHD increased each early (HR = 2.7, P < 0.001) and late (HR = 4.9, P < 0.001) mortality after UCBT. The occurrence of grade II-IV acute or chronic GVHD each increases overall mortality after UCBT for AML mitigating the possible graft-versus-leukemia effect of GVHD. © 2017 The Association for the Publication of the Journal of Internal Medicine.

Pentraxin-3 levels in graft-versus-host disease during allogeneic hematopoietic stem cell transplantation.

PubMed

Doehn, Jan-Moritz; Winkler, Andreas; Kuzmina, Zoya; Hladik, Anastasiya; Greinix, Hildegard; Knapp, Sylvia; Robak, Oliver

2016-10-01

Acute and chronic graft-versus-host-diseases (aGVHD and cGVHD, respectively) are serious complications after hematopoietic stem cell transplantation (HSCT), impairing survival and quality of life. Because the underlying pathomechanism of GVHD is still poorly understood, we investigated the novel inflammatory marker Pentraxin-3 (PTX3) for its potential role in acute and chronic GVHD compared with autologous HSCT and healthy individuals. We collected plasma samples from patients undergoing autologous (n = 12) and allogeneic (n = 28) HSCT and from healthy individuals (n = 15) throughout 7 days before and up to 1 year after HSCT. PTX3 levels in patients with aGVHD were significantly higher (36.4 ± 23.6 ng/mL) than in allogeneic patients without aGVHD (10.4 ± 4.4 ng/mL, p = 0.0001), autologous controls (11.4 ± 6.7 ng/mL, p = 0.001), or healthy individuals (1.9 ± 0.6 ng/mL, p < 0.001). PTX3 levels in patients with cGVHD (13.6 ± 6.3 ng/mL) were significantly lower than in allogeneic patients without cGVHD (25.1 ± 13.8 ng/mL, p = 0.04) and higher than in autologous controls (8.9 ± 7.8 ng/mL, p = 0.07) and healthy individuals (1.9 ± 0.6 ng/mL, p < 0.001). Severity of aGVHD and cGVHD correlated with PTX3 levels. Rising PTX3 levels after HSCT indicated unfavorable outcome. We show that PTX3 levels correlate with the severity of aGVHD, cGVHD, and-with reservations-survival in patients undergoing allogeneic HSCT. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

[Prevalence of target organ damage and metabolic abnormalities in resistant hypertension].

PubMed

Armario, Pedro; Oliveras, Anna; Hernández Del Rey, Raquel; Ruilope, Luis Miguel; De La Sierra, Alejandro

2011-10-15

Patients with resistant hypertension (RH) are relatively frequently visited in specialized units of hypertension. The aim of this study was to assess the prevalence of target organ damage, central obesity and metabolic syndrome in a cohort of patients with RH consecutively included in the Register of Resistant Hypertension of the Spanish Society of Hypertension (SHE-LELHA). Cross-sectional, multicenter epidemiologic study in usual clinical practice conditions. Patients with clinical diagnosis of resistant hypertension, that is, office systolic and diastolic blood pressure ≥ 140 mm Hg and/or ≥ 90 mm Hg, respectively, despite a prescribed therapeutic schedule with an appropriate combination of three or more full-dose antihypertensive drugs, including a diuretic, were consecutively recruited from specialized hypertension units spread through Spain. Demographic and anthropometric characteristics as well as cardiovascular risk factors and associated conditions were recorded, and all the subjects underwent 24-h ambulatory blood pressure monitoring. Left ventricular hypertrophy was considered as a left ventricular mass index ≥ 125 g/m(2) in males and ≥ 110 g/m(2) in females. Left atrial enlargement was defined as an indexed left atrium diameter ≥ 26 mm/m(2). Microalbuminuria was defined as a urinary albumin/creatinine ratio ≥ 22 mg/g in males and ≥ 31 mg/g in females. 513 patients were included, aged 64±11 years old, 47% women. Central obesity was present in 65.7% (CI 95% 61.6-69.9), 38.6% (CI 95% 34.4-42.8) had diabetes and 63.7% (CI 95% 59.4-67.9) had metabolic syndrome. The prevalence of left ventricular hypertrophy and left atrial enlargement, determined by echocardiography was 57.1% (CI 95% 50.8-63.5) and 10.0% (CI 95% 6.3-13.7) respectively. Microalbuminuria was found in 46.6% (CI 95% 41.4-51.8) of the subjects. Patients with metabolic syndrome were significantly older (65.4±11 and 62.5±12 years; P=.0052), presented a higher prevalence of diabetes

Effector T cells require fatty acid metabolism during murine graft-versus-host disease

PubMed Central

Byersdorfer, Craig A.; Tkachev, Victor; Opipari, Anthony W.; Goodell, Stefanie; Swanson, Jacob; Sandquist, Stacy; Glick, Gary D.; Ferrara, James L. M.

2013-01-01

Activated T cells require increased energy to proliferate and mediate effector functions, but the metabolic changes that occur in T cells following stimulation in vivo are poorly understood, particularly in the context of inflammation. We have previously shown that T cells activated during graft-versus-host disease (GVHD) primarily rely on oxidative phosphorylation to synthesize adenosine 5′-triphosphate. Here, we demonstrate that alloreactive effector T cells (Teff) use fatty acids (FAs) as a fuel source to support their in vivo activation. Alloreactive T cells increased FA transport, elevated levels of FA oxidation enzymes, up-regulated transcriptional coactivators to drive oxidative metabolism, and increased their rates of FA oxidation. Importantly, increases in FA transport and up-regulation of FA oxidation machinery occurred specifically in T cells during GVHD and were not seen in Teff following acute activation. Pharmacological blockade of FA oxidation decreased the survival of alloreactive T cells but did not influence the survival of T cells during normal immune reconstitution. These studies suggest that pathways controlling FA metabolism might serve as therapeutic targets to treat GVHD and other T-cell–mediated immune diseases. PMID:24046012

Intestinal Microbiota at Engraftment Influence Acute Graft-Versus-Host Disease via the Treg/Th17 Balance in Allo-HSCT Recipients.

PubMed

Han, Lijie; Jin, Hua; Zhou, Lizhi; Zhang, Xin; Fan, Zhiping; Dai, Min; Lin, Qianyun; Huang, Fen; Xuan, Li; Zhang, Haiyan; Liu, Qifa

2018-01-01

Animal models have indicated that intestinal microbiota influence acute graft-versus-host disease (aGVHD) by modulating immune homeostasis. But, in humans, the mechanism by which the microbiota induces aGVHD remains unclear. In this study, we investigated the relationship between the intestinal microbiota and T cell subsets in patients who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT) to explore the mechanism by which microbiota induced aGVHD. Based on aGVHD, this study was categorized into two groups: grades II-IV aGVHD (aGVHD group, n  = 32) and grade 0-I aGVHD (non-aGVHD group, n  = 49). The intestinal microbiota was detected by 16S rRNA gene sequencing, and the T cell subsets and histone 3 (H3) acetylation in CD4+ T cells in the peripheral blood was assayed by flow cytometry at the time of engraftment. The aGVHD group had greater low microbial diversity than the non-aGVHD group (56.3 versus 24.5%, p  = 0.004). The bacterial community was depleted of Clostridia (e.g., the Lachnospiraceae and Ruminococcaceae families) and enriched for Gammaproteobacteria (e.g., the Enterobacteriaceae family) in the aGVHD group compared with the non-aGVHD group. The relative abundance of Lachnospiraceae and Ruminococcaceae was positively correlated with the Treg/Th17 ratio counts ( r  = 0.469 and 0.419; p  < 0.001 and <0.001, respectively), whereas Enterobacteriaceae was negatively correlated with the Treg/Th17 ratio ( r  = -0.277; p  = 0.012). The level of acetylated H3 in CD4+ T cells was not only correlated with Lachnospiraceae/Ruminococcaceae, but also with the Treg/Th17 ratio ( r  = 0.354; p  = 0.001). In conclusions, our results suggest that decreased Lachnospiraceae and Ruminococcaceae and increased Enterobacteriaceae, correlate with a Treg/Th17 imbalance, which might be through acetylated H3 in CD4+ T cells. These findings suggest that intestinal microbiota might induce aGVHD by influencing the Treg/Th17 balance.

Sample Analysis at Mars (SAM) and Mars Organic Molecule Analyzer (MOMA) as Critical In Situ Investigation for Targeting Mars Returned Samples

NASA Astrophysics Data System (ADS)

Freissinet, C.; Glavin, D. P.; Mahaffy, P. R.; Szopa, C.; Buch, A.; Goesmann, F.; Goetz, W.; Raulin, F.; SAM Science Team; MOMA Science Team

2018-04-01

SAM (Curiosity) and MOMA (ExoMars) Mars instruments, seeking for organics and biosignatures, are essential to establish taphonomic windows of preservation of molecules, in order to target the most interesting samples to return from Mars.

Vulvovaginal Graft-Versus-Host Disease.

PubMed

Kornik, Rachel I; Rustagi, Alison S

2017-09-01

Vulvovaginal chronic graft-versus-host disease (cGVHD) is an underrecognized complication of stem cell transplantation. Early recognition may prevent severe sequelae. Genital involvement is associated with oral, ocular, and skin manifestations. Treatment includes topical immunosuppression, dilator use, and adjuvant topical estrogen. Clinical and histologic features may mimic other inflammatory vulvar conditions. In the right clinical context, these findings are diagnostic of chronic GVHD. Female recipients of allo-hematopoietic stem cell transplantation (HCT) are at higher risk of condylomas, cervical dysplasia, and neoplasia. The National Institutes of Health publishes guidelines for the diagnosis, grading, management, and supportive care for HCT patients by organ system. Copyright © 2017 Elsevier Inc. All rights reserved.

Quality of laboratory studies assessing effects of Bt-proteins on non-target organisms: minimal criteria for acceptability.

PubMed

De Schrijver, Adinda; Devos, Yann; De Clercq, Patrick; Gathmann, Achim; Romeis, Jörg

2016-08-01

The potential risks that genetically modified plants may pose to non-target organisms and the ecosystem services they contribute to are assessed as part of pre-market risk assessments. This paper reviews the early tier studies testing the hypothesis whether exposure to plant-produced Cry34/35Ab1 proteins as a result of cultivation of maize 59122 is harmful to valued non-target organisms, in particular Arthropoda and Annelida. The available studies were assessed for their scientific quality by considering a set of criteria determining their relevance and reliability. As a case-study, this exercise revealed that when not all quality criteria are met, weighing the robustness of the study and its relevance for risk assessment is not obvious. Applying a worst-case expected environmental concentration of bioactive toxins equivalent to that present in the transgenic crop, confirming exposure of the test species to the test substance, and the use of a negative control were identified as minimum criteria to be met to guarantee sufficiently reliable data. This exercise stresses the importance of conducting studies meeting certain quality standards as this minimises the probability of erroneous or inconclusive results and increases confidence in the results and adds certainty to the conclusions drawn.

Effects of manufactured nanomaterials on fishes: a target organ and body systems physiology approach.

PubMed

Handy, R D; Al-Bairuty, G; Al-Jubory, A; Ramsden, C S; Boyle, D; Shaw, B J; Henry, T B

2011-10-01

Manufactured nanomaterials (NM) are already used in consumer products and exposure modelling predicts releases of ng to low µg l(-1) levels of NMs into surface waters. The exposure of aquatic ecosystems, and therefore fishes, to manufactured NMs is inevitable. This review uses a physiological approach to describe the known effects of NMs on the body systems of fishes and to identify the internal target organs, as well as outline aspects of colloid chemistry relevant to fish biology. The acute toxicity data, suggest that the lethal concentration for many NMs is in the mg l(-1) range, and a number of sublethal effects have been reported at concentrations from c. 100 µg to 1 mg l(-1). Exposure to NMs in the water column can cause respiratory toxicity involving altered ventilation, mucus secretion and gill pathology. This may not lead, however, to overt haematological disturbances in the short term. The internal target organs include the liver, spleen and haematopoietic system, kidney, gut and brain; with toxic effects involving oxidative stress, ionoregulatory disturbances and organ pathologies. Some pathology appears to be novel for NMs, such as vascular injury in the brain of rainbow trout Oncorhynchus mykiss with carbon nanotubes. A lack of analytical methods, however, has prevented the reporting of NM concentrations in fish tissues, and the precise uptake mechanisms across the gill or gut are yet to be elucidated. The few dietary exposure studies conducted show no effects on growth or food intake at 10-100 mg kg(-1) inclusions of NMs in the diet of O. mykiss, but there are biochemical disturbances. Early life stages are sensitive to NMs with reports of lethal toxicity and developmental defects. There are many data gaps, however, including how water quality alters physiological responses, effects on immunity and chronic exposure data at environmentally relevant concentrations. Overall, the data so far suggest that the manufactured NMs are not as toxic as some

Pharmacological AMP Kinase Activators Target the Nucleolar Organization and Control Cell Proliferation

PubMed Central

Kodiha, Mohamed; Salimi, Ali; Wang, Yi Meng; Stochaj, Ursula

2014-01-01

Aims Phenformin, resveratrol and AICAR stimulate the energy sensor 5′-AMP activated kinase (AMPK) and inhibit the first step of ribosome biogenesis, de novo RNA synthesis in nucleoli. Nucleolar activities are relevant to human health, because ribosome production is crucial to the development of diabetic complications. Although the function of nucleoli relies on their organization, the impact of AMPK activators on nucleolar structures is not known. Here, we addressed this question by examining four nucleolar proteins that are essential for ribosome biogenesis. Methods Kidney cells were selected as model system, because diabetic nephropathy is one of the complications associated with diabetes mellitus. To determine the impact of pharmacological agents on nucleoli, we focused on the subcellular and subnuclear distribution of B23/nucleophosmin, fibrillarin, nucleolin and RPA194. This was achieved by quantitative confocal microscopy at the single-cell level in combination with cell fractionation and quantitative Western blotting. Results AMPK activators induced the re-organization of nucleoli, which was accompanied by changes in cell proliferation. Among the compounds tested, phenformin and resveratrol had the most pronounced impact on nucleolar organization. For B23, fibrillarin, nucleolin and RPA194, both agents (i) altered the nucleocytoplasmic distribution and nucleolar association and (ii) reduced significantly the retention in the nucleus. (iii) Phenformin and resveratrol also increased significantly the total concentration of B23 and nucleolin. Conclusions AMPK activators have unique effects on the subcellular localization, nuclear retention and abundance of nucleolar proteins. We propose that the combination of these events inhibits de novo ribosomal RNA synthesis and modulates cell proliferation. Our studies identified nucleolin as a target that is especially sensitive to pharmacological AMPK activators. Because of its response to pharmacological agents

Pharmacological AMP kinase activators target the nucleolar organization and control cell proliferation.

PubMed

Kodiha, Mohamed; Salimi, Ali; Wang, Yi Meng; Stochaj, Ursula

2014-01-01

Phenformin, resveratrol and AICAR stimulate the energy sensor 5'-AMP activated kinase (AMPK) and inhibit the first step of ribosome biogenesis, de novo RNA synthesis in nucleoli. Nucleolar activities are relevant to human health, because ribosome production is crucial to the development of diabetic complications. Although the function of nucleoli relies on their organization, the impact of AMPK activators on nucleolar structures is not known. Here, we addressed this question by examining four nucleolar proteins that are essential for ribosome biogenesis. Kidney cells were selected as model system, because diabetic nephropathy is one of the complications associated with diabetes mellitus. To determine the impact of pharmacological agents on nucleoli, we focused on the subcellular and subnuclear distribution of B23/nucleophosmin, fibrillarin, nucleolin and RPA194. This was achieved by quantitative confocal microscopy at the single-cell level in combination with cell fractionation and quantitative Western blotting. AMPK activators induced the re-organization of nucleoli, which was accompanied by changes in cell proliferation. Among the compounds tested, phenformin and resveratrol had the most pronounced impact on nucleolar organization. For B23, fibrillarin, nucleolin and RPA194, both agents (i) altered the nucleocytoplasmic distribution and nucleolar association and (ii) reduced significantly the retention in the nucleus. (iii) Phenformin and resveratrol also increased significantly the total concentration of B23 and nucleolin. AMPK activators have unique effects on the subcellular localization, nuclear retention and abundance of nucleolar proteins. We propose that the combination of these events inhibits de novo ribosomal RNA synthesis and modulates cell proliferation. Our studies identified nucleolin as a target that is especially sensitive to pharmacological AMPK activators. Because of its response to pharmacological agents, nucleolin represents a potential

Contrasting acute graft-versus-host disease effects of Tim-3/galectin-9 pathway blockade dependent upon the presence of donor regulatory T cells

PubMed Central

Veenstra, Rachelle G.; Taylor, Patricia A.; Zhou, Qing; Panoskaltsis-Mortari, Angela; Hirashima, Mitsuomi; Flynn, Ryan; Liu, Derek; Anderson, Ana C.; Strom, Terry B.; Kuchroo, Vijay K.

2012-01-01

T-cell immunoglobulin mucin-3 (Tim-3) is expressed on pathogenic T cells, and its ligand galectin-9 (gal-9) is up-regulated in inflamed tissues. When Tim-3+ T cells encounter high gal-9 levels, they are deleted. Tim-3 is up-regulated on activated T cells during GVHD. Inhibition of Tim-3/gal-9 binding by infusion of a Tim-3-Ig fusion protein or Tim-3−/− donor T cells increased T-cell proliferation and GVHD lethality. When the Tim-3/gal-9 pathway engagement was augmented using gal-9 transgenic recipients, GVHD lethality was slowed. Together, these data indicate a potential for modulating this pathway to reduce disease by increasing Tim-3 or gal-9 engagement. Paradoxically, when Tim-3/gal-9 was inhibited in the absence of donor T-regulatory cells (Tregs), GVHD was inhibited. GVHD reduction was associated with decreased colonic inflammatory cytokines as well as epithelial barrier destruction. CD25-depleted Tim-3−/− donor T cells underwent increased activation-induced cell death because of increased IFN-γ production. To our knowledge, these studies are the first to show that although the absence of Tim-3/gal-9 pathway interactions augments systemic GVHD, concurrent donor Treg depletion paradoxically and surprisingly inhibits GVHD. Thus, although donor Tregs typically inhibit GVHD, under some conditions, such Tregs actually may contribute to GVHD by reducing activation-induced T-cell death. PMID:22677125

Role of CD8 Regulatory T Cells versus Tc1 and Tc17 Cells in the Development of Human Graft-versus-Host Disease.

PubMed

Gutiérrez-Hoya, Adriana; López-Santiago, Rubén; Vela-Ojeda, Jorge; Montiel-Cervantes, Laura; Rodríguez-Cortés, Octavio; Rosales-García, Víctor; Paredes-Cervantes, Vladimir; Flores-Mejía, Raúl; Sandoval-Borrego, Daniela; Moreno-Lafont, Martha

2017-01-01

CD8 + T cells that secrete proinflammatory cytokines play a central role in exacerbation of inflammation; however, a new subpopulation of CD8 regulatory T cells has recently been characterized. This study analyzes the prominent role of these different subpopulations in the development of graft-versus-host disease (GVHD). Samples from 8 healthy donors mobilized with Filgrastim® (G-CSF) and 18 patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) were evaluated by flow cytometry. Mobilization induced an increase in Tc1 ( p < 0.01), Th1 ( p < 0.001), Tc17 ( p < 0.05), and CD8 + IL-10 + cells ( p < 0.05), showing that G-CSF induces both pro- and anti-inflammatory profiles. Donor-patient correlation revealed a trend ( p = 0.06) toward the development of GVHD in patients who receive a high percentage of Tc1 cells. Patients with acute GVHD (aGVHD), either active or controlled, and patients without GVHD were evaluated; patients with active aGVHD had a higher percentage of Tc1 ( p < 0.01) and Tc17 ( p < 0.05) cells, as opposed to patients without GVHD in whom a higher percentage of CD8 Treg cells ( p < 0.01) was found. These findings indicate that the increase in Tc1 and Tc17 cells is associated with GVHD development, while regulatory CD8 T cells might have a protective role in this disease. These tests can be used to monitor and control GVHD.

Role of CD8 Regulatory T Cells versus Tc1 and Tc17 Cells in the Development of Human Graft-versus-Host Disease

PubMed Central

Gutiérrez-Hoya, Adriana; López-Santiago, Rubén; Vela-Ojeda, Jorge; Montiel-Cervantes, Laura; Rodríguez-Cortés, Octavio; Rosales-García, Víctor; Flores-Mejía, Raúl; Sandoval-Borrego, Daniela

2017-01-01

CD8+ T cells that secrete proinflammatory cytokines play a central role in exacerbation of inflammation; however, a new subpopulation of CD8 regulatory T cells has recently been characterized. This study analyzes the prominent role of these different subpopulations in the development of graft-versus-host disease (GVHD). Samples from 8 healthy donors mobilized with Filgrastim® (G-CSF) and 18 patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) were evaluated by flow cytometry. Mobilization induced an increase in Tc1 (p < 0.01), Th1 (p < 0.001), Tc17 (p < 0.05), and CD8+IL-10+ cells (p < 0.05), showing that G-CSF induces both pro- and anti-inflammatory profiles. Donor-patient correlation revealed a trend (p = 0.06) toward the development of GVHD in patients who receive a high percentage of Tc1 cells. Patients with acute GVHD (aGVHD), either active or controlled, and patients without GVHD were evaluated; patients with active aGVHD had a higher percentage of Tc1 (p < 0.01) and Tc17 (p < 0.05) cells, as opposed to patients without GVHD in whom a higher percentage of CD8 Treg cells (p < 0.01) was found. These findings indicate that the increase in Tc1 and Tc17 cells is associated with GVHD development, while regulatory CD8 T cells might have a protective role in this disease. These tests can be used to monitor and control GVHD. PMID:28164135

Graft versus host disease after stem cell allotransplantation with low-dose total body irradiation, fludarabine, and antithymocyte globulin.

PubMed

Grosskreutz, Celia; Scigliano, Eileen; Osman, Keren; Isola, Luis

2007-09-15

We previously showed that antithymocyte globulin (ATG) given with total body irradiation (TBI) 200 cGy and fludarabine results in high rate of donor engraftment. Its influence on acute and chronic graft versus host disease (GVHD) and on graft versus tumor effect is less known. Sixty-five patients underwent nonmyeloablative stem cell transplant with ATG, TBI 200 cGy, and fludarabine. GVHD prophylaxis was mycophenolate mofetil and cyclosporine. Forty-two patients (pts) (65%) had match related donors, 18 (27%) match unrelated, 1 (1.5%) mismatch related, and 4 (6%) mismatch unrelated donors. At a median follow-up of 862 days, 24 patients (37%) developed GVHD. The median age of the patients with and without GVHD was 56 years respectively. Acute GVHD grade II-IV developed in 19 pts (29%). Fatal GVHD of liver and/or gut occurred in nine pts (14%). Forty-one pts survived more than 100 days. Five pts (12%) had chronic GVHD, two had extensive, and three had limited involvement. Relapsed disease was observed in 22 pts (34%). Infections occurred in 15 pts (23%) and were fatal in 13 (20%). The addition of ATG to TBI 200cGy and fludarabine resulted in a modest incidence of GVHD. The best transplant outcomes were observed in pts with lymphoid malignancies.

Skin: Major target organ of allergic reactions to small molecular weight compounds

DOE Office of Scientific and Technical Information (OSTI.GOV)

Merk, Hans F.; Baron, Jens M.; Neis, Mark M.

2007-11-01

Skin is a major target organ for allergic reactions to small molecular weight compounds. Drug allergic reactions may be life-threatening such as in the case of anaphylactic reactions or bullous drug reactions and occur in about 5% of all hospitalized patients. Allergic contact dermatitis has an enormous influence on the social life of the patient because it is the most frequent reason for occupational skin diseases and the treatment and prevention of this disease cost approximately Euro 3 billion per year in Germany. The different proposed pathophysiological pathways leading to a drug eruption are discussed in this paper. All majormore » enzymes which are involved in the metabolism of xenobiotica were shown to be present in skin. Evidence supporting the role of metabolism in the development of drug allergy and allergic contact dermatitis is demonstrated in the example of sulphonamides and fragrances.« less

How I treat acute graft-versus-host disease of the gastrointestinal tract and the liver.

PubMed

McDonald, George B

2016-03-24

Treatment of acute graft-versus-host disease (GVHD) has evolved from a one-size-fits-all approach to a more nuanced strategy based on predicted outcomes. Lower and time-limited doses of immune suppression for patients predicted to have low-risk GVHD are safe and effective. In more severe GVHD, prolonged exposure to immunosuppressive therapies, failure to achieve tolerance, and inadequate clinical responses are the proximate causes of GVHD-related deaths. This article presents acute GVHD-related scenarios representing, respectively, certainty of diagnosis, multiple causes of symptoms, jaundice, an initial therapy algorithm, secondary therapy, and defining futility of treatment. © 2016 by The American Society of Hematology.

Hispanic organ donation: impact of a Spanish-language organ donation campaign.

PubMed Central

Alvaro, Eusebio M.; Jones, Sara Pace; Robles, Antonio Santa Maria; Siegel, Jason

2006-01-01

OBJECTIVES: Hispanic Americans have a substantial need for organ transplants and are underrepresented among organ donors, yet very little is known about how to increase available donors in this community. This study assesses the impact of a Spanish-language media campaign targeting organ donation among Hispanic Americans in two urban Arizona counties. METHODS: The study collected data via four surveys conducted before and after implementation of a Spanish-language media campaign targeting organ donation among Spanish-dominant Hispanic Americans in Pima and Maricopa counties in Arizona. The main intervention consisted of four Spanish-language television advertisements and two Spanish-language radio advertisements. RESULTS: The media campaign was successfully implemented and attained substantial exposure among the target audience. Postintervention beliefs were more prodonation, and there was more family discussion postintervention. In both counties, residents exposed to the campaign reported more prodonation beliefs and family discussion. Exposed Maricopa residents were also more likely to be potential donors. CONCLUSIONS: Study data indicate a positive impact of a media campaign targeting organ donation beliefs and behaviors among Spanish-dominant Hispanic Americans in Arizona. It is hoped that these findings will stimulate further research in this important area. PMID:16532975

Plasma Cardiotrophin-1 as a Marker of Hypertension and Diabetes-Induced Target Organ Damage and Cardiovascular Risk

PubMed Central

Gamella-Pozuelo, Luis; Fuentes-Calvo, Isabel; Gómez-Marcos, Manuel A.; Recio-Rodriguez, José I.; Agudo-Conde, Cristina; Fernández-Martín, José L.; Cannata-Andía, Jorge B.; López-Novoa, José M.; García-Ortiz, Luis; Martínez-Salgado, Carlos

2015-01-01

Abstract The search for biomarkers of hypertension and diabetes-induced damage to multiple target organs is a priority. We analyzed the correlation between plasma cardiotrophin-1 (CT-1), a chemokine that participates in cardiovascular remodeling and organ fibrosis, and a wide range of parameters currently used to diagnose morphological and functional progressive injury in left ventricle, arteries, and kidneys of diabetic and hypertensive patients, in order to validate plasma levels of CT-1 as clinical biomarker. This is an observational study with 93 type 2-diabetic patients, 209 hypertensive patients, and 82 healthy controls in which we assessed the following parameters: plasma CT-1, basal glycaemia, systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), left ventricular hypertrophy (LVH by electrocardiographic indexes), peripheral vascular disease (by pulse wave velocity—PWV, carotid intima-media thickness—C-IMT, and ankle-brachial index—ABI), and renal impairment (by microalbuminuria, albumin/creatinine urinary ratio, plasma creatinine concentrations, and glomerular filtration rate). Hypertensive or diabetic patients have higher plasma CT-1 than control patients. CT-1 positively correlates with basal glycaemia, SBP, DBP, PP, LVH, arterial damage (increased IMT, decreased ABI), and early renal damage (microalbuminuria, elevated albumin/creatinine ratio). CT-1 also correlates with increased 10-year cardiovascular risk. Multiple linear regression analysis confirmed that CT-1 was associated with arterial injury assessed by PWV, IMT, ABI, and cardiac damage evaluated by Cornell voltage duration product. Increases in plasma CT-1 are strongly related to the intensity of several parameters associated to target organ damage supporting further investigation of its diagnostic capacity as single biomarker of cardiovascular injury and risk and, possibly, of subclinical renal damage. PMID:26222851

Cannabidiol for the Prevention of Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation: Results of a Phase II Study.

PubMed

Yeshurun, Moshe; Shpilberg, Ofer; Herscovici, Corina; Shargian, Liat; Dreyer, Juliet; Peck, Anat; Israeli, Moshe; Levy-Assaraf, Maly; Gruenewald, Tsipora; Mechoulam, Raphael; Raanani, Pia; Ram, Ron

2015-10-01

Graft-versus-host-disease (GVHD) is a major obstacle to successful allogeneic hematopoietic cell transplantation (alloHCT). Cannabidiol (CBD), a nonpsychotropic ingredient of Cannabis sativa, possesses potent anti-inflammatory and immunosuppressive properties. We hypothesized that CBD may decrease GVHD incidence and severity after alloHCT. We conducted a phase II study. GVHD prophylaxis consisted of cyclosporine and a short course of methotrexate. Patients transplanted from an unrelated donor were given low-dose anti-T cell globulin. CBD 300 mg/day was given orally starting 7 days before transplantation until day 30. Forty-eight consecutive adult patients undergoing alloHCT were enrolled. Thirty-eight patients (79%) had acute leukemia or myelodysplastic syndrome and 35 patients (73%) were given myeloablative conditioning. The donor was either an HLA-identical sibling (n = 28), a 10/10 matched unrelated donor (n = 16), or a 1-antigen-mismatched unrelated donor (n = 4). The median follow-up was 16 months (range, 7 to 23). No grades 3 to 4 toxicities were attributed to CBD. None of the patients developed acute GVHD while consuming CBD. In an intention-to-treat analysis, we found that the cumulative incidence rates of grades II to IV and grades III to IV acute GVHD by day 100 were 12.1% and 5%, respectively. Compared with 101 historical control subjects given standard GVHD prophylaxis, the hazard ratio of developing grades II to IV acute GVHD among subjects treated with CBD plus standard GVHD prophylaxis was .3 (P = .0002). Rates of nonrelapse mortality at 100 days and at 1 year after transplantation were 8.6% and 13.4%, respectively. Among patients surviving more than 100 days, the cumulative incidences of moderate-to-severe chronic GVHD at 12 and 18 months were 20% and 33%, respectively. The combination of CBD with standard GVHD prophylaxis is a safe and promising strategy to reduce the incidence of acute GVHD. A randomized double-blind controlled study is warranted

Analysis of results of acute graft-versus-host disease prophylaxis with donor multipotent mesenchymal stromal cells in patients with hemoblastoses after allogeneic bone marrow transplantation.

PubMed

Shipounova, I N; Petinati, N A; Bigildeev, A E; Zezina, E A; Drize, N I; Kuzmina, L A; Parovichnikova, E N; Savchenko, V G

2014-12-01

Allogeneic bone marrow transplantation (allo-BMT) is currently the only way to cure many hematoproliferative disorders. However, allo-BMT use is limited by severe complications, the foremost being graft-versus-host disease (GVHD). Due to the lack of efficiency of the existing methods of GVHD prophylaxis, new methods are being actively explored, including the use of donors' multipotent mesenchymal stromal cells (MMSC). In this work, we analyzed the results of acute GVHD (aGVHD) prophylaxis by means of MMSC injections after allo-BMT in patients with hematological malignancies. The study included 77 patients. They were randomized into two groups - those receiving standard prophylaxis of aGVHD and those who were additionally infused with MMSC derived from the bone marrow of hematopoietic stem cell donors. We found that the infusion of MMSC halves the incidence of aGVHD and increases the overall survival of patients. Four of 39 MMSC samples were ineffective for preventing aGVHD. Analysis of individual donor characteristics (gender, age, body mass index) and the MMSC properties of these donors (growth parameters, level of expression of 30 genes involved in proliferation, differentiation, and immunomodulation) revealed no significant difference between the MMSC that were effective or ineffective for preventing aGVHD. We used multiple logistic regression to establish a combination of features that characterize the most suitable MMSC samples for the prevention of aGVHD. A model predicting MMSC sample success for aGVHD prophylaxis was constructed. Significant model parameters were increased relative expression of the FGFR1 gene in combination with reduced expression levels of the PPARG and IGF1 genes. Depending on the chosen margin for probability of successful application of MMSC, this model correctly predicts the outcome of the use of MMSC in 82-94% of cases. The proposed model of prospective evaluation of the effectiveness of MMSC samples will enable prevention of the

Reaching to multiple targets when standing: the spatial organization of feedforward postural adjustments.

PubMed

Leonard, Julia A; Brown, Ryan H; Stapley, Paul J

2009-04-01

We examined the spatial organization of feedforward postural adjustments produced prior to and during voluntary arm reaching movements executed while standing. We sought to investigate whether the activity of postural muscles before and during reaching was directionally tuned and whether a strategy of horizontal force constraint could be observed. To this end, eight human subjects executed self-paced reach-to-point movements on the random illumination of one of 13 light targets placed within a 180 degrees array centered along the midline of the body. Analysis was divided into two periods: a first corresponding to the 250 ms preceding the onset of the reaching movements (termed pPA period) and a second 250-ms period immediately preceding target attainment (the aPA period). For both periods, electromyographic activity of the lower limb muscles revealed a clear directional tuning, with groups of muscles being activated for similar directions of reach. Analysis of horizontal ground reaction forces supported the existence of a force constraint strategy only for the pPA period, however, with those in the aPA period being more widely dispersed. We suggest that the strategy adopted for feedforward pPAs is one where the tuned muscle synergies constrain the forces diagonally away from the center of mass (CoM) to move it within the support base. However, the need to control for final finger and body position for each target during the aPA phase resulted in a distribution of vectors across reaching directions. Overall, our results would support the idea that endpoint limb force during postural tasks depends on the use of functional muscle synergies, which are used to displace the CoM or decelerate the body at the end of the reach.

Erectile dysfunction and target organ damage in the early stages of hypertension.

PubMed

Kakkavas, Apostolos; Tsioufis, Costas; Tsiachris, Dimitris; Thomopoulos, Costas; Dimitriadis, Kyriakos; Milkas, Anastasios; Alexopoulos, Dimitrios; Kallikazaros, Ioannis; Stefanadis, Christodoulos

2013-09-01

The authors investigated whether erectile dysfunction (ED) in the early stages of hypertension is associated with heightened end-organ damage. A total of 174 consecutive men with untreated, newly diagnosed essential hypertension (aged 50.3 years, office blood pressure [BP] 150/98 mm Hg) were studied. All participants underwent 24-hour ambulatory BP monitoring, blood examination, albumin-creatinine ratio, carotid-femoral pulse-wave velocity assessment, and echocardiography for estimation of left ventricular mass index and diastolic function. Hypertensive men with ED (n=43, 24.7%) compared with those without ED were older (by 6.4 years, P<.05), had greater 24-hour pulse pressure (by 4.3 mm Hg, P=.011) and a greater prevalence of nondipping status (72.2% vs 46.7%, P=.008), while the two groups did not differ in plasma glucose, lipid, creatinine, and albumin/creatinine ratio levels. Regarding cardiac adaptations, hypertensive men with ED exhibited only significantly lower tissue Doppler imaging-derived Em (by 1.6 cm/s, adjusted P=.035), while no difference in left ventricular mass index or pulse wave velocity were detected. ED in the setting of untreated newly diagnosed essential hypertension does not have an unfavorable impact on traditional markers of target organ damage. This finding suggests that ED assessment might not refine the traditional risk stratification procedure at least in the early stages of hypertensive disease. ©2013 Wiley Periodicals, Inc.

A Critical Appraisal of Extracorporeal Photopheresis as a Treatment Modality for Acute and Chronic Graft-Versus-Host Disease

PubMed Central

Rafei, Hind; A. Kharfan-Dabaja, Mohamed

2017-01-01

Although significant advances have been made in the biologic understanding of graft-versus-host disease (GVHD) and its treatment options, GVHD remains the single most challenging obstacle to the success of allogeneic hematopoietic cell transplantation (HCT) due to high risk of disabling morbidity and mortality. Extracorporeal photopheresis (ECP) has promising effects in controlling steroid-refractory GVHD, both acute and chronic, and it has been studied extensively. Its putative immunomodulatory mechanisms, while not immunosuppressive, position ECP as an attractive treatment strategy for GVHD patients who are already receiving global immunosuppression. However, ECP is relatively underutilized due in part to limited access and time commitment. Here, we review the recent findings on the ECP efficacy in both acute and chronic GVHD, primarily for steroid-refractory status, and we critically appraise its benefits. We also explore salient considerations on the optimal use of ECP in the treatment of refractory GVHD. PMID:29019937

Heterogeneity of chronic graft-versus-host disease biomarkers: association with CXCL10 and CXCR3+ NK cells

PubMed Central

Kariminia, Amina; Holtan, Shernan G.; Ivison, Sabine; Rozmus, Jacob; Hebert, Marie-Josée; Martin, Paul J.; Lee, Stephanie J.; Wolff, Daniel; Subrt, Peter; Abdossamadi, Sayeh; Sung, Susanna; Storek, Jan; Levings, Megan; Aljurf, Mahmoud; Arora, Mukta; Cutler, Corey; Gallagher, Geneviève; Kuruvilla, John; Lipton, Jeff; Nevill, Thomas J.; Newell, Laura F.; Panzarella, Tony; Pidala, Joseph; Popradi, Gizelle; Szwajcer, David; Tay, Jason; Toze, Cynthia L.; Walker, Irwin; Couban, Stephen; Storer, Barry E.

2016-01-01

Chronic graft-versus-host disease (cGVHD) remains one of the most significant long-term complications after allogeneic blood and marrow transplantation. Diagnostic biomarkers for cGVHD are needed for early diagnosis and may guide identification of prognostic markers. No cGVHD biomarker has yet been validated for use in clinical practice. We evaluated both previously known markers and performed discovery-based analysis for cGVHD biomarkers in a 2 independent test sets (total of 36 cases ≤1 month from diagnosis and 31 time-matched controls with no cGVHD). On the basis of these results, 11 markers were selected and evaluated in 2 independent replication cohorts (total of 134 cGVHD cases and 154 controls). cGVHD cases and controls were evaluated for several clinical covariates, and their impact on biomarkers was identified by univariate analysis. The 2 replications sets were relatively disparate in the biomarkers they replicated. Only sBAFF and, most consistently, CXCL10 were identified as significant in both replication sets. Other markers identified as significant in only 1 replication set included intercellular adhesion molecule 1 (ICAM-1), anti-LG3, aminopeptidase N, CXCL9, endothelin-1, and gelsolin. Multivariate analysis found that all covariates evaluated affected interpretation of the biomarkers. CXCL10 had an increased significance in combination with anti-LG3 and CXCL9, or inversely with CXCR3+CD56bright natural killer (NK) cells. There was significant heterogeneity of cGVHD biomarkers in a large comprehensive evaluation of cGVHD biomarkers impacted by several covariates. Only CXCL10 strongly correlated in both replication sets. Future analyses for plasma cGVHD biomarkers will need to be performed on very large patient groups with consideration of multiple covariates. PMID:27020088

Post-Transplant Cyclophosphamide and Tacrolimus-Mycophenolate Mofetil Combination Prevents Graft-versus-Host Disease in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors.

PubMed

Carnevale-Schianca, Fabrizio; Caravelli, Daniela; Gallo, Susanna; Coha, Valentina; D'Ambrosio, Lorenzo; Vassallo, Elena; Fizzotti, Marco; Nesi, Francesca; Gioeni, Luisa; Berger, Massimo; Polo, Alessandra; Gammaitoni, Loretta; Becco, Paolo; Giraudo, Lidia; Mangioni, Monica; Sangiolo, Dario; Grignani, Giovanni; Rota-Scalabrini, Delia; Sottile, Antonino; Fagioli, Franca; Aglietta, Massimo

2017-03-01

Allogeneic hematopoietic cell transplant (HCT) remains the only curative therapy for many hematologic malignancies but it is limited by high nonrelapse mortality (NRM), primarily from unpredictable control of graft-versus-host disease (GVHD). Recently, post-transplant cyclophosphamide demonstrated improved GVHD control in allogeneic bone marrow HCT. Here we explore cyclophosphamide in allogeneic peripheral blood stem cell transplantation (alloPBSCT). Patients with high-risk hematologic malignancies received alloPBSCT from HLA-matched unrelated/related donors. GVHD prophylaxis included combination post-HCT cyclophosphamide 50 mg/kg (days +3 and +4) and tacrolimus/mofetil mycophenolate (T/MMF) (day +5 forward). The primary objective was the cumulative incidence of acute and chronic GVHD. Between March 2011 and May 2015, 35 consecutive patients received the proposed regimen. MMF was stopped in all patients at day +28; the median discontinuation of tacrolimus was day +113. Acute and chronic GVHD cumulative incidences were 17% and 7%, respectively, with no grade IV GVHD events, only 2 patients requiring chronic GVHD immunosuppression control, and no deaths from GVHD. Two-year NRM, overall survival, event-free survival, and chronic GVHD event-free survival rates were 3%, 77%, 54%, and 49%, respectively. The graft-versus-tumor effect was maintained as 5 of 15 patients (33%) who received HCT with evidence of disease experienced further disease response. A post-transplant cyclophosphamide + T/MMF combination strategy effectively prevented acute and chronic GVHD after alloPBSCT from HLA-matched donors and achieved an unprecedented low NRM without losing efficacy in disease control or impaired development of the graft-versus-tumor effect. This trial is registered at clinicaltrials.gov as NCT02300571. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Housing Temperature-Induced Stress Is Suppressing Murine Graft-versus-Host Disease through β2-Adrenergic Receptor Signaling.

PubMed

Leigh, Nicholas D; Kokolus, Kathleen M; O'Neill, Rachel E; Du, Wei; Eng, Jason W-L; Qiu, Jingxin; Chen, George L; McCarthy, Philip L; Farrar, J David; Cao, Xuefang; Repasky, Elizabeth A

2015-11-15

Graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic cell transplantation, a potentially curative therapy for hematologic diseases. It has long been thought that murine bone marrow-derived T cells do not mediate severe GVHD because of their quantity and/or phenotype. During the course of experiments testing the impact of housing temperatures on GVHD, we discovered that this apparent resistance is a function of the relatively cool ambient housing temperature. Murine bone marrow-derived T cells have the ability to mediate severe GVHD in mice housed at a thermoneutral temperature. Specifically, mice housed at Institutional Animal Care and Use Committee-mandated, cool standard temperatures (∼ 22°C) are more resistant to developing GVHD than are mice housed at thermoneutral temperatures (∼ 30°C). We learned that the mechanism underlying this housing-dependent immunosuppression is associated with increased norepinephrine production and excessive signaling through β-adrenergic receptor signaling, which is increased when mice are cold stressed. Treatment of mice housed at 22°C with a β2-adrenergic antagonist reverses the norepinephrine-driven suppression of GVHD and yields similar disease to mice housed at 30°C. Conversely, administering a β2-adrenergic agonist decreases GVHD in mice housed at 30°C. In further mechanistic studies using β2-adrenergic receptor-deficient (β2-AR(-/-)) mice, we found that it is host cell β2-AR signaling that is essential for decreasing GVHD. These data reveal how baseline levels of β-adrenergic receptor signaling can influence murine GVHD and point to the feasibility of manipulation of β2-AR signaling to ameliorate GVHD in the clinical setting. Copyright © 2015 by The American Association of Immunologists, Inc.

Pentraxin 3 plasma levels at graft-versus-host disease onset predict disease severity and response to therapy in children given haematopoietic stem cell transplantation.

PubMed

Dander, Erica; De Lorenzo, Paola; Bottazzi, Barbara; Quarello, Paola; Vinci, Paola; Balduzzi, Adriana; Masciocchi, Francesca; Bonanomi, Sonia; Cappuzzello, Claudia; Prunotto, Giulia; Pavan, Fabio; Pasqualini, Fabio; Sironi, Marina; Cuccovillo, Ivan; Leone, Roberto; Salvatori, Giovanni; Parma, Matteo; Terruzzi, Elisabetta; Pagni, Fabio; Locatelli, Franco; Mantovani, Alberto; Fagioli, Franca; Biondi, Andrea; Garlanda, Cecilia; Valsecchi, Maria Grazia; Rovelli, Attilio; D'Amico, Giovanna

2016-12-13

Acute Graft-versus-Host Disease (GvHD) remains a major complication of allogeneic haematopoietic stem cell transplantation, with a significant proportion of patients failing to respond to first-line systemic corticosteroids. Reliable biomarkers predicting disease severity and response to treatment are warranted to improve its management. Thus, we sought to determine whether pentraxin 3 (PTX3), an acute-phase protein produced locally at the site of inflammation, could represent a novel acute GvHD biomarker. Using a murine model of the disease, we found increased PTX3 plasma levels after irradiation and at GvHD onset. Similarly, plasma PTX3 was enhanced in 115 pediatric patients on day of transplantation, likely due to conditioning, and at GvHD onset in patients experiencing clinical symptoms of the disease. PTX3 was also found increased in skin and colon biopsies from patients with active disease. Furthermore, PTX3 plasma levels at GvHD onset were predictive of disease outcome since they resulted significantly higher in both severe and therapy-unresponsive patients. Multiple injections of rhPTX3 in the murine model of GvHD did not influence the disease course. Taken together, our results indicate that PTX3 constitutes a biomarker of GvHD severity and therapy response useful to tailor treatment intensity according to early risk-stratification of GvHD patients.

IL-17 genetic and immunophenotypic evaluation in chronic graft-versus-host disease.

PubMed

Resende, Renata Gonçalves; Correia-Silva, Jeane de Fátima; Silva, Tarcília Aparecida; Salomão, Ulisses Eliezer; Marques-Silva, Luciano; Vieira, Érica Leandro Marciano; Dutra, Walderez Ornelas; Gomez, Ricardo Santiago

2014-01-01

Although interleukin-17 (IL-17) is a recently discovered cytokine associated with several autoimmune diseases, its role in the pathogenesis of chronic graft-versus-host disease (cGVHD) was not established yet. The objective of this study was to investigate the association of IL17A and IL17F genes polymorphisms and IL-17A and IL-17F levels with cGVHD. IL-17A expression was also investigated in CD4(+) T cells of patients with systemic cGVHD. For Part I of the study, fifty-eight allo-HSCT recipients and donors were prospectively studied. Blood samples were obtained to determine IL17A and IL17F genes polymorphisms. Cytokines levels in blood and saliva were assessed by ELISA at days +35 and +100 after HSCT. In Part II, for the immunophenotypic evaluation, eight patients with systemic cGVHD were selected and the expression of IL-17A was evaluated. We found association between recipient AA genotype with systemic cGVHD. No association was observed between IL-17A levels and cGVHD. Lower IL-17A levels in the blood were associated with AA genotype. In flow cytometry analysis, decreased expression of IL-17A was observed in patients with cGVHD after stimulation. In conclusion, IL-17A may have an important role in the development of systemic cGVHD.

Acute cutaneous graft-vs.-host disease compared to drug hypersensitivity reaction with vacuolar interface changes: a blinded study of microscopic and immunohistochemical features.

PubMed

Lehman, Julia S; Gibson, Lawrence E; el-Azhary, Rokea A; Chavan, Rahul N; Hashmi, Shahrukh K; Lohse, Christine M; Flotte, Thomas J

2015-01-01

Complications from graft-vs.-host disease (GVHD), a major contributor to morbidity and mortality following hematopoietic cell transplantation, may be mitigated by early diagnosis and intervention. However, differentiation between acute cutaneous GVHD and other common skin eruptions that develop in the post-transplantation period, such as drug hypersensitivity reaction, can be challenging clinically and microscopically. Because recent evidence indicates that CD123, a marker of plasmacytoid dendritic cells, can help to distinguish gastrointestinal GVHD from the clinicopathologic mimic cytomegalovirus colitis, we aimed to determine whether CD123 could aid in the diagnosis of acute cutaneous GVHD. We studied 12 skin specimens of patients with grades I-II cutaneous GVHD and 12 from patients who had drug hypersensitivity reaction with vacuolar interface changes on biopsy. No differences were seen between the two groups with regards to density or distribution of CD123 expression. Specimens representing GVHD showed significantly less spongiosis (P < 0.001) and fewer dermal eosinophils (P = 0.03) compared to those representing drug hypersensitivity reaction. We conclude that CD123 does not appear to be a useful ancillary test in the diagnosis of acute cutaneous GVHD. Careful correlation between clinical findings and features with microscopy remains the cornerstone of accurate diagnosis of acute cutaneous GVHD. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Effect of mannose targeting of hydroxyl PAMAM dendrimers on cellular and organ biodistribution in a neonatal brain injury model.

PubMed

Sharma, Anjali; Porterfield, Joshua E; Smith, Elizabeth; Sharma, Rishi; Kannan, Sujatha; Kannan, Rangaramanujam M

2018-06-05

Neurotherapeutics for the treatment of central nervous system (CNS) disorders must overcome challenges relating to the blood-brain barrier (BBB), brain tissue penetration, and the targeting of specific cells. Neuroinflammation mediated by activated microglia is a major hallmark of several neurological disorders, making these cells a desirable therapeutic target. Building on the promise of hydroxyl-terminated generation four polyamidoamine (PAMAM) dendrimers (D4-OH) for penetrating the injured BBB and targeting activated glia, we explored if conjugation of targeting ligands would enhance and modify brain and organ uptake. Since mannose receptors [cluster of differentiation (CD) 206] are typically over-expressed on injured microglia, we conjugated mannose to the surface of multifunctional D4-OH using highly efficient, atom-economical, and orthogonal Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC) click chemistry and evaluated the effect of mannose conjugation on the specific cell uptake of targeted and non-targeted dendrimers both in vitro and in vivo. In vitro results indicate that the conjugation of mannose as a targeting ligand significantly changes the mechanism of dendrimer internalization, giving mannosylated dendrimer a preference for mannose receptor-mediated endocytosis as opposed to non-specific fluid phase endocytosis. We further investigated the brain uptake and biodistribution of targeted and non-targeted fluorescently labeled dendrimers in a maternal intrauterine inflammation-induced cerebral palsy (CP) rabbit model using quantification methods based on fluorescence spectroscopy and confocal microscopy. We found that the conjugation of mannose modified the distribution of D4-OH throughout the body in this neonatal rabbit CP model without lowering the amount of dendrimer delivered to injured glia in the brain, even though significantly higher glial uptake was not observed in this model. Mannose conjugation to the dendrimer modifies the dendrimer

Intra-arterial Methylprednisolone Infusion in Treatment-Resistant Graft-Versus-Host Disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weintraub, Joshua L., E-mail: Joshua.Weintraub@mssm.edu; Belanger, Adam R.; Sung, Chris C.

Acute graft-versus-host disease (GVHD) is a potentially fatal complication following allogeneic hematopoietic stem cell transplant. Standard primary therapy for acute GVHD includes systemic steroids, often in combination with other agents. Unfortunately, primary treatment failure is common and carries a high mortality. There is no generally accepted secondary therapy for acute GVHD. Although few data on localized therapy for GVHD have been published, intra-arterial injection of high-dose corticosteroids may be a viable option. We treated 11 patients with steroid-resistant GVHD using a single administration of intra-arterial high-dose methylprednisolone. Three patients (27%) died periprocedurally. Four patients (36%) had a partial response tomore » intra-arterial treatment and were discharged on total parenteral nutrition and oral medication. Four patients (36%) had a complete response and were discharged on oral diet and oral medication. No immediate treatment or procedure-related complications were noted. Twenty-seven percent of patients survived long-term. Our preliminary results suggest that regional intra-arterial treatment of steroid-resistant GVHD is a safe and potentially viable secondary therapy in primary treatment-resistant GVHD.« less

Successful treatment of oral lichen planus-like chronic graft-versus-host disease with topical tacrolimus: a case report.

PubMed

Sánchez, Andrés R; Sheridan, Phillip J; Rogers, Roy S

2004-04-01

Bone marrow transplantation (BMT) is a common treatment used for deficiencies of host marrow or in the control of blood malignancies. Post-allogeneic BMT complications include graft-versus-host disease (GVHD). GVHD occurs when immunologically active T lymphocytes are transplanted into an immunosuppressed recipient who is genetically disparate from the donor. In this case report we describe the occurrence of oral lichen planus-like lesions as the first manifestation of chronic GVHD (c-GVHD) and the subsequent management of this disease with topical tacrolimus. Diagnostic aids included routine histology and direct immunofluorescence studies to rule out immunobullous diseases and to confirm the c-GVHD. Treatment consisted of topical application of 0.1% tacrolimus ointment three times a day. Routine histology confirmed the clinical diagnosis of oral lichen planus-like c-GVHD. Treatment with tacrolimus ointment completely resolved the oral lesions after 2 months of therapy. Topical tacrolimus at low concentrations (0.1%) shows promise in the management of oral lichen planus-like c-GVHD. Controlled studies are necessary to assess the efficacy, the duration of therapy required for effective results, and the safety of this treatment over the long-term.

Association of mixed hematopoietic chimerism with elevated circulating autoantibodies and chronic graft-versus-host disease occurrence.

PubMed

Perruche, Sylvain; Marandin, Aliette; Kleinclauss, François; Angonin, Régis; Fresnay, Stéphanie; Baron, Marie Hélène; Tiberghien, Pierre; Saas, Philippe

2006-02-27

Use of a reduced-intensity conditioning regimen before an allogeneic hematopoietic cell transplantation is frequently associated with an early state of mixed hematopoietic chimerism. Such a coexistence of both host and donor hematopoietic cells may influence posttransplant alloreactivity and may affect the occurrence and severity of acute and chronic graft-versus-host disease (GVHD) as well as the intensity of the graft-versus-leukemia effect. Here we evaluated the relation between chimerism state after reduced-intensity conditioning transplantation (RICT), autoantibody production, and chronic GVHD (cGVHD)-related pathology. Chimerism state, circulating anticardiolipin, and antidouble stranded DNA autoantibody (Ab) titers as well as occurrence of cGVHD-like lesions were investigated in a murine RICT model. We observed a novel association between mixed chimerism state, high levels of pathogenic IgG autoantibodies, and subsequent development of cGVHD-like lesions. Furthermore, we found that the persistence of host B cells, but not dendritic cell origin or subset, was a factor associated with the appearance of cGVHD-like lesions. The implication of host B cells was confirmed by a host origin of autoantibodies. Recipient B cell persistence may contribute to the frequency and/or severity of cGVHD after RICT.

Presentations and treatment of childhood scleroderma: localized scleroderma, eosinophilic fasciitis, systemic sclerosis, and graft-versus-host disease.

PubMed

Hedrich, Christian Michael; Fiebig, Barbara; Hahn, Gabriele; Suttorp, Meinolf; Gahr, Manfred

2011-07-01

Juvenile scleroderma is a rare connective tissue disease that involves the skin and subcutaneous tissue. Among all presentations of juvenile scleroderma, localized scleroderma (JLSc) is the most frequent, followed by systemic disease (JSSc) and eosinophilic fasciitis (EF). In posttransplantation chronic graft-versus-host disease (GvHD), scleroderma-like skin involvement can occur. Systemic forms of juvenile scleroderma and GvHD can affect the internal organs, such as the lungs, the gastrointestinal tract, the heart, and kidneys and cause disability and severe, sometimes lethal, complications. Here, the authors give an overview of different presentations of juvenile scleroderma. They report their experience with the different forms and presentations of scleroderma, diagnostic workups, treatment, and outcome of all forms of childhood scleroderma in the context of the existing literature.

Drug target identification in protozoan parasites.

PubMed

Müller, Joachim; Hemphill, Andrew

2016-08-01

Despite the fact that diseases caused by protozoan parasites represent serious challenges for public health, animal production and welfare, only a limited panel of drugs has been marketed for clinical applications. Herein, the authors investigate two strategies, namely whole organism screening and target-based drug design. The present pharmacopoeia has resulted from whole organism screening, and the mode of action and targets of selected drugs are discussed. However, the more recent extensive genome sequencing efforts and the development of dry and wet lab genomics and proteomics that allow high-throughput screening of interactions between micromolecules and recombinant proteins has resulted in target-based drug design as the predominant focus in anti-parasitic drug development. Selected examples of target-based drug design studies are presented, and calcium-dependent protein kinases, important drug targets in apicomplexan parasites, are discussed in more detail. Despite the enormous efforts in target-based drug development, this approach has not yet generated market-ready antiprotozoal drugs. However, whole-organism screening approaches, comprising of both in vitro and in vivo investigations, should not be disregarded. The repurposing of already approved and marketed drugs could be a suitable strategy to avoid fastidious approval procedures, especially in the case of neglected or veterinary parasitoses.

Drug target identification in protozoan parasites

PubMed Central

Müller, Joachim; Hemphill, Andrew

2016-01-01

Introduction Despite the fact that diseases caused by protozoan parasites represent serious challenges for public health, animal production and welfare, only a limited panel of drugs has been marketed for clinical applications. Areas covered Herein, the authors investigate two strategies, namely whole organism screening and target-based drug design. The present pharmacopoeia has resulted from whole organism screening, and the mode of action and targets of selected drugs are discussed. However, the more recent extensive genome sequencing efforts and the development of dry and wet lab genomics and proteomics that allow high-throughput screening of interactions between micromolecules and recombinant proteins has resulted in target-based drug design as the predominant focus in anti-parasitic drug development. Selected examples of target-based drug design studies are presented, and calcium-dependent protein kinases, important drug targets in apicomplexan parasites, are discussed in more detail. Expert opinion Despite the enormous efforts in target-based drug development, this approach has not yet generated market-ready antiprotozoal drugs. However, whole-organism screening approaches, comprising of both in vitro and in vivo investigations, should not be disregarded. The repurposing of already approved and marketed drugs could be a suitable strategy to avoid fastidious approval procedures, especially in the case of neglected or veterinary parasitoses. PMID:27238605

Low dose anti-thymocyte globulin reduces chronic graft-versus-host disease incidence rates after matched unrelated donor transplantation.

PubMed

Tandra, Anand; Covut, Fahrettin; Cooper, Brenda; Creger, Richard; Brister, Lauren; McQuigg, Bernadette; Caimi, Paolo; Malek, Ehsan; Tomlinson, Ben; Lazarus, Hillard M; Otegbeye, Folashade; Kolk, Merle; de Lima, Marcos; Metheny, Leland

2017-12-04

Anti-thymocyte globulin (ATG) is often added to hematopoietic stem cell transplant conditioning regimens to prevent graft rejection and reduce graft-versus-host disease (GVHD). Doses used in retrospective and prospective clinical trials have ranged from 2.5 to 20 mg/kg with rates of grade II-IV acute GVHD and chronic GVHD up to 40 and 60%, respectively. We retrospectively compared outcomes in recipients of matched unrelated donor (MUD) grafts given low dose rabbit ATG IV 3 mg/kg (n = 52) versus recipients of matched related donor (MRD) grafts (n = 48) without ATG. One year cumulative incidence of chronic GVHD was 25.2% in the MUD group versus 33.3% in the MRD group (p = .5). One-year cumulative incidence of extensive chronic GVHD was 9.6% in the MUD group versus 26.6% in the MRD group (p = .042). Our analysis supports the use of low dose ATG in MUD transplantation as an effective therapy to prevent chronic GVHD.

Inhibition of plasmin attenuates murine acute graft-versus-host disease mortality by suppressing the matrix metalloproteinase-9-dependent inflammatory cytokine storm and effector cell trafficking.

PubMed

Sato, A; Nishida, C; Sato-Kusubata, K; Ishihara, M; Tashiro, Y; Gritli, I; Shimazu, H; Munakata, S; Yagita, H; Okumura, K; Tsuda, Y; Okada, Y; Tojo, A; Nakauchi, H; Takahashi, S; Heissig, B; Hattori, K

2015-01-01

The systemic inflammatory response observed during acute graft-versus-host disease (aGVHD) is driven by proinflammatory cytokines, a 'cytokine storm'. The function of plasmin in regulating the inflammatory response is not fully understood, and its role in the development of aGVHD remains unresolved. Here we show that plasmin is activated during the early phase of aGVHD in mice, and its activation correlated with aGVHD severity in humans. Pharmacological plasmin inhibition protected against aGVHD-associated lethality in mice. Mechanistically, plasmin inhibition impaired the infiltration of inflammatory cells, the release of membrane-associated proinflammatory cytokines including tumor necrosis factor-α (TNF-α) and Fas-ligand directly, or indirectly via matrix metalloproteinases (MMPs) and alters monocyte chemoattractant protein-1 (MCP-1) signaling. We propose that plasmin and potentially MMP-9 inhibition offers a novel therapeutic strategy to control the deadly cytokine storm in patients with aGVHD, thereby preventing tissue destruction.

A new approach to data evaluation in the non-target screening of organic trace substances in water analysis.

PubMed

Müller, Alexander; Schulz, Wolfgang; Ruck, Wolfgang K L; Weber, Walter H

2011-11-01

Non-target screening via high performance liquid chromatography-mass spectrometry (HPLC-MS) has gained increasingly in importance for monitoring organic trace substances in water resources targeted for the production of drinking water. In this article a new approach for evaluating the data from non-target HPLC-MS screening in water is introduced and its advantages are demonstrated using the supply of drinking water as an example. The crucial difference between this and other approaches is the comparison of samples based on compounds (features) determined by their full scan data. In so doing, we take advantage of the temporal, spatial, or process-based relationships among the samples by applying the set operators, UNION, INTERSECT, and COMPLEMENT to the features of each sample. This approach regards all compounds, detectable by the used analytical method. That is the fundamental meaning of non-target screening, which includes all analytical information from the applied technique for further data evaluation. In the given example, in just one step, all detected features (1729) of a landfill leachate sample could be examined for their relevant influences on water purification respectively drinking water. This study shows that 1721 out of 1729 features were not relevant for the water purification. Only eight features could be determined in the untreated water and three of them were found in the final drinking water after ozonation. In so doing, it was possible to identify 1-adamantylamine as contamination of the landfill in the drinking water at a concentration in the range of 20 ng L(-1). To support the identification of relevant compounds and their transformation products, the DAIOS database (Database-Assisted Identification of Organic Substances) was used. This database concept includes some functions such as product ion search to increase the efficiency of the database query after the screening. To identify related transformation products the database function

Surrogate species selection for assessing potential adverse environmental impacts of genetically engineered insect-resistant plants on non-target organisms

PubMed Central

Carstens, Keri; Cayabyab, Bonifacio; De Schrijver, Adinda; Gadaleta, Patricia G; Hellmich, Richard L; Romeis, Jörg; Storer, Nicholas; Valicente, Fernando H; Wach, Michael

2014-01-01

Most regulatory authorities require that developers of genetically engineered insect-resistant (GEIR) crops evaluate the potential for these crops to have adverse impacts on valued non-target organisms (NTOs), i.e., organisms not intended to be controlled by the trait. In many cases, impacts to NTOs are assessed using surrogate species, and it is critical that the data derived from surrogates accurately predict any adverse impacts likely to be observed from the use of the crop in the agricultural context. The key is to select surrogate species that best represent the valued NTOs in the location where the crop is going to be introduced, but this selection process poses numerous challenges for the developers of GE crops who will perform the tests, as well as for the ecologists and regulators who will interpret the test results. These issues were the subject of a conference “Surrogate Species Selection for Assessing Potential Adverse Environmental Impacts of Genetically Engineered Plants on Non-Target Organisms” convened by the Center for Environmental Risk Assessment, ILSI Research Foundation. This report summarizes the proceedings of the conference, including the presentations, discussions and the points of consensus agreed to by the participants. PMID:24637519

Effect of the entomopathogenic fungus Lecanicillium muscariumon the predatory mite Phytoseiulus persimilis as a non-target organism.

PubMed

Donka, András; Sermann, Helga; Büttner, Carmen

2008-01-01

In biological control, different benefit organisms have to combine for an effective management. If entomopathogenic fungi will be integrated, than it has to be considered also the effect on non-target organisms Like beneficial arthropods. Because of the high importance of predatory mite Phytoseiulus persimilis in biological control it was to determine side effects of Leconicillium muscarium on this species. In two standardised biotests in petri dish and on plants (P. vulgaris) individuals were dipped in suspension or set down on leafs after spraying with L. muscarium at different spore density. Results indicate pathogenicity for the predatory mite in principle. But the dimension of infection risk decrease, all the more conditions approach to practical sequence. Under practical conditions on plants and in practical relevant concentration of 10(6) and 10(7) sp./ml no risk is to expect on the plant.

Graft-versus-leukemia effects of transplantation and donor lymphocytes.

PubMed

Kolb, Hans-Jochem

2008-12-01

Allogeneic transplantation of hematopoietic cells is an effective treatment of leukemia, even in advanced stages. Allogeneic lymphocytes produce a strong graft-versus-leukemia (GVL) effect, but the beneficial effect is limited by graft-versus-host disease (GVHD). Depletion of T cells abrogates GVHD and GVL effects. Delayed transfusion of donor lymphocytes into chimeras after T cell-depleted stem cell transplantation produces a GVL effect without necessarily producing GVHD. Chimerism and tolerance provide a platform for immunotherapy using donor lymphocytes. The allogeneic GVL effects vary from one disease to another, the stage of the disease, donor histocompatibility, the degree of chimerism, and additional treatment. Immunosuppressive therapy before donor lymphocyte transfusions may augment the effect as well as concomitant cytokine treatment. Possible target antigens are histocompatibility antigens and tumor-associated antigens. Immune escape of tumor cells and changes in the reactivity of T cells are to be considered. Durable responses may be the result of the elimination of leukemia stem cells or the establishment of a durable immune control on their progeny. Recently, we have learned from adoptive immunotherapy of viral diseases and HLA-haploidentical stem cell transplantation that T-cell memory may be essential for the effective treatment of leukemia and other malignancies.

Pharyngeal cavity and the gills are the target organ for the repellent action of pardaxin in shark.

PubMed

Primor, N

1985-05-15

Pardaxin, an active principle of the repellent secretion of the Red Sea flatfish, Pardachirus marmoratus, elicited severe struggling, mouth paralysis, and transient increase in urea leakage from the gills only when administered to the medium bathing the shark's pharyngeal cavity and gills. An apparatus was constructed which prevents a mixing of the outflow from shark's gills with water bathing its surface skin. It is concluded that in sharks the gills and/or the pharyngeal cavity are the target organ for the repellent action of pardaxin.

Association between a high BK virus load in urine samples of patients with graft-versus-host disease and development of hemorrhagic cystitis after hematopoietic stem cell transplantation.

PubMed

Bogdanovic, G; Priftakis, P; Giraud, G; Kuzniar, M; Ferraldeschi, R; Kokhaei, P; Mellstedt, H; Remberger, M; Ljungman, P; Winiarski, J; Dalianis, T

2004-11-01

BK virus (BKV) load in urine alone or in combination with acute graft-versus-host disease (GVHD) was correlated to development of hemorrhagic cystitis (HC). BKV load in combination with acute GVHD discriminated the best, while BKV and viral load alone, but not GVHD, still showed predictive ability for HC.

Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius.

PubMed

Socié, Gérard; Schmoor, Claudia; Bethge, Wolfgang A; Ottinger, Hellmut D; Stelljes, Matthias; Zander, Axel R; Volin, Liisa; Ruutu, Tapani; Heim, Dominik A; Schwerdtfeger, Rainer; Kolbe, Karin; Mayer, Jiri; Maertens, Johan A; Linkesch, Werner; Holler, Ernst; Koza, Vladimir; Bornhäuser, Martin; Einsele, Hermann; Kolb, Hans-Jochem; Bertz, Hartmut; Egger, Matthias; Grishina, Olga; Finke, Jürgen

2011-06-09

Previous randomized graft-versus-host disease (GVHD)-prophylaxis trials have failed to demonstrate reduced incidence and severity of chronic GVHD (cGVHD). Here we reanalyzed and updated a randomized phase 3 trial comparing standard GVHD prophylaxis with or without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before transplantation from unrelated donors. The cumulative incidence of extensive cGVHD after 3 years was 12.2% in the ATG-F group versus 45.0% in the control group (P < .0001). The 3-year cumulative incidence of relapse and of nonrelapse mortality was 32.6% and 19.4% in the ATG-F group and 28.2% and 33.5% in the control group (hazard ratio [HR] = 1.21, P = .47, and HR = 0.68, P = .18), respectively. This nonsignificant reduction in nonrelapse mortality without increased relapse risk led to an overall survival rate after 3 years of 55.2% in the ATG-F group and 43.3% in the control group (HR = 0.84, P = .39, nonsignificant). The HR for receiving immunosuppressive therapy (IST) was 0.31 after ATG-F (P < .0001), and the 3-year probability of survival free of IST was 52.9% and 16.9% in the ATG-F versus control, respectively. The addition of ATG-F to standard cyclosporine, methotrexate GVHD prophylaxis lowers the incidence and severity of cGVHD, and the risk of receiving IST without raising the relapse rate. ATG-F prophylaxis reduces cGVHD morbidity.

Donor interleukin-22 and host type I interferon signaling pathway participate in intestinal graft-versus-host disease via STAT1 activation and CXCL10.

PubMed

Lamarthée, B; Malard, F; Gamonet, C; Bossard, C; Couturier, M; Renauld, J-C; Mohty, M; Saas, P; Gaugler, B

2016-03-01

Acute graft-versus-host disease (aGVHD) remains a major complication following allogeneic hematopoietic cell transplantation, limiting the success of this therapy. We previously reported that interleukin-22 (IL-22) participates to aGVHD development, but the underlying mechanisms of its contribution remain poorly understood. In this study, we analyzed the mechanism of the pathological function of IL-22 in intestinal aGVHD. Ex-vivo colon culture experiments indicated that IL-22 was able to induce Th1-like inflammation via signal transducer and activator of transcription factor-1 (STAT1) and CXCL10 induction in the presence of type I interferon (IFN). To evaluate a potential synergy between IL-22 and type I IFN in aGVHD, we transplanted recipient mice, either wild-type (WT) or type I IFN receptor deficient (IFNAR(-/-)), with bone marrow cells and WT or IL-22 deficient (IL-22(-/-)) T cells. We observed a decreased GVHD severity in IFNAR(-/-) recipient of IL-22(-/-) T cells, which was associated with a lower level of STAT1 activation and reduced CXCL10 expression in the large intestine. Finally, immunohistochemistry staining of STAT1 performed on gastrointestinal biopsies of 20 transplanted patients showed exacerbated STAT1 activation in gastrointestinal tissues of patients with aGVHD as compared with those without aGVHD. Thus, interfering with both IL-22 and type I IFN signaling may provide a novel approach to limit aGVHD.

Visual target modulation of functional connectivity networks revealed by self-organizing group ICA.

PubMed

van de Ven, Vincent; Bledowski, Christoph; Prvulovic, David; Goebel, Rainer; Formisano, Elia; Di Salle, Francesco; Linden, David E J; Esposito, Fabrizio

2008-12-01

We applied a data-driven analysis based on self-organizing group independent component analysis (sogICA) to fMRI data from a three-stimulus visual oddball task. SogICA is particularly suited to the investigation of the underlying functional connectivity and does not rely on a predefined model of the experiment, which overcomes some of the limitations of hypothesis-driven analysis. Unlike most previous applications of ICA in functional imaging, our approach allows the analysis of the data at the group level, which is of particular interest in high order cognitive studies. SogICA is based on the hierarchical clustering of spatially similar independent components, derived from single subject decompositions. We identified four main clusters of components, centered on the posterior cingulate, bilateral insula, bilateral prefrontal cortex, and right posterior parietal and prefrontal cortex, consistently across all participants. Post hoc comparison of time courses revealed that insula, prefrontal cortex and right fronto-parietal components showed higher activity for targets than for distractors. Activation for distractors was higher in the posterior cingulate cortex, where deactivation was observed for targets. While our results conform to previous neuroimaging studies, they also complement conventional results by showing functional connectivity networks with unique contributions to the task that were consistent across subjects. SogICA can thus be used to probe functional networks of active cognitive tasks at the group-level and can provide additional insights to generate new hypotheses for further study. Copyright 2007 Wiley-Liss, Inc.

Synthetic PAMAM-RGD conjugates target and bind to odontoblast-like MDPC 23 cells and the predentin in tooth organ cultures.

PubMed

Hill, Elliott; Shukla, Rameshwer; Park, Steve S; Baker, James R

2007-01-01

Screening techniques now allow for the identification of small peptides that bind specifically to molecules like cells. However, despite the enthusiasm for this approach, single peptides often lack the binding affinity to target in vivo and regulate cell function. We took peptides containing the Arg-Gly Asp(RGD) motif that bind to the alpha Vbeta 3 integrin and have shown potential as therapeutics. To improve their binding affinity, we synthesized polyamidoamine (PAMAM) dendrimer-RGD conjugates that that contain 12-13 copies of the peptide. When cultured with human dermal microvessel endothelial cells (HDMEC), human vascular endothelial cells (HUVEC), or odontoblast-like MDPC-23 cells, the PAMAM dendrimer conjugate targets this receptor in a manner that is both time- and dose-dependent. Finally, this conjugate selectively targets RGD binding sites in the predentin of human tooth organ cultures. Taken together, these studies provide proof of principle that synthetic PAMAM-RGD conjugates could prove useful as carriers for the tissue-specific delivery of integrin-targeted therapeutics or imaging agents and could be used to engineer tissue regeneration.

Potential of targeting TGF-β for organ transplant patients

PubMed Central

Iwashima, Makio; Love, Robert

2015-01-01

TGF-β was originally considered as an immunoregulatory cytokine, but accumulating data demonstrate that it also plays a critical role in development of effector immunity. Since TGF-β has a potent ability to alter immune responses, modulation of the TGF-β pathway for treatment of transplantation patients could be effective if carried out in a target selective manner. This review will focus on the role of TGF-β in T cell differentiation and discuss the prospect of TGF-β as the therapeutic target of lung transplantation acceptance. PMID:23464518

Graft-versus-host disease management.

PubMed

Mistrik, M; Bojtarova, E; Sopko, L; Masakova, L; Roziakova, L; Martinka, J; Batorova, A

Graft-versus-host disease (GVHD) remains a major problem of allogeneic hematopoietic-stem cell transplantation (HSCT) and an obstacle for successful outcome. Clinically significant acute GVHD (grade II or higher) developed in 20 to 65 percent of the patients. Death due to this complication accounts for approximately 50 percent of the deaths that are not due to a relapse of the neoplasm. Up to 70 % of patients who survive beyond day 100 develop chronic GVHD and it is the leading cause of nonrelapse mortality more than 2 years after allogeneic HSCT. In addition, chronic GVHD is associated with decreased quality of life, impaired functional status, and ongoing need for immunosuppressive medications. The incidence of chronic GVHD is increasing because of expansion of the donor population beyond HLA-identical siblings, older recipient age, use of peripheral blood cells as the graft source, and infusion of donor lymphocytes for treatment of recurrent malignancy after HSCT. With the current rush in new findings related to GVHD, we see a significant advancement in its management. Given these various new options and challenges, it is important to identify the minimal requirements for diagnosis and treatment of GVHD, as access to the most sophisticated advances may vary depending on local circumstances (Tab. 4, Fig. 1, Ref. 51).

Correlation of Tc17 cells at early stages after allogeneic hematopoietic stem cell transplantation with acute graft-versus-host disease.

PubMed

Wang, Ling; Zhao, Peng; Song, Lingling; Yan, Fahong; Shi, Chunlei; Li, Ying; Han, Mingzhe; Lan, Ketao

2016-12-01

Acute graft-versus-host disease (aGVHD) is associated with an immune dysregulation usually mediated by T lymphocytes. Recently, IL-17-producing T cells including Th17 and Tc17 cells have been implicated in immune-related diseases. However, their roles in aGVHD remain uncertain. In the study, we analyzed IL-17-producing cell recovery and association with the occurrence of aGVHD. While Th17 cells steadily recovered, Tc17 cell numbers remained unaltered during the first 3months after transplantation. Occurrence of aGVHD was correlated with increased level of Tc17 cells at the second months after allo-SCT. Interestingly, Tc17 cells were negatively associated with CD4 + CD25 + FOXP3 + regulatory T (Treg) cells, which was an important prognostic predictor in patients with aGVHD. In addition, we found that Tc17 numbers increased as the increased concentrations of TGF-β and IL-6, which are known to drive Th17 polarization. These finding supported that Tc17 subset is involved in the immunopathology of aGVHD. Blocking the abnormally increased number of Tc17 may be a reasonable therapeutic strategy for aGVHD. Copyright © 2016 Elsevier B.V. All rights reserved.

Graft-versus-host disease: regulation by microbe-associated molecules and innate immune receptors.

PubMed

Penack, Olaf; Holler, Ernst; van den Brink, Marcel R M

2010-03-11

Acute graft-versus-host disease (GVHD) remains the major obstacle to a more favorable therapeutic outcome of allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is characterized by tissue damage in gut, liver, and skin, caused by donor T cells that are critical for antitumor and antimicrobial immunity after HSCT. One obstacle in combating GVHD used to be the lack of understanding the molecular mechanisms that are involved in the initiation phase of this syndrome. Recent research has demonstrated that interactions between microbial-associated molecules (pathogen-associated molecular patterns [PAMPs]) and innate immune receptors (pathogen recognition receptors [PRRs]), such as NOD-like receptors (NLRs) and Toll-like receptors (TLRs), control adaptive immune responses in inflammatory disorders. Polymorphisms of the genes encoding NOD2 and TLR4 are associated with a higher incidence of GVHD in HSC transplant recipients. Interestingly, NOD2 regulates GVHD through its inhibitory effect on antigen-presenting cell (APC) function. These insights identify important mechanisms regarding the induction of GVHD through the interplay of microbial molecules and innate immunity, thus opening a new area for future therapeutic approaches. This review covers current knowledge of the role of PAMPs and PRRs in the control of adaptive immune responses during inflammatory diseases, particularly GVHD.

Acute graft-versus-host disease biomarkers measured during therapy can predict treatment outcomes: a Blood and Marrow Transplant Clinical Trials Network study

PubMed Central

Logan, Brent R.; Wu, Juan; Alousi, Amin M.; Bolaños-Meade, Javier; Ferrara, James L. M.; Ho, Vincent T.; Weisdorf, Daniel J.

2012-01-01

Acute graft-versus-host disease (GVHD) is the primary limitation of allogeneic hematopoietic cell transplantation, and once it develops, there are no reliable diagnostic tests to predict treatment outcomes. We hypothesized that 6 previously validated diagnostic biomarkers of GVHD (IL-2 receptor-α; tumor necrosis factor receptor-1; hepatocyte growth factor; IL-8; elafin, a skin-specific marker; and regenerating islet–derived 3-α, a gastrointestinal tract–specific marker) could discriminate between therapy responsive and nonresponsive patients and predict survival in patients receiving GVHD therapy. We measured GVHD biomarker concentrations from samples prospectively obtained at the initiation of treatment, day 14, and day 28, on a multicenter, randomized, 4-arm phase 2 clinical trial for newly diagnosed acute GVHD. We found that at each of 3 time points, GVHD onset, 2 weeks into treatment, and 4 weeks into treatment, a 6-protein biomarker panel predicted for the important clinical outcomes of day 28 posttherapy nonresponse and mortality at day 180 from onset. GVHD biomarker panels can be used for early identification of patients at high or low risk for treatment nonresponsiveness or death, and they may provide opportunities for early intervention and improved survival after hematopoietic cell transplantation. The study was registered in clinicaltrials.gov as NCT00224874. PMID:22383800

Association of mixed hematopoietic chimerism with elevated circulating autoantibodies and chronic graft-versus-host disease occurrence

PubMed Central

Perruche, Sylvain; Marandin, Aliette; Kleinclauss, François M.; Angonin, Régis; Fresnay, Stéphanie; Baron, Marie Hélène; Tiberghien, Pierre; Saas, Philippe

2006-01-01

Background Use of a reduced intensity conditioning regimen before an allogeneic hematopoietic cell transplantation is frequently associated with an early state of mixed hematopoietic chimerism. Such a co-existence of both host and donor hematopoietic cells may influence post-transplant alloreactivity and may affect the occurrence and severity of acute and chronic graft-versus-host disease (GVHD) as well as the intensity of the graft-versus-leukemia effect. Here we evaluated the relation between chimerism state after reduced intensity conditioning transplantation (RICT), auto-antibody production and chronic GVHD (cGVHD)-related pathology. Methods Chimerism state, circulating anti-cardiolipin and anti-double stranded DNA auto-antibody (Ab) titers as well as occurrence of cGVHD-like lesions were investigated in a murine RICT model. Results We observed a novel association between mixed chimerism state, high levels of pathogenic IgG auto-Abs and subsequent development of cGVHD-like lesions. Furthermore, we found that the persistence of host B cells, but not dendritic cell origin or subset, was a factor associated with the appearance of cGVHD-like lesions. The implication of host B cells was confirmed by a host origin of auto-Abs. Conclusions Recipient B cell persistence may therefore contribute to the frequency and/or severity of cGVHD after RICT. PMID:16495806

Association between a High BK Virus Load in Urine Samples of Patients with Graft-Versus-Host Disease and Development of Hemorrhagic Cystitis after Hematopoietic Stem Cell Transplantation

PubMed Central

Bogdanovic, G.; Priftakis, P.; Giraud, G.; Kuzniar, M.; Ferraldeschi, R.; Kokhaei, P.; Mellstedt, H.; Remberger, M.; Ljungman, P.; Winiarski, J.; Dalianis, T.

2004-01-01

BK virus (BKV) load in urine alone or in combination with acute graft-versus-host disease (GVHD) was correlated to development of hemorrhagic cystitis (HC). BKV load in combination with acute GVHD discriminated the best, while BKV and viral load alone, but not GVHD, still showed predictive ability for HC. PMID:15528753

Pioneering topological methods for network-based drug-target prediction by exploiting a brain-network self-organization theory.

PubMed

Durán, Claudio; Daminelli, Simone; Thomas, Josephine M; Haupt, V Joachim; Schroeder, Michael; Cannistraci, Carlo Vittorio

2017-04-26

The bipartite network representation of the drug-target interactions (DTIs) in a biosystem enhances understanding of the drugs' multifaceted action modes, suggests therapeutic switching for approved drugs and unveils possible side effects. As experimental testing of DTIs is costly and time-consuming, computational predictors are of great aid. Here, for the first time, state-of-the-art DTI supervised predictors custom-made in network biology were compared-using standard and innovative validation frameworks-with unsupervised pure topological-based models designed for general-purpose link prediction in bipartite networks. Surprisingly, our results show that the bipartite topology alone, if adequately exploited by means of the recently proposed local-community-paradigm (LCP) theory-initially detected in brain-network topological self-organization and afterwards generalized to any complex network-is able to suggest highly reliable predictions, with comparable performance with the state-of-the-art-supervised methods that exploit additional (non-topological, for instance biochemical) DTI knowledge. Furthermore, a detailed analysis of the novel predictions revealed that each class of methods prioritizes distinct true interactions; hence, combining methodologies based on diverse principles represents a promising strategy to improve drug-target discovery. To conclude, this study promotes the power of bio-inspired computing, demonstrating that simple unsupervised rules inspired by principles of topological self-organization and adaptiveness arising during learning in living intelligent systems (like the brain) can efficiently equal perform complicated algorithms based on advanced, supervised and knowledge-based engineering. © The Author 2017. Published by Oxford University Press.

Vitamin A-coupled liposomes containing siRNA against HSP47 ameliorate skin fibrosis in chronic graft-versus-host disease.

PubMed

Yamakawa, Tomohiro; Ohigashi, Hiroyuki; Hashimoto, Daigo; Hayase, Eiko; Takahashi, Shuichiro; Miyazaki, Miyono; Minomi, Kenjiro; Onozawa, Masahiro; Niitsu, Yoshiro; Teshima, Takanori

2018-03-29

Chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (SCT) is characterized by multiorgan fibrosis and profoundly affects the quality of life of transplant survivors. Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, plays a critical role in collagen synthesis in myofibroblasts. We explored the role of HSP47 in the fibrotic process of cutaneous chronic GVHD in mice. Immunohistochemical analysis showed massive fibrosis with elevated amounts of collagen deposits and accumulation of F4/80 + macrophages, as well as myofibroblasts expressing HSP47 and retinol-binding protein 1 in the skin after allogeneic SCT. Repeated injection of anti-colony-stimulating factor (CSF-1) receptor-blocking antibodies significantly reduced HSP47 + myofibroblasts in the skin, indicating a macrophage-dependent accumulation of myofibroblasts. Vitamin A-coupled liposomes carrying HSP47 small interfering RNA (siRNA) (VA-lip HSP47) delivered HSP47 siRNA to cells expressing vitamin A receptors and knocked down their HSP47 in vitro. Intravenously injected VA-lip HSP47 were specifically distributed to skin fibrotic lesions and did not affect collagen synthesis in healthy skin. VA-lip HSP47 knocked down HSP47 expression in myofibroblasts and significantly reduced collagen deposition without inducing systemic immunosuppression. It also abrogated fibrosis in the salivary glands. These results highlight a cascade of fibrosis in chronic GVHD; macrophage production of transforming growth factor β mediates fibroblast differentiation to HSP47 + myofibroblasts that produce collagen. VA-lip HSP47 represent a novel strategy to modulate fibrosis in chronic GVHD by targeting HSP47 + myofibroblasts without inducing immunosuppression. © 2018 by The American Society of Hematology.

Adoptive immunotherapy against allogeneic kidney grafts in dogs with stable hematopoietic trichimerism.

PubMed

Graves, Scott S; Hogan, William J; Kuhr, Christian; Diaconescu, Razvan; Harkey, Michael; Sale, George E; Stone, Brad; Georges, George E; Storb, Rainer

2008-11-01

Dogs given nonmyeloablative conditioning and marrow grafts from 2 dog leukocyte antigen (DLA)-identical littermate donors developed stable trichimerism and stably accepted a subsequent kidney graft from one of the marrow donors without the need for immunosuppression. In this study, we used trichimeras to evaluate strategies for adoptive immunotherapy to solid tumors, using the kidney as a tumor surrogate. Three DLA-identical trichimeric recipients were established by simultaneously infusing marrow from 2 DLA-identical donor dogs into a DLA-identical recipient conditioned with 2 Gy of total body irradiation (TBI) and given a short course of postgraft immunosuppression. After stable hematopoietic engraftment was confirmed, a kidney was transplanted from 1 of the 2 marrow donors into each respective trichimeric recipient. Peripheral blood lymphocytes from each kidney donor were then used to sensitize the alternate marrow donor. The trichimeric recipients were given donor lymphocyte infusions (DLIs) from the sensitized dogs and monitored for chimerism, graft-versus-host disease (GVHD), and kidney rejection. After DLI, we observed both prompt rejection of the transplanted marrow and donor kidney and disappearance of corresponding hematopoietic chimerism. Presumably due to shared minor histocompatibility antigens, host chimerism also disappeared, and GVHD in skin, gut, and liver developed. The native kidneys, although exhibiting lymphocytic infiltration, remained functionally normal. This study demonstrates that under certain experimental conditions, the kidney--an organ ordinarily not involved in graft-versus-host reactions--can be targeted by sensitized donor lymphocytes.

Adoptive Immunotherapy against Allogeneic Kidney Grafts in Dogs with Stable Hematopoietic Trichimerism

PubMed Central

Graves, Scott S.; Hogan, William J.; Kuhr, Christian; Diaconescu, Razvan; Harkey, Michael; Sale, George E.; Stone, Brad; Georges, George E.; Storb, Rainer

2008-01-01

Dogs given nonmyeloablative conditioning and marrow grafts from two dog leukocyte antigen- (DLA) identical littermate donors developed stable trichimerism and stably accepted a subsequent kidney graft from one of the marrow donors without the need for immunosuppression. Here, we used trichimeras to evaluate strategies of adoptive immunotherapy to solid tumors, using the kidney as a tumor surrogate. Three DLA-identical trichimeric recipients were established by simultaneously infusing marrow from two DLA-identical donor dogs into a DLA-identical recipient conditioned with 2 Gy total body irradiation and given a short course of postgrafting immunosuppression. After confirming stable hematopoietic engraftment, a kidney was transplanted from one of the two marrow donors into each respective trichimeric recipient. Peripheral blood lymphocytes (PBL) from each kidney donor were then used to sensitize the alternate marrow donor. Donor lymphocyte infusions (DLI) from the sensitized dogs were given to the trichimeric recipients, whereupon chimerism, graft-versus-host disease (GvHD), and kidney rejection were monitored. After DLI, we observed both prompt rejection of the transplanted marrow-donor kidney and disappearance of corresponding hematopoietic chimerism. Presumably, owing to shared minor histocompatibility antigens, host chimerism also disappeared and GvHD in skin, gut, and liver developed. The native kidneys, while showing lymphocytic infiltration, remained functionally normal. The current study demonstrated that under certain experimental conditions, the kidney, an organ ordinarily not involved in graft-versus-host reactions, can be targeted by sensitized donor lymphocytes. PMID:18940673

Steroid treatment of acute graft-versus-host disease grade I: a randomized trial.

PubMed

Bacigalupo, Andrea; Milone, Giuseppe; Cupri, Alessandra; Severino, Antonio; Fagioli, Franca; Berger, Massimo; Santarone, Stella; Chiusolo, Patrizia; Sica, Simona; Mammoliti, Sonia; Sorasio, Roberto; Massi, Daniela; Van Lint, Maria Teresa; Raiola, Anna Maria; Gualandi, Francesca; Selleri, Carmine; Sormani, Maria Pia; Signori, Alessio; Risitano, Antonio; Bonifazi, Francesca

2017-12-01

Patients with acute graft- versus -host disease (GvHD) grade I were randomized to an observation arm (n=85) or to a treatment arm (n=86) consisting of 6-methylprednisolone 1 mg/kg/day, after stratification for age and donor type. The primary end point was development of grade II-IV GvHD. The cumulative incidence of grade II-IV GvHD was 50% in the observation arm and 33% in the treatment arm ( P =0.005). However, grade III-IV GvHD was comparable (13% vs 10%, respectively; P =0.6), and this was true for sibling and alternative donor transplants. Moderate/severe chronic GvHD was also comparable (17% vs 9%). In multivariate analysis, an early interval between transplant and randomization (GvHD. Patients in the observation arm had less infectious bacterial episodes (12 vs 25; P =0.04), less severe infectious fungal episodes (0 vs 3; P =0.04), and less severe adverse events (3 vs 11; P =0.07). At five years, non-relapse mortality was 20% versus 26% ( P =0.2), relapse-related mortality 25% versus 21%, and actuarial survival was 51% versus 41% ( P =0.3) in the observation and treatment arms, respectively. In multivariate analysis, advanced disease phase, older age and an early onset of GvHD were significant negative predictors of survival, independent of the randomization arm. In conclusion, steroid treatment of acute grade I GvHD prevents progression to grade II but not to grade III-IV GvHD, and there is no effect on non-relapse mortality and survival. Patients treated with steroids are at a higher risk of developing infections and have more adverse events. ( Trial registered as EUDTRACT 2008-000413-29 ). Copyright© 2017 Ferrata Storti Foundation.

Vision-Related Quality of Life in Patients with Ocular Graft-versus-Host Disease.

PubMed

Saboo, Ujwala S; Amparo, Francisco; Abud, Tulio B; Schaumberg, Debra A; Dana, Reza

2015-08-01

To assess the vision-related quality of life (QOL) in a cohort of patients with ocular graft-versus-host disease (GVHD). Prospective study. Eighty-four patients diagnosed with chronic ocular GVHD. We assessed the vision-related QOL with the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25). The symptoms of ocular GVHD were assessed using the Ocular Surface Disease Index (OSDI) and Symptom Assessment in Dry Eye (SANDE) questionnaires. We assessed vision-related QOL with the NEI-VFQ-25 and compared the scores obtained from patients with ocular GVHD with those from a healthy population. In the ocular GVHD population, we also evaluated the associations between the NEI-VFQ-25 and the dry eye symptoms measured by the OSDI and SANDE questionnaires, age, duration of disease, best-corrected visual acuity (BCVA), corneal fluorescein staining (CFS), tear break-up time, and Schirmer test. The mean composite NEI-VFQ-25 score in patients with ocular GVHD was 76.5±17. Compared with healthy subjects, patients with ocular GVHD reported reduced scores on all NEI-VFQ-25 subscales (each P < 0.001) with the exception of color vision (P = 0.11). The NEI-VFQ-25 composite scores significantly correlated with OSDI (R = -0.81, P < 0.001), SANDE (R = -0.56, P < 0.001), CFS (R = -0.36, P = 0.001), and BCVA (R = -0.30, P = 0.004). Patients with ocular GVHD experience measurable impairment of vision-related QOL. This study highlights the impact of ocular GVHD on the vision-related QOL, and thus the importance of comprehensive diagnosis and treatment of this condition. Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Vision-Related Quality of Life in Patients with Ocular Graft-versus-host Disease

PubMed Central

Saboo, Ujwala S; Amparo, Francisco; Abud, Tulio B; Schaumberg, Debra A; Dana, Reza

2015-01-01

Objective To assess the vision-related quality of life in a cohort of patients with ocular graft-versus-host disease (GVHD). Design Prospective study. Participants Eighty-four patients diagnosed with chronic ocular GVHD Methods We assessed the vision-related quality of life with the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25). The symptoms of ocular GVHD were assessed using the Ocular Surface Disease Index (OSDI) and Symptom Assessment in Dry Eye (SANDE) questionnaires. Main outcome measures We assessed vision-related quality of life with NEI-VFQ-25 and compared the scores obtained from patients with ocular GVHD to those from a healthy population. In the ocular GVHD population, we also evaluated the associations between the NEI-VFQ-25 and dry eye symptoms measured by OSDI and SANDE questionnaires, age, duration of disease, best-corrected visual acuity, corneal fluorescein staining, tear break-up time, and Schirmer test. Results The mean composite NEI-VFQ-25 score in patients with ocular GVHD was 76.5 ± 17. Compared to healthy subjects, ocular GVHD patients reported reduced scores on all NEI-VFQ-25 subscales (each P < 0.001) with exception of color vision (P = 0.11). The NEI-VFQ-25 composite scores significantly correlated with OSDI (R = −0.81, P < 0.001), SANDE (R = −0.56, P < 0.001), corneal fluorescein staining (R = −0.36, P = 0.001) and best-corrected visual acuity (R = −0.30, P = 0.004). Conclusion Patients with ocular GVHD experience measurable impairment of vision-related quality of life. This study highlights the impact of ocular GVHD on the vision-related quality of life, and hence the importance of comprehensive diagnosis and treatment of this condition. PMID:26001816

Fabrication of 14 different RNA nanoparticles for specific tumor targeting without accumulation in normal organs

PubMed Central

Shu, Yi; Haque, Farzin; Shu, Dan; Li, Wei; Zhu, Zhenqi; Kotb, Malak; Lyubchenko, Yuri; Guo, Peixuan

2013-01-01

Due to structural flexibility, RNase sensitivity, and serum instability, RNA nanoparticles with concrete shapes for in vivo application remain challenging to construct. Here we report the construction of 14 RNA nanoparticles with solid shapes for targeting cancers specifically. These RNA nanoparticles were resistant to RNase degradation, stable in serum for >36 h, and stable in vivo after systemic injection. By applying RNA nanotechnology and exemplifying with these 14 RNA nanoparticles, we have established the technology and developed “toolkits” utilizing a variety of principles to construct RNA architectures with diverse shapes and angles. The structure elements of phi29 motor pRNA were utilized for fabrication of dimers, twins, trimers, triplets, tetramers, quadruplets, pentamers, hexamers, heptamers, and other higher-order oligomers, as well as branched diverse architectures via hand-in-hand, foot-to-foot, and arm-on-arm interactions. These novel RNA nanostructures harbor resourceful functionalities for numerous applications in nanotechnology and medicine. It was found that all incorporated functional modules, such as siRNA, ribozymes, aptamers, and other functionalities, folded correctly and functioned independently within the nanoparticles. The incorporation of all functionalities was achieved prior, but not subsequent, to the assembly of the RNA nanoparticles, thus ensuring the production of homogeneous therapeutic nanoparticles. More importantly, upon systemic injection, these RNA nanoparticles targeted cancer exclusively in vivo without accumulation in normal organs and tissues. These findings open a new territory for cancer targeting and treatment. The versatility and diversity in structure and function derived from one biological RNA molecule implies immense potential concealed within the RNA nanotechnology field. PMID:23604636

Target Organ Damage and Target Systolic Blood Pressure in Clinical Practice: The Campania Salute Network.

PubMed

D'Amato, Andrea; Mancusi, Costantino; Losi, Maria Angela; Izzo, Raffaele; Arnone, Maria Immacolata; Canciello, Grazia; Senese, Salvatore; De Luca, Nicola; de Simone, Giovanni; Trimarco, Bruno

2018-05-07

Lowering systolic blood pressure (SBP) below the conventional threshold (140 mm Hg) reduces left ventricular (LV) hypertrophy and incident cardiovascular (CV) events. We assessed whether different thresholds of SBP as the average value during follow-up (FU) have different impact on changes in target organ damage (TOD). From the Campania Salute Network registry, we selected 4,148 hypertensive patients with average SBP-FU <140 mm Hg, and without history of prevalent CV or chronic kidney disease (i.e.,

Cutaneous Chronic Graft Versus Host Disease Following Allogeneic Haematopoietic Stem Cell Transplantation in Children: A Retrospective Study.

PubMed

Shreberk-Hassidim, Rony; Neumark, Michal; Greenberger, Shoshana; Goldstein, Gal; Hassidim, Ayal; Dukler, Yuval; Maly, Alexander; Stepensky, Polina; Molho-Pessach, Vered

2018-02-07

Chronic graft versus host disease (cGVHD) is a complication of allogeneic haematopoietic stem cell transplantation (HSCT). The aim of this study was to clinically characterize childhood cutaneous cGVHD. A retrospective study of children treated with HSCT at 2 tertiary medical centres in Israel between 2011 and 2014 was performed. A total of 112 children were included. Cutaneous cGVHD developed in 18% of subjects. Risk factors were older age, HSCT from peripheral blood and acute lymphoblastic leukaemia. The eruption was lichenoid in 90% of subjects, of whom one-third progressed to sclerosis. Topical treatments were usually sufficient in localized disease. Widespread eruption necessitated phototherapy, extracorporeal photopheresis and/or systemic immunosuppressants. Patients presenting with palmoplantar keratoderma, developed sclerosis. To the best of our knowledge, this is the first study describing childhood cutaneous cGVHD. Lichenoid eruption is the most common cutaneous pattern of cGVHD in children. Sclerotic changes may be associated with prior keratoderma. cGVHD poses a therapeutic challenge and better treatments should be sought.

Graft versus host disease: what should the oculoplastic surgeon know?

PubMed

Tung, Cynthia I

2017-09-01

To provide a concise review of the oculoplastic manifestations of ocular graft versus host disease (GVHD), and to discuss their management. Ocular GVHD occurs as a common immune-mediated complication of hematopoietic stem cell transplantation that presents as a Stevens-Johnson-like syndrome in the acute phase or a Sjögren-like syndrome in the chronic phase. Cicatricial conjunctivitis may be underreported in ocular GVHD. The spectrum of oculoplastic manifestations includes GVHD of the skin, cicatricial entropion, nasolacrimal duct obstruction, and lacrimal gland dysfunction. Surgical treatment is indicated for patients with significant corneal complications from entropion. Surgical approach to repair of nasolacrimal duct obstruction is presented in this review, including modified approaches for treating patients at risk for keratitis sicca. Management of the ocular graft versus host patient may require a multidisciplinary approach involving collaboration from the oculoplastic surgeon, the corneal specialist, and the stem cell transplant physician. Oculoplastic manifestations of ocular GVHD typically present as cicatricial changes in the eyelid and lacrimal system. Careful oculoplastic and corneal evaluation are necessary when considering surgical management for the ocular GVHD patient.

Localization of sclerotic-type chronic graft-vs-host disease to sites of skin injury: potential insight into the mechanism of isomorphic and isotopic responses.

PubMed

Martires, Kathryn J; Baird, Kristin; Citrin, Deborah E; Hakim, Fran T; Pavletic, Steven Z; Cowen, Edward W

2011-09-01

The mechanisms responsible for the variable manifestations of chronic cutaneous graft-vs-host disease (cGVHD) are poorly understood. Localization of sclerotic-type chronic graft-vs-host disease to sites of skin injury (isomorphic and isotopic responses), a recognized phenomenon in morphea, suggests a potential common pathway between cGVHD and other sclerotic skin conditions. Four cases of sclerotic-type cGVHD developed at the site of disparate skin injuries (ionizing radiotherapy, repeated needle sticks, central catheter site, and varicella-zoster virus infection). We review the spectrum of previously reported cases of sclerotic and nonsclerotic cGVHD relating to external forces on the skin. Localization of sclerotic-type cGVHD may occur after many types of skin injury, including UV and ionizing radiotherapy, needle sticks, viral infection, and pressure or friction. Recognition of this phenomenon may be helpful for the early diagnosis of sclerotic disease. Recent insights into the immunological consequences of minor skin injury may provide important clues to the underlying pathogenesis of cGVHD-mediated skin disease.

Alemtuzumab as treatment of steroid-refractory acute graft-versus-host disease: results of a phase II study.

PubMed

Martínez, Carmen; Solano, Carlos; Ferrá, Christelle; Sampol, Antonia; Valcárcel, David; Pérez-Simón, José Antonio

2009-05-01

We conducted a phase II trial to investigate the safety and efficacy of alemtuzumab in treating steroid-refractory acute graft-versus-host disease (aGVHD) grade II or higher after stem cell transplantation. Ten adult patients (6 with aGVHD grade III and 4 with aGVHD grade IV) were included in the study. Nine patients had gastrointestinal tract involvement, 7 had skin involvement, and 5 had liver involvement. Five patients responded to treatment, 2 with complete response and 3 with partial response. Eight infectious events (4 of grade 3-4) and 7 cytomegalovirus (CMV) reactivations were observed. Six patients had grade 3-4 cytopenia. All 10 patients died (7 resulting from aGVHD progression, 2 from severe infection, and 1 from to leukemia relapse), at a median of 40 days (range, 4 to 88 days) after alemtuzumab treatment. Overall, our findings suggest that steroid-refractory aGVHD may be improved by treatment with alemtuzumab, but that this treatment does not overcome the dismal prognosis of patients with severe aGVHD, demonstrating the need for alternative therapies to treat this complication.

Multipotent Mesenchymal Stromal Cells for the Prophylaxis of Acute Graft-versus-Host Disease—A Phase II Study

PubMed Central

Kuzmina, Larisa A.; Petinati, Natalia A.; Parovichnikova, Elena N.; Lubimova, Lidia S.; Gribanova, Elena O.; Gaponova, Tatjana V.; Shipounova, Irina N.; Zhironkina, Oxana A.; Bigildeev, Alexey E.; Svinareva, Daria A.; Drize, Nina J.; Savchenko, Valery G.

2012-01-01

The efficacy and the safety of the administration of multipotent mesenchymal stromal cells (MMSCs) for acute graft-versus-host disease (aGVHD) prophylaxis following allogeneic hematopoietic cell transplantation (HSCT) were studied. This prospective clinical trial was based on the random patient allocation to the following two groups receiving (1) standard GVHD prophylaxis and (2) standard GVHD prophylaxis combined with MMSCs infusion. Bone marrow MMSCs from hematopoietic stem cell donors were cultured and administered to the recipients at doses of 0.9–1.3 × 106/kg when the blood counts indicated recovery. aGVHD of stage II–IV developed in 38.9% and 5.3% of patients in group 1 and group 2, respectively, (P = 0.002). There were no differences in the graft rejection rates, chronic GVHD development, or infectious complications. Overall mortality was 16.7% for patients in group 1 and 5.3% for patients in group 2. The efficacy and the safety of MMSC administration for aGVHD prophylaxis were demonstrated in this study. PMID:22242033

Multipotent Mesenchymal Stromal Cells for the Prophylaxis of Acute Graft-versus-Host Disease-A Phase II Study.

PubMed

Kuzmina, Larisa A; Petinati, Natalia A; Parovichnikova, Elena N; Lubimova, Lidia S; Gribanova, Elena O; Gaponova, Tatjana V; Shipounova, Irina N; Zhironkina, Oxana A; Bigildeev, Alexey E; Svinareva, Daria A; Drize, Nina J; Savchenko, Valery G

2012-01-01

The efficacy and the safety of the administration of multipotent mesenchymal stromal cells (MMSCs) for acute graft-versus-host disease (aGVHD) prophylaxis following allogeneic hematopoietic cell transplantation (HSCT) were studied. This prospective clinical trial was based on the random patient allocation to the following two groups receiving (1) standard GVHD prophylaxis and (2) standard GVHD prophylaxis combined with MMSCs infusion. Bone marrow MMSCs from hematopoietic stem cell donors were cultured and administered to the recipients at doses of 0.9-1.3 × 10(6)/kg when the blood counts indicated recovery. aGVHD of stage II-IV developed in 38.9% and 5.3% of patients in group 1 and group 2, respectively, (P = 0.002). There were no differences in the graft rejection rates, chronic GVHD development, or infectious complications. Overall mortality was 16.7% for patients in group 1 and 5.3% for patients in group 2. The efficacy and the safety of MMSC administration for aGVHD prophylaxis were demonstrated in this study.

Natural products from marine organisms with neuroprotective activity in the experimental models of Alzheimer's disease, Parkinson's disease and ischemic brain stroke: their molecular targets and action mechanisms.

PubMed

Choi, Dong-Young; Choi, Hyukjae

2015-02-01

Continuous increases in the incidence of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and brain stroke demand the urgent development of therapeutics. Marine organisms are well-known producers of natural products with diverse structures and pharmacological activities. Therefore, researchers have endeavored to identify marine natural products with neuroprotective effects. In this regard, this review summarizes therapeutic targets for AD, PD, and ischemic brain stroke and marine natural products with pharmacological activities on the targets according to taxonomies of marine organisms. Furthermore, several marine natural products on the clinical trials for the treatment of neurological disorders are discussed.

Peripheral Blood CD38 Bright CD8+ Effector Memory T Cells Predict Acute Graft-versus-Host Disease.

PubMed

Khandelwal, Pooja; Lane, Adam; Chaturvedi, Vijaya; Owsley, Erika; Davies, Stella M; Marmer, Daniel; Filipovich, Alexandra H; Jordan, Michael B; Marsh, Rebecca A

2015-07-01

Acute graft-versus-host disease (aGVHD) is mediated by allogeneic T cell responses. We hypothesized that increases of peripheral blood-activated CD8+ effector memory T (TEM) cells would be observed after hematopoietic stem cell transplantation (HSCT) before onset of aGVHD symptoms. Blood was collected twice weekly after HSCT for 7 weeks in 49 consecutive pediatric and adult HSCT recipients. Samples were incubated with fluorochrome-conjugated antibodies against CD45, CD3, CD8, CD38, CD45RA, and CCR7 and analyzed using flow cytometry. TEM cells were defined as CD3+ CD8+ CCR7- CD45RA(-) lymphocytes. CD38 expression was used as a marker of T cell activation. Patients were followed for 100 days for development of aGVHD. Twenty-three patients developed grade 1 to 4 aGVHD at a median of 37 days (range, 15 to 79 days) after HCST. Absolute CD38 bright CD8+ TEM of > 35 cells/μL predicted aGVHD at a median of 8 days (range, 1 to 34) before aGVHD onset with a sensitivity of 82.6% and specificity of 91.6%. The cumulative incidence of aGVHD was 90% in patients with absolute CD38 bright CD8+ TEM >35 cells/μL and 15% in patients without (P < .0001). Quantification of CD38 bright CD8+ TEM cells may predict aGVHD in children and young adult HSCT recipients. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Segmentation of skin lesions in chronic graft versus host disease photographs with fully convolutional networks

NASA Astrophysics Data System (ADS)

Wang, Jianing; Chen, Fuyao; Dellalana, Laura E.; Jagasia, Madan H.; Tkaczyk, Eric R.; Dawant, Benoit M.

2018-02-01

Chronic graft-versus-host disease (cGVHD) is a frequent and potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (HCT) and commonly affects the skin, resulting in distressing patient morbidity. The percentage of involved body surface area (BSA) is commonly used for diagnosing and scoring the severity of cGVHD. However, the segmentation of the involved BSA from patient whole body serial photography is challenging because (1) it is difficult to design traditional segmentation method that rely on hand crafted features as the appearance of cGVHD lesions can be drastically different from patient to patient; (2) to the best of our knowledge, currently there is no publicavailable labelled image set of cGVHD skin for training deep networks to segment the involved BSA. In this preliminary study we create a small labelled image set of skin cGVHD, and we explore the possibility to use a fully convolutional neural network (FCN) to segment the skin lesion in the images. We use a commercial stereoscopic Vectra H1 camera (Canfield Scientific) to acquire 400 3D photographs of 17 cGVHD patients aged between 22 and 72. A rotational data augmentation process is then applied, which rotates the 3D photos through 10 predefined angles, producing one 2D projection image at each position. This results in 4000 2D images that constitute our cGVHD image set. A FCN model is trained and tested using our images. We show that our method achieves encouraging results for segmenting cGVHD skin lesion in photographic images.

Less graft-versus-host disease after rabbit antithymocyte globulin conditioning in unrelated bone marrow transplantation for leukemia and myelodysplasia: comparison with matched related bone marrow transplantation.

PubMed

Atta, Elias Hallack; de Oliveira, Danielli Cristina Muniz; Bouzas, Luis Fernando; Nucci, Márcio; Abdelhay, Eliana

2014-01-01

One of the major drawbacks for unrelated donor (UD) bone marrow transplantation (BMT) is graft-versus-host disease (GVHD). Despite results from randomized trials, antithymocyte globulin (ATG) is not routinely included for GVHD prophylaxis in UD BMT by many centers. One of ways to demonstrate the usefulness of rabbit ATG in UD BMT is to evaluate how its results approximate to those observed in matched related (MRD) BMT. Therefore, we compared the outcomes between UD BMT with rabbit ATG (Thymoglobulin) for GVHD prophylaxis (n = 25) and MRD BMT (n = 91) for leukemia and myelodysplasia. All but one patient received a myeloablative conditioning regimen. Grades II-IV acute GVHD were similar (39.5% vs. 36%, p = 0.83); however, MRD BMT recipients developed more moderate-severe chronic GVHD (36.5% vs. 8.6%, p = 0.01) and GVHD-related deaths (32.5% vs. 5.6%, p = 0.04). UD BMT independently protected against chronic GVHD (hazard ratio 0.23, p = 0.04). The 6-month transplant-related mortality, 1-year relapse incidence, and 5-year survival rates were similar between patients with non-advanced disease in the MRD and UD BMT groups, 13.8% vs. 16.6% (p = 0.50), 20.8% vs. 16.6% (p = 0.37), and 57% vs. 50% (p = 0.67), respectively. Stable full donor chimerism was equally achieved (71.3% vs. 71.4%, p = 1). Incorporation of rabbit ATG in UD BMT promotes less GVHD, without jeopardizing chimerism evolution, and may attain similar survival outcomes as MRD BMT for leukemia and myelodysplasia especially in patients without advanced disease.

Evaluation of the biological activity of the molluscicidal fraction of Solanum sisymbriifolium against non target organisms.

PubMed

Bagalwa, Jean-Jacques M; Voutquenne-Nazabadioko, Laurence; Sayagh, Charlotte; Bashwira, Augustin S

2010-10-01

The evaluation of the biocidal activity of the fruit of Solanum sisymbriifolium involving non target organisms such as aquatic insects, fish and snails lead to the isolation of the steroidal alkaloids, solamargine and β-solamarine, from the active fractions. The fractions A3 and C, with biological activity against fish, snail and aquatic insect and larvae, are able to affect the good functioning of ecosystem found on alimentary chain. The fraction B seems to be less toxic to fish and aquatic insect and larvae. The fraction B could thus be used as molluscicide in the future. Copyright © 2010 Elsevier B.V. All rights reserved.

Control of Sand Flies with Attractive Toxic Sugar Baits (ATSB) and Potential Impact on Non-Target Organisms in Morocco

DTIC Science & Technology

2015-02-08

dinotefuran has successful con- trolled Culex and Aedes spp. in similar field sites in Morocco [22]. However, this if the first report of the use of...et al. Control of Aedes abopttus with attractive toxic sugar baits (A TSB) and potential Impact on non target organisms In St. Augustine, Florida...of Anopheles sergenti and Aedes CO!Pk.JS populations following presentation of attractive toxic (splnosad) sugar bait stations In an oasis. J Am

Donor Cell Composition and Reactivity Predict Risk of Acute Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation.

PubMed

Sairafi, Darius; Stikvoort, Arwen; Gertow, Jens; Mattsson, Jonas; Uhlin, Michael

2016-01-01

Background . Graft-versus-host disease (GVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). We designed a functional assay for assessment of individual risk for acute GVHD. Study Design and Methods . Blood samples were collected from patients and donors before HSCT. Two groups of seven patients each were selected, one in which individuals developed acute GVHD grades II-IV and one in which none showed any clinical signs of GVHD. Peripheral blood mononuclear cells (PBMCs) isolated from donors were incubated in mixed lymphocyte cultures (MLCs) with recipient PBMCs. The cells were characterized by flow cytometry before and after MLC. Results . Samples from donors in the GVHD group contained significantly lower frequencies of naïve γδ T-cells and T-cells expressing NK-cell markers CD56 and CD94. Donor samples in this group also exhibited lower frequencies of naïve CD95 + T-cells compared to controls. After MLC, there were dissimilarities in the CD4/CD8 T-cell ratio and frequency of CD69 + T-cells between the two patient groups, with the non-GVHD group showing higher frequencies of CD8 + and CD69 + T-cells. Conclusion . We conclude that a thorough flow cytometric analysis of donor cells for phenotype and allogeneic reactivity may be of value when assessing pretransplant risk for severe acute GVHD.

Evaluation of interleukin 12 and CD56+ lymphocyte cells in pediatric hematopoietic stem cell transplantation for early diagnosis of acute graft versus host disease.

PubMed

Tootoonchian, Raziyeh; Pak, Fatemeh; Ardekani, Ali M; Sehati, Nasrin; Abedi-Valugerdi, Manuchehr; Kokhaei, Parviz

2016-11-01

The present study tried to explain CD56+ lymphocyte cells activities and possible prognostic role of these cells in Graft-Versus-Host-Disease (GVHD). The role of IL-12 activation and function is of interest in this study. Peripheral blood samples of 51 Hematopoietic Stem Cell Transplantation (HSCT) recipients collected at before (day -8) and after (days 7 and 14). PBMC were collected by Ficoll separation and analyzed by Flow Cytometry using triple antibody (CD45-PerCP, CD56-FITC, and CD69-PE staining and control antibody. Levels of the cytokine IL-12 in the patient's serum were evaluated by ELISA. Percentage of CD56+ lymphocytes (CD56+ bright ) cells was significantly increased at day 14 in patients with acute GVHD and percentage of lymphocytes expressing CD69 was significantly increased at days 7 and 14 posts HSCT in patients with acute GVHD in comparison to those in non-GVHD patients. Baseline serum IL-12 levels (pre-HSCT, day -8) were significantly higher in those HSCT recipients who did not develop GVHD. This study showed that post-transplant CD56+ lymphocytes and pre-transplant serum levels of IL-12 play significant roles in the induction of and protection against GVHD, respectively. The increase in the percentage of CD69+ cells indicates the activation of lymphocyte in acute GVHD group. Copyright © 2016 Elsevier B.V. All rights reserved.

Development of a qualitative real-time PCR method to detect 19 targets for identification of genetically modified organisms.

PubMed

Peng, Cheng; Wang, Pengfei; Xu, Xiaoli; Wang, Xiaofu; Wei, Wei; Chen, Xiaoyun; Xu, Junfeng

2016-01-01

As the amount of commercially available genetically modified organisms (GMOs) grows recent years, the diversity of target sequences for molecular detection techniques are eagerly needed. Considered as the gold standard for GMO analysis, the real-time PCR technology was optimized to produce a high-throughput GMO screening method. With this method we can detect 19 transgenic targets. The specificity of the assays was demonstrated to be 100 % by the specific amplification of DNA derived from reference material from 20 genetically modified crops and 4 non modified crops. Furthermore, most assays showed a very sensitive detection, reaching the limit of ten copies. The 19 assays are the most frequently used genetic elements present in GM crops and theoretically enable the screening of the known GMO described in Chinese markets. Easy to use, fast and cost efficient, this method approach fits the purpose of GMO testing laboratories.

Association of target organ damage with 24-hour systolic and diastolic blood pressure levels and hypertension subtypes in untreated Chinese.

PubMed

Wei, Fang-Fei; Li, Yan; Zhang, Lu; Xu, Ting-Yan; Ding, Feng-Hua; Staessen, Jan A; Wang, Ji-Guang

2014-02-01

The association of target organ damage with 24-hour systolic and diastolic blood pressure levels and ambulatory hypertension subtypes has not yet been examined in untreated Chinese patients. We measured left ventricular mass index by echocardiography (n=619), the urinary albumin:creatinine ratio (n=1047), and aortic pulse wave velocity by tonometry (n=1013) in 1047 untreated subjects (mean age, 50.6 years; 48.9% women). Normotension was a 24-hour systolic/diastolic blood pressure <130/<80 mm Hg. Hypertension subtypes were isolated diastolic hypertension and mixed systolic plus diastolic hypertension. We assessed associations of interest by multivariable-adjusted linear models. Using normotension as reference, mixed hypertension was associated with higher (P≤0.003) left ventricular mass index (+4.31 g/m(2)), urinary albumin:creatinine ratio (+1.63 mg/mmol), and pulse wave velocity (+0.76 m/s); and isolated diastolic hypertension was associated with similar left ventricular mass index and pulse wave velocity (P≥0.39), but higher urinary albumin:creatinine ratio (+1.24 mg/mmol; P=0.002). In younger participants (<55 years), the mutually independent effect sizes associated with 1 SD increases in 24-hour systolic/diastolic blood pressure were +3.31/-0.36 g/m(2) (P=0.009/0.79) for left ventricular mass index, +1.15/+1.14 mg/mmol (P=0.02/0.04) for the urinary albumin:creatinine ratio, and +0.54/-0.05 m/s (P<0.001/0.54) for pulse wave velocity. In older participants, these estimates were +3.58/+0.30 g/m(2) (P=0.045/0.88), +1.23/+1.05 mg/mmol (P=0.002/0.54), and +0.76/-0.49 m/s (P<0.001/<0.001), respectively. In conclusion, 24-hour systolic blood pressure and mixed hypertension are major determinants of target organ damage irrespective of age and target organ, whereas 24-hour diastolic blood pressure and isolated diastolic hypertension only relate to the urinary albumin:creatinine ratio below middle age.

Target and non-target toxicity of fern extracts against mosquito vectors and beneficial aquatic organisms.

PubMed

Kamaraj, Chinnaperumal; Deepak, Paramasivam; Balasubramani, Govindasamy; Karthi, Sengodan; Arul, Dhayalan; Aiswarya, Dilipkumar; Amutha, Vadivel; Vimalkumar, Elangovan; Mathivanan, Damodaran; Suseem, Sundaram Renjitham; Muthu-Pandian, Chanthini Kanagaraj; Senthil-Nathan, Sengottayan; Perumal, Pachiappan

2018-06-06

Dengue and malaria are significant mosquito-borne diseases that are rapidly spread worldwide, mainly in temperate countries. Pteridophytes were identified to be a significant source of novel mosquitocidal agents. The present research was to explore the eco-friendly larvicides from methanol extracts of ferns, viz., Actiniopteris radiata, Adiantum caudatum, Cheilanthes swartzii, Hemionitis arifolia and Lycopodium clavatum. The larvicidal potential of the extracts screened using larvae of dengue vector Aedes aegypti (III and IV instar) and malarial vector Anopheles stephensi (III and IV instar), showed 10-100% mortality rates. Biosafety assessment was made on embryos of Danio rerio and Artemia nauplii. The phyto-constituents of the methanol extract of A. radiata leaves were identified through gas chromatography-mass spectrometry (GC-MS). Methanolic leaf extracts of A. radiata, A. caudatum and C. swartzii exhibited larvicidal activity against III and IV instar larvae of Ae. aegypti (LC 50 : 37.47, 74.51 and 152.38 and 67.58, 95.89 and 271.46 ppm) and An. stephensi (LC 50 : 70.35, 112.12 and 301.05 and 113.83, 175.30 and 315.19 ppm), respectively. The GC-MS of the methanol extract of A. radiata leaves revealed the presence of 7 phyto-components among which, Carbamic acid, phenyl-, (2-Nitrophenyl) methyl ester (1), Benzoic acid, 3- methylbenzoate (2) and 4-(benzylimino)- 1,4-dihydro-1-(p-toluoylmethyl) pyridine (3) were dominant. Biosafety assessment of methanol extract of A. radiata leaves on embryos of Danio rerio (Zebra fish) and Artemia nauplii (micro crustacean) revealed that there were no destructive or teratogenic effects. To conclude, the larvicidal activity and insignificant toxicity to non-target aquatic organisms of A. radiata leaves makes it a potential and environment safe biocontrol agent against dengue and malarial vectors. Copyright © 2018. Published by Elsevier Inc.

Temporal organization as a therapeutic target

PubMed Central

Wirz-Justice, Anna

2012-01-01

Biological functions occur at many different frequencies, and each has its healthy and pathological ranges, patterns, and properties. Physiology, biochemistry, and behavior are not only organized at the morphological level in cells and organs, but separated or coordinated in time for minimal interference and optimal function. One of the most important temporal frameworks is that of the 24-hour day-night cycle, and its change in day length with season. Robust circadian rhythms are important for mental and physical well-being. Though rhythms have been long neglected as irrelevant (in spite of the high prevalence of sleep disorders in nearly every psychiatric illness), we now have tools to document rhythm disruption and, through better understanding of underlying molecular and physiological mechanisms, to develop therapeutic applications. Light as the major synchronizing agent of the biological clock is becoming a treatment option not only for winter depression but other, nonseasonal forms, as well as an adjunct in optimizing sleep-wake cycles, daytime alertness, cognition, and mood in many neuropsychiatric illnesses. Melatonin is the signal of darkness and promotes sleep onset. Manipulation of sleep (wake therapy, phase advance) has yielded the most rapid, nonpharmacological antidepressant effect known, and combinations (with light, medication) provide long-lasting response. Thus, by analogy, new molecules to augment synchronization or mimic changes occuring during night-time wakefulness may yield novel treatments. This issue on biological rhythms contains articles on a variety of different frequencies not included in the usual definition of chronobiology, but which open up interesting approaches to time and illness. PMID:23393412

Organ donor screening practices for Strongyloides stercoralis infection among US organ procurement organizations.

PubMed

Abanyie, Francisca A; Valice, Emily; Delli Carpini, Kristin W; Gray, Elizabeth B; McAuliffe, Isabel; Chin-Hong, Peter V; Handali, Sukwan; Montgomery, Susan P; Huprikar, Shirish

2018-03-07

Targeted donor screening for strongyloidiasis performed at the time of organ procurement can prevent this life-threatening donor-derived infection. The Association of Organ Procurement Organizations surveyed members to determine the number of US organ procurement organizations (OPOs) performing donor screening for Strongyloides infection and their screening practices. All 58 OPOs responded to the survey. Only 6 (10%) currently screen donors for strongyloidiasis; most OPOs started 6-36 months before the survey and one started 6 years prior. All used risk-based criteria to determine which donors to screen, though the criteria varied among OPOs. A median of 56 donors have been screened at each OPO since initiating their screening programs, with a median of 2 infected donors (range 0-13) identified. Overall, 53 organs have been transplanted from 22 infected donors, including hearts, lungs, kidneys, and livers. Of 52 OPOs not currently screening, 20 had considered screening and one plans to start screening in the near future. Of those considering risk-based screening, most had not decided on the criteria. Uncertainty about the benefits of and guidelines for screening and misconceptions about the interpretation of test results were concerns shared by non-screening OPOs. Continued education and advocacy on the importance of targeted donor screening are needed. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.

Blockade of p38 Mitogen-Activated Protein Kinase Inhibits Murine Sclerodermatous Chronic Graft-versus-Host Disease.

PubMed

Matsushita, Takashi; Date, Mutsumi; Kano, Miyu; Mizumaki, Kie; Tennichi, Momoko; Kobayashi, Tadahiro; Hamaguchi, Yasuhito; Hasegawa, Minoru; Fujimoto, Manabu; Takehara, Kazuhiko

2017-04-01

Bone marrow transplantation (BMT) of B10.D2 mice into sublethally irradiated BALB/c mice across minor histocompatibility loci is a well-established animal model for human sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) and systemic sclerosis (SSc). The p38 mitogen-activated protein kinase (MAPK) pathway is a key regulator of inflammation and cytokine production. Furthermore, the activation of p38 MAPK plays an important role in collagen production in SSc. We investigated the effects of p38 MAPK inhibitor, VX-702, on Scl-cGVHD mice. VX-702 was orally administered to Scl-cGVHD mice from day 7 to 35 after BMT. We compared skin fibrosis of Scl-cGVHD mice between the VX-702-treated group and control group. Allogeneic BMT increased the phosphorylation of p38 MAPK in the skin. The administration of VX-702 attenuated the skin fibrosis of Scl-cGVHD compared to the control mice. Immunohistochemical staining showed that VX-702 suppressed the infiltration of CD4 + T cells, CD8 + T cells, and CD11b + cells into the dermis of Scl-cGVHD mice compared to the control mice. VX-702 attenuated the mRNA expression of extracellular matrix and fibrogenic cytokines, such as IL-6 and IL-13, in the skin of Scl-cGVHD mice. In addition, VX-702 directly inhibited collagen production from fibroblasts in vitro. VX-702 was shown to be a promising candidate for use in treating patients with Scl-cGVHD and SSc. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Monitoring the World Health Organization Global Target 2025 for Exclusive Breastfeeding: Experience From the United States.

PubMed

Gupta, Priya M; Perrine, Cria G; Chen, Jian; Elam-Evans, Laurie D; Flores-Ayala, Rafael

2017-08-01

Exclusive breastfeeding under 6 months, calculated from a single 24-hour recall among mothers of children 0 to 5 months of age, is a World Health Organization (WHO) indicator used to monitor progress on the 2025 global breastfeeding target. Many upper-middle-income and high-income countries, including the United States, do not have estimates for this indicator. Research aim: To describe the prevalence of exclusive breastfeeding under 6 months in the United States. We used a single 24-hour dietary recall from the National Health and Nutrition Examination Survey 2009-2012 to calculate the prevalence of exclusive breastfeeding under 6 months. We discuss our results in the context of routine breastfeeding surveillance, which is reported from a national survey with different methodology. Among children younger than 6 months, 24.4%, 95% confidence interval [17.6, 31.1], were exclusively breastfed the previous day. To our knowledge, this is the first estimate of the WHO indicator of exclusive breastfeeding under 6 months for the United States. This study supports the global surveillance and data strategy for reporting to the WHO on the 2025 target for exclusive breastfeeding.

High mobility high efficiency organic films based on pure organic materials

DOEpatents

Salzman, Rhonda F [Ann Arbor, MI; Forrest, Stephen R [Ann Arbor, MI

2009-01-27

A method of purifying small molecule organic material, performed as a series of operations beginning with a first sample of the organic small molecule material. The first step is to purify the organic small molecule material by thermal gradient sublimation. The second step is to test the purity of at least one sample from the purified organic small molecule material by spectroscopy. The third step is to repeat the first through third steps on the purified small molecule material if the spectroscopic testing reveals any peaks exceeding a threshold percentage of a magnitude of a characteristic peak of a target organic small molecule. The steps are performed at least twice. The threshold percentage is at most 10%. Preferably the threshold percentage is 5% and more preferably 2%. The threshold percentage may be selected based on the spectra of past samples that achieved target performance characteristics in finished devices.

Open-target sparse sensing of biological agents using DNA microarray

PubMed Central

2011-01-01

Background Current biosensors are designed to target and react to specific nucleic acid sequences or structural epitopes. These 'target-specific' platforms require creation of new physical capture reagents when new organisms are targeted. An 'open-target' approach to DNA microarray biosensing is proposed and substantiated using laboratory generated data. The microarray consisted of 12,900 25 bp oligonucleotide capture probes derived from a statistical model trained on randomly selected genomic segments of pathogenic prokaryotic organisms. Open-target detection of organisms was accomplished using a reference library of hybridization patterns for three test organisms whose DNA sequences were not included in the design of the microarray probes. Results A multivariate mathematical model based on the partial least squares regression (PLSR) was developed to detect the presence of three test organisms in mixed samples. When all 12,900 probes were used, the model correctly detected the signature of three test organisms in all mixed samples (mean(R2)) = 0.76, CI = 0.95), with a 6% false positive rate. A sampling algorithm was then developed to sparsely sample the probe space for a minimal number of probes required to capture the hybridization imprints of the test organisms. The PLSR detection model was capable of correctly identifying the presence of the three test organisms in all mixed samples using only 47 probes (mean(R2)) = 0.77, CI = 0.95) with nearly 100% specificity. Conclusions We conceived an 'open-target' approach to biosensing, and hypothesized that a relatively small, non-specifically designed, DNA microarray is capable of identifying the presence of multiple organisms in mixed samples. Coupled with a mathematical model applied to laboratory generated data, and sparse sampling of capture probes, the prototype microarray platform was able to capture the signature of each organism in all mixed samples with high sensitivity and specificity. It was demonstrated

The Role of Intestinal Microbiota in Acute Graft-versus-Host Disease.

PubMed

Chen, Yuanyuan; Zhao, Ye; Cheng, Qiao; Wu, Depei; Liu, Haiyan

2015-01-01

The mammalian intestinal microbiota is a complex ecosystem that plays an important role in host immune responses. Recent studies have demonstrated that alterations in intestinal microbiota composition are linked to multiple inflammatory diseases in humans, including acute graft-versus-host disease (aGVHD). aGVHD is one of the major obstacles in allogeneic hematopoietic stem cell transplantation (allo-HSCT), characterized by tissue damage in the gastrointestinal (GI) tract, liver, lung, and skin. Here, we review the current understanding of the role of intestinal microbiota in the control of immune responses during aGVHD. Additionally, the possibility of using probiotic strains for potential treatment or prevention of aGVHD will be discussed.

Effects of carvedilol or amlodipine on target organ damage in L-NAME hypertensive rats: their relationship with blood pressure variability.

PubMed

Del Mauro, Julieta S; Prince, Paula D; Donato, Martín; Fernandez Machulsky, Nahuel; Morettón, Marcela A; González, Germán E; Bertera, Facundo M; Carranza, Andrea; Gorzalczany, Susana B; Chiappetta, Diego A; Berg, Gabriela; Morales, Celina; Gelpi, Ricardo J; Taira, Carlos A; Höcht, Christian

2017-04-01

The aim of the study was to compare the effects of chronic oral treatment with carvedilol or amlodipine on blood pressure, blood pressure variability and target organ damage in N-nitro-l-arginine methyl ester (L-NAME) hypertensive rats. Wistar rats were treated with L-NAME administered in the drinking water for 8 weeks together with oral administration of carvedilol 30 mg/kg (n = 6), amlodipine 10 mg/kg (n = 6), or vehicle (n = 6). At the end of the treatment, echocardiographic evaluation, blood pressure, and short-term variability measurements were performed. Left ventricular and thoracic aortas were removed to assess activity of metalloproteinase 2 and 9 and expression levels of transforming growth factor β, tumor necrosis factor α, and interleukin 6. Histological samples were prepared from both tissues. Carvedilol and amlodipine induced a comparable reduction of systolic and mean arterial pressure and its short-term variability in L-NAME rats. The expression of transforming growth factor β, tumor necrosis factor α, and interleukin 6 decreased in both organs after carvedilol or amlodipine treatment and the activity of metalloproteinase was reduced in aortic tissue. Treatment with carvedilol or amlodipine completely prevented left ventricular collagen deposition and morphometric alterations in aorta. Oral chronic treatment with carvedilol or amlodipine significantly attenuates blood pressure variability and reduces target organ damage and biomarkers of tissue fibrosis and inflammation in L-NAME hypertensive rats. Copyright © 2017 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

Drugs and Targets in Fibrosis

PubMed Central

Li, Xiaoyi; Zhu, Lixin; Wang, Beibei; Yuan, Meifei; Zhu, Ruixin

2017-01-01

Fibrosis contributes to the development of many diseases and many target molecules are involved in fibrosis. Currently, the majority of fibrosis treatment strategies are limited to specific diseases or organs. However, accumulating evidence demonstrates great similarities among fibroproliferative diseases, and more and more drugs are proved to be effective anti-fibrotic therapies across different diseases and organs. Here we comprehensively review the current knowledge on the pathological mechanisms of fibrosis, and divide factors mediating fibrosis progression into extracellular and intracellular groups. Furthermore, we systematically summarize both single and multiple component drugs that target fibrosis. Future directions of fibrosis drug discovery are also proposed. PMID:29218009

[Late onset, non-infectious pulmonary complications after haematological stem cell transplantation].

PubMed

Bergeron, A; Feuillet, S; Meignin, V; Socie, G; Tazi, A

2008-02-01

Non infectious pulmonary complications which frequently occur in the late follow-up of haemopoietic stem cell transplant (HSCT) recipients account for an increase in mortality and morbidity. Different histological entities have been described among which bronchiolitis obliterans is the most common. Because of the absence of prospective epidemiological studies and the difficulties in obtaining surgical lung biopsies from these frail patients little is known about these conditions. Although their pathogenesis is poorly understood they probably result from a chronic pulmonary graft versus host disease (GVHD). The introduction of or increase in systemic immunosuppressive treatment, usually indicated for controlling extra-thoracic manifestations of GVHD, may lead to the resolution of an organising pneumonia but is usually ineffective in the treatment of bronchiolitis obliterans. Current prospective cohort studies together with randomised prospective studies evaluating more targeted treatments should help determine the frequency, the risk factors and the precise characteristics of the different entities of late non-infectious pulmonary diseases following HSCT and should also improve their management. Furthermore, the recent demonstration of lung abnormalities in animal models of chronic GVHD, similar to those observed in humans, should allow a better understanding of the pathogenesis. The prevalence of these diseases is increasing throughout the world. More precise analysis, the identification of risk factors and study of the pathophysiological mechanisms involved should allow better understanding and management than at present.

Case report: Central nervous system involvement of human graft versus host disease: Report of 7 cases and a review of literature.

PubMed

Ruggiu, Mathilde; Cuccuini, Wendy; Mokhtari, Karima; Meignin, Véronique; Peffault de Latour, Régis; Robin, Marie; Fontbrune, Flore Sicre de; Xhaard, Aliénor; Socié, Gérard; Michonneau, David

2017-10-01

Central nervous system (CNS) involvement of graft versus host disease (GvHD) is a rare cause of CNS disorders after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Chronic CNS GvHD symptoms are heterogeneous and include cerebrovascular manifestations, demyelinating disease and immune-mediated encephalitis. CNS-Acute GvHD is not formally defined in literature. We report 7 cases of CNS-GvHD among which two had histological-proven disease. We reviewed 32 additional cases of CNS GvHD published in literature since 1990. In this cohort, 34 patients were transplanted for hematologic malignancies, and 5 for non-malignant hematopoiesis disorders. Of these patients, 25 had a history of chronic GvHD and immunosuppressive treatment had been decreased or discontinued in 14 patients before neurological symptoms onset. Median neurological disorder onset was 385 days [7-7320]. Patients had stroke-like episodes (n = 7), lacunar syndromes (n = 3), multiple sclerosis-like presentations (n = 7), acute demyelinating encephalomyelitis-like symptoms (n = 4), encephalitis (n = 14), mass syndrome (n = 1), and 3 had non-specific symptoms. Median neurological symptoms onset was 81.5 days [7-1095] for patients without chronic GVHD history versus 549 days [11-7300] for patients with chronic GVHD (P = 0.001). Patients with early involvement of CNS after allo-HSCT and no chronic GVHD symptoms were more frequently suffering from encephalitis (64% versus 28%, P = 0.07), whereas stroke-like episodes and lacunar symptoms were less frequent (9% versus 36%, P = 0.13). 34 patients with CNS-GvHD were treated with immunosuppressive therapy, including corticosteroids for 31 of them. Other treatments were intravenous immunoglobulin, plasmapheresis, cyclophosphamide, calcineurin inhibitors, mycophenolic acid, methotrexate and etoposide. 27 patients achieved a response: 10 complete responses, 15 partial responses and 2 transient responses. Of 25 patients

Protective Role of Myeloid Cells Expressing a G-CSF Receptor Polymorphism in an Induced Model of Lupus.

PubMed

Sivakumar, Ramya; Abboud, Georges; Mathews, Clayton E; Atkinson, Mark A; Morel, Laurence

2018-01-01

The genetic analysis of the lupus-prone NZM2410 mouse has identified a suppressor locus, Sle2c2 , which confers resistance to spontaneous lupus in combination with NZM2410 susceptibility loci, or in the chronic graft-versus-host disease (cGVHD) induced model of lupus in the B6. Sle2c2 congenic strain. The candidate gene for  Sle2c2 , the Csf3r gene encoding the granulocyte colony-stimulating factor receptor (G-CSF-R/CD114), was validated when cGVHD was restored in B6. Sle2c2 mice after treatment with G-CSF. The goal of the project reported herein was to investigate the myeloid cells that confer resistance to cGVHD and to ascertain if the mechanism behind their suppression involves the G-CSF pathway. We showed that despite expressing the highest levels of G-CSF-R, neutrophils play only a modest role in the autoimmune activation induced by cGVHD. We also found reduced expression levels of G-CSF-R on the surface of dendritic cells (DCs) and a differential distribution of DC subsets in response to cGVHD in B6. Sle2c2 versus B6 mice. The CD8α + DC subset, known for its tolerogenic phenotype, was expanded upon induction of cGVHD in B6. Sle2c2 mice. In addition, the deficiency of CD8α + DC subset enhanced the severity of cGVHD in B6. Batf3 -/- and B6 .Sle2c2 mice, confirming their role in suppression of cGVHD. B6. Sle2c2 DCs presented lowered activation and antigen presentation abilities and expressed lower levels of genes associated with DC activation and maturation. Exposure to exogenous G-CSF reversed the majority of these phenotypes, suggesting that tolerogenic DCs maintained through a defective G-CSF-R pathway mediated the resistance to cGVHD in B6. Sle2c2 mice.

Prospective, Randomized, Double-Blind, Phase III Clinical Trial of Anti-T-Lymphocyte Globulin to Assess Impact on Chronic Graft-Versus-Host Disease-Free Survival in Patients Undergoing HLA-Matched Unrelated Myeloablative Hematopoietic Cell Transplantation.

PubMed

Soiffer, Robert J; Kim, Haesook T; McGuirk, Joseph; Horwitz, Mitchell E; Johnston, Laura; Patnaik, Mrinal M; Rybka, Witold; Artz, Andrew; Porter, David L; Shea, Thomas C; Boyer, Michael W; Maziarz, Richard T; Shaughnessy, Paul J; Gergis, Usama; Safah, Hana; Reshef, Ran; DiPersio, John F; Stiff, Patrick J; Vusirikala, Madhuri; Szer, Jeff; Holter, Jennifer; Levine, James D; Martin, Paul J; Pidala, Joseph A; Lewis, Ian D; Ho, Vincent T; Alyea, Edwin P; Ritz, Jerome; Glavin, Frank; Westervelt, Peter; Jagasia, Madan H; Chen, Yi-Bin

2017-12-20

Purpose Several open-label randomized studies have suggested that in vivo T-cell depletion with anti-T-lymphocyte globulin (ATLG; formerly antithymocyte globulin-Fresenius) reduces chronic graft-versus-host disease (cGVHD) without compromising survival. We report a prospective, double-blind phase III trial to investigate the effect of ATLG (Neovii Biotech, Lexington, MA) on cGVHD-free survival. Patients and Methods Two hundred fifty-four patients 18 to 65 years of age with acute leukemia or myelodysplastic syndrome who underwent myeloablative HLA-matched unrelated hematopoietic cell transplantation (HCT) were randomly assigned one to one to placebo (n =128 placebo) or ATLG (n = 126) treatment at 27 sites. Patients received either ATLG or placebo 20 mg/kg per day on days -3, -2, -1 in addition to tacrolimus and methotrexate as GVHD prophylaxis. The primary study end point was moderate-severe cGVHD-free survival. Results Despite a reduction in grade 2 to 4 acute GVHD (23% v 40%; P = .004) and moderate-severe cGVHD (12% v 33%; P < .001) in ATLG recipients, no difference in moderate-severe cGVHD-free survival between ATLG and placebo was found (2-year estimate: 48% v 44%, respectively; P = .47). Both progression-free survival (PFS) and overall survival (OS) were lower with ATLG (2-year estimate: 47% v 65% [ P = .04] and 59% v 74% [ P = .034], respectively). Multivariable analysis confirmed that ATLG was associated with inferior PFS (hazard ratio, 1.55; 95% CI, 1.05 to 2.28; P = .026) and OS (hazard ratio, 1.74; 95% CI, 1.12 to 2.71; P = .01). Conclusion In this prospective, randomized, double-blind trial of ATLG in unrelated myeloablative HCT, the incorporation of ATLG did not improve moderate-severe cGVHD-free survival. Moderate-severe cGVHD was significantly lower with ATLG, but PFS and OS also were lower. Additional analyses are needed to understand the appropriate role for ATLG in HCT.

Blockade of Syk ameliorates the development of murine sclerodermatous chronic graft-versus-host disease.

PubMed

Le Huu, Doanh; Kimura, Hiroshi; Date, Mutsumi; Hamaguchi, Yasuhito; Hasegawa, Minoru; Hau, Khang Tran; Fujimoto, Manabu; Takehara, Kazuhiko; Matsushita, Takashi

2014-06-01

Murine sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) is a model for human Scl-cGVHD and systemic sclerosis (SSc). Syk is expressed in most of hematopoietic cells, fibroblasts, and endothelial cells. Syk is a protein tyrosine kinase that has an important role in transmitting signals from a variety of cell surface receptors. This study aims to investigate the effect of R788 (fostamatinib sodium), an oral prodrug that is rapidly converted to a potent inhibitor of Syk, R406, on Scl-cGVHD. R788 was orally administered twice a day to allogeneic recipients from day 14 to day 42 after bone marrow transplantation (BMT). In vitro, proliferation of GVHD-derived CD4(+) T cells and CD11b(+) cells was analyzed by R406. Allogeneic BMT increased Syk phosphorylation in T, B, and CD11b(+) cells. The administration of R788 attenuated severity and fibrosis of Scl-cGVHD. The elevated expressions of CXCR4 on T cells, B cells, and CD11b(+) cells were significantly down-regulated by R788 treatment. R788 reduced memory CD4(+) T cells (CD44(hi)CD62L(-)CD4(+)). R406 inhibited proliferation of GVHD CD4(+) T cells and CD11b(+) cells in vitro. In addition, R788 treatment, inhibited proliferation of CD11b(+) cells in Scl-cGVHD mice. R788 treatment also reduced skin mRNA expressions of MCP-1, MIP-1α, IFN-γ, IL-13, IL-17A, and TGF-β1, but not influenced RANTES, CXCL12, and TFN-α. Blockade of Syk suppressed migration factor of immune cells and antigen-specific memory CD4(+) T cells and proliferation and activation of GVHD CD4(+) T cells and CD11b(+) cells. The current studies suggested that Syk inhibitor is a potential candidate for use in treating patients with Scl-cGVHD and SSc. Copyright © 2014 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Hypertensive crisis with 2 target organ impairment induced by glycyrrhizin

PubMed Central

Li, Jing; Fan, Xiaoli; Wang, Qin

2018-01-01

Abstract Rationale: Glycyrrhizin is the main active component of licorice. Licorice and glycyrrhizin induced hypertension has been widely reported, yet licorice and glycyrrhizin induced hypertensive crisis has been rarely known. Patient concerns: The case of this report was a 47-year-old woman, who took 225 mg of glycyrrhizin daily for 3 years due to primary biliary cholangitis. She was found to have a dramatically elevated blood pressure of about 230/110 mmHg without a history of hypertension and was referred to the emergency department. Diagnoses: Hypokalemia, hypertensive retinopathy, and nephropathy were found during the following work-up. Since no other risk factors of hypertension were identified, she was suspected to have glycyrrhizin induced pseudo-hyperaldosteronism. Interventions: Glycyrrhizin was discontinued. Intravenous sodium nitroprusside was used during the first few days. Nifedipine and irbesartan were taken after discharge, and the dosage was reduced gradually under supervision. Outcomes: She stopped all the anti-hypertensive drugs 6 months since glycyrrhizin was stopped. Her blood pressure was about 110/60 mmHg after repetitive measurement. Her serum potassium and urine albumin/creatinine ratio were also normalized. Lessons: Licorice and glycyrrhizin induced hypertension due to pseudo-hyperaldosteronism has been widely reported, yet only 3 cases reported that excessive consumption of licorice could lead to hypertensive emergencies. This is the first case that glycyrrhizin induced hypertensive crisis with target organ impairment. By presenting this case, we remind clinicians of glycyrrhizin induced hypertension, a condition which could lead to medical emergencies. PMID:29538199

Gastrointestinal tract and liver graft-versus-host disease in pediatric patients with hematopoietic progenitor cell transplantation at a tertiary care center in Mexico.

PubMed

Jaramillo-Esparza, C M; Consuelo-Sánchez, A; Acosta-Rodríguez-Bueno, C P; Ramón-García, G; Sadowinski-Pine, S W; Escobar-Sánchez, M A; Castorena-Villa, I; Gaytán-Morales, F; Vázquez-Frias, R

2018-02-24

Graft-versus-host disease (GVHD) is a common multisystemic complication of allogeneic hematopoietic cell transplantation. The most frequent presentations of graft-versus-host disease involve the skin, the gastrointestinal tract, and the liver. The aim of the present study was to know the frequency of gastrointestinal tract and liver GVHD and the characteristics of disease presentation in pediatric patients that underwent hematopoietic stem cell transplantation (HSCT) at a tertiary care hospital center in Mexico City. A retrospective study was carried out, utilizing the case records of patients that underwent HSCT in 2015, to determine the frequency of GVHD in pediatric patients at a Mexican tertiary care hospital center. In 2015, 16 HSCT were performed, 11 of which were carried out in males (68%). Only 3 patients developed graft-versus-host disease (18.7%). One patient presented with skin and liver GVHD and 2 patients presented with gastrointestinal tract and liver GVHD, which was the most frequent type. HSCT is still an uncommon procedure in Mexico and there is a lower frequency of gastrointestinal tract and liver GVHD than that reported in other studies. Most certainly, there will be an increase in this type of patient and risk factors in the Mexican population must still be determined to help predict the onset of GVHD. Copyright © 2018 Asociación Mexicana de Gastroenterología. Publicado por Masson Doyma México S.A. All rights reserved.

Eosinophils from hematopoietic stem cell recipients suppress allogeneic T cell proliferation.

PubMed

Andersson, Jennie; Cromvik, Julia; Ingelsten, Madeleine; Lingblom, Christine; Andersson, Kerstin; Johansson, Jan-Erik; Wennerås, Christine

2014-12-01

Eosinophilia has been associated with less severe graft-versus-host disease (GVHD), but the underlying mechanism is unknown. We hypothesized that eosinophils diminish allogeneic T cell activation in patients with chronic GVHD. The capacity of eosinophils derived from healthy subjects and hematopoietic stem cell (HSC) transplant recipients, with or without chronic GVHD, to reduce allogeneic T cell proliferation was evaluated using a mixed leukocyte reaction. Eosinophil-mediated inhibition of proliferation was observed for the eosinophils of both healthy subjects and patients who underwent HSC transplantation. Eosinophils from patients with and without chronic GVHD were equally suppressive. Healthy eosinophils required cell-to-cell contact for their suppressive capacity, which was directed against CD4(+) T cells and CD8(+) T cells. Neither eosinophilic cationic protein, eosinophil-derived neurotoxin, indoleamine 2,3-dioxygenase, or increased numbers of regulatory T cells could account for the suppressive effect of healthy eosinophils. Real-time quantitative PCR analysis revealed significantly increased mRNA levels of the immunoregulatory protein galectin-10 in the eosinophils of both chronic GVHD patients and patients without GVHD, as compared with those from healthy subjects. The upregulation of galectin-10 expression in eosinophils from patients suggests a stimulatory effect of HSC transplantation in itself on eosinophilic galectin-10 expression, regardless of chronic GVHD status. To conclude, eosinophils from HSC transplant recipients and healthy subjects have a T cell suppressive capacity. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Selective Detection of Target Volatile Organic Compounds in Contaminated Humid Air Using a Sensor Array with Principal Component Analysis

PubMed Central

Itoh, Toshio; Akamatsu, Takafumi; Tsuruta, Akihiro; Shin, Woosuck

2017-01-01

We investigated selective detection of the target volatile organic compounds (VOCs) nonanal, n-decane, and acetoin for lung cancer-related VOCs, and acetone and methyl i-butyl ketone for diabetes-related VOCs, in humid air with simulated VOC contamination (total concentration: 300 μg/m3). We used six “grain boundary-response type” sensors, including four commercially available sensors (TGS 2600, 2610, 2610, and 2620) and two Pt, Pd, and Au-loaded SnO2 sensors (Pt, Pd, Au/SnO2), and two “bulk-response type” sensors, including Zr-doped CeO2 (CeZr10), i.e., eight sensors in total. We then analyzed their sensor signals using principal component analysis (PCA). Although the six “grain boundary-response type” sensors were found to be insufficient for selective detection of the target gases in humid air, the addition of two “bulk-response type” sensors improved the selectivity, even with simulated VOC contamination. To further improve the discrimination, we selected appropriate sensors from the eight sensors based on the PCA results. The selectivity to each target gas was maintained and was not affected by contamination. PMID:28753948

Impact of age on the association between 24-h ambulatory blood pressure measurements and target organ damage.

PubMed

Olesen, Thomas B; Pareek, Manan; Stidsen, Jacob V; Blicher, Marie K; Rasmussen, Susanne; Vishram-Nielsen, Julie K K; Kjaer-Hansen, Kathrine; Olsen, Michael H

2018-05-17

The aim of this study was to evaluate the impact of age on the associations between hemodynamic components derived from 24-h ambulatory blood pressure (24-h ABPM) and target organ damage, in apparently healthy, nonmedicated individuals. Twenty-four-hour ABPM and target organ damage (left ventricular mass index, pulse wave velocity, urine albumin : creatinine ratio and carotid atherosclerotic plaques) were evaluated in 1408 individuals. Associations were examined in regression models, stratified for age [middle-aged (41 or 51 years) or elderly (61 or 71 years)], and adjusted for sex, smoking status, and total-cholesterol. In middle-aged individuals, an increase of 10 mmHg in 24-h SBP was independently associated with an increase of 3.8 (2.7-4.8) g/m in LVMI. The effect was nearly doubled in the elderly subgroup, where the same increase resulted in an increase in LVMI of 6.3 (5.0-7.6) g/m (P for interaction <0.01). An increase of 10 mmHg of 24-h SBP was associated with a 6.7% increase in pulse wave velocity in middle-aged individuals and with an 9.1% increase in elderly individuals (P for interaction <0.01). An independent association between 24-h ABPM and urine albumin : creatinine ratio was only observed in the elderly subgroup. Associations between the presence of atherosclerotic plaques and components from 24-h ABPM except 24-h DBP were not modified by age (all P for interaction >0.26). Age enhances the associations between hemodynamic components obtained from 24-h ABPM and measures of arterial stiffness, microvascular damage, and cardiac structure, but not atherosclerosis.

Targeted polypeptide degradation

DOEpatents

Church, George M [Brookline, MA; Janse, Daniel M [Brookline, MA

2008-05-13

This invention pertains to compositions, methods, cells and organisms useful for selectively localizing polypeptides to the proteasome for degradation. Therapeutic methods and pharmaceutical compositions for treating disorders associated with the expression and/or activity of a polypeptide by targeting these polypeptides for degradation, as well as methods for targeting therapeutic polypeptides for degradation and/or activating therapeutic polypeptides by degradation are provided. The invention provides methods for identifying compounds that mediate proteasome localization and/or polypeptide degradation. The invention also provides research tools for the study of protein function.

Reversal of CD8 T-Cell–Mediated Mucocutaneous Graft-Versus-Host-Like Disease by the JAK Inhibitor Tofacitinib

PubMed Central

Okiyama, Naoko; Furumoto, Yasuko; Villarroel, Vadim A; Linton, Jay T; Tsai, Wanxia L; Gutermuth, Jan; Ghoreschi, Kamran; Gadina, Massimo; O'Shea, John J; Katz, Stephen I

2014-01-01

The utility of allogeneic hematopoietic stem cell transplantation is limited by graft-versus-host disease (GVHD), a significant cause of morbidity and mortality. Patients with GVHD exhibit cutaneous manifestations with histological features of interface dermatitis followed by scleroderma-like changes. JAK inhibitors represent a class of immunomodulatory drugs that inhibit signaling by multiple cytokines. Herein we report the effects of tofacitinib in a murine model of GVHD. Oral administration of tofacitinib prevented GVHD-like disease manifested by weight loss and mucocutaneous lesions. More importantly, tofacitinib was also effective in reversing established disease. Tofacitinib diminished the expansion and activation of murine CD8 T cells in this model, and had similar effects on IL-2-stimulated human CD8 T cells. Tofacitinib also inhibited the expression of IFN-γ-inducible chemoattractants by keratinocytes, and IFN-γ-inducible cell death of keratinocytes. Tofacitinib may be an effective drug for treatment against CD8 T-cell–mediated mucocutaneous diseases in patients with GVHD. PMID:24213371

Viral infections in acute graft-versus-host disease: a review of diagnostic and therapeutic approaches.

PubMed

Tong, Lana X; Worswick, Scott D

2015-04-01

While immunosuppressive therapy for acute graft-versus-host disease (aGVHD) advances, viral reactivation has been found to be an increasingly common complication in these patients. Dermatologists may often be consulted on inpatient services for evaluation. We investigated the literature for the role of viral infections in aGVHD and review the current evidence regarding management. Articles in the public domain regarding aGVHD, cytomegalovirus, Epstein-Barr virus, varicella zoster virus, hepatitis viruses, parvovirus B19, and respiratory viruses were included. Dermatologic findings vary between different viral antigens, and some infections may be a marker for the development of aGVHD or worsen prognosis. The heterogeneous cohorts of the studies reviewed often preclude direct comparison between results. The relationship between viral reactivation and aGVHD may be bidirectional and is worthy of further exploration. Additional studies are needed to determine appropriate prophylaxis and treatment. Copyright © 2014 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Refractory Graft-Versus-Host Disease-Free, Relapse-Free Survival as an Accurate and Easy-to-Calculate Endpoint to Assess the Long-Term Transplant Success.

PubMed

Kawamura, Koji; Nakasone, Hideki; Kurosawa, Saiko; Yoshimura, Kazuki; Misaki, Yukiko; Gomyo, Ayumi; Hayakawa, Jin; Tamaki, Masaharu; Akahoshi, Yu; Kusuda, Machiko; Kameda, Kazuaki; Wada, Hidenori; Ishihara, Yuko; Sato, Miki; Terasako-Saito, Kiriko; Kikuchi, Misato; Kimura, Shun-Ichi; Tanihara, Aki; Kako, Shinichi; Kanamori, Heiwa; Mori, Takehiko; Takahashi, Satoshi; Taniguchi, Shuichi; Atsuta, Yoshiko; Kanda, Yoshinobu

2018-02-21

The aim of this study was to develop a new composite endpoint that accurately reflects the long-term success of allogeneic hematopoietic stem cell transplantation (allo-HSCT), as the conventional graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) overestimates the impact of GVHD. First, we validated current GRFS (cGRFS), which recently was proposed as a more accurate endpoint of long-term transplant success. cGRFS was defined as survival without disease relapse/progression or active chronic GVHD at a given time after allo-HSCT, calculated using 2 distinct methods: a linear combination of a Kaplan-Meier estimates approach and a multistate modelling approach. Next, we developed a new composite endpoint, refractory GRFS (rGRFS). rGRFS was calculated similarly to conventional GRFS treating grade III to IV acute GVHD, chronic GVHD requiring systemic treatment, and disease relapse/progression as events, except that GVHD that resolved and did not require systemic treatment at the last evaluation was excluded as an event in rGRFS. The 2 cGRFS curves obtained using 2 different approaches were superimposed and both were superior to that of conventional GRFS, reflecting the proportion of patients with resolved chronic GVHD. Finally, the curves of cGRFS and rGRFS overlapped after the first 2 years of post-transplant follow-up. These results suggest that cGRFS and rGRFS more accurately reflect transplant success than conventional GRFS. Especially, rGRFS can be more easily calculated than cGRFS and analyzed with widely used statistical approaches, whereas cGRFS more accurately represents the burden of GVHD-related morbidity in the first 2 years after transplantation. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

A Crucial Role for Host APCs in the Induction of Donor CD4+CD25+ Regulatory T Cell-Mediated Suppression of Experimental Graft-versus-Host Disease

PubMed Central

Tawara, Isao; Shlomchik, Warren D.; Jones, Angela; Zou, Weiping; Nieves, Evelyn; Liu, Chen; Toubai, Tomomi; Duran-Struuck, Raimon; Sun, Yaping; Clouthier, Shawn G.; Evers, Rebecca; Lowler, Kathleen P.; Levy, Robert B.; Reddy, Pavan

2010-01-01

Allogeneic bone marrow transplantation is an effective treatment for a number of malignant and nonmalignant diseases (Applebaum. 2001. Nature. 411: 385–389 and Copelan. 2006. N Engl J Med. 354: 1813–1826). However, the application of this therapeutic modality has been impeded by a number of confounding side effects, the most frequent and severe of which is the development of graft-versus-host disease (GVHD) (Copelan. 2006. N Engl J Med. 354: 1813–1826 and Blazar and Murphy. 2005. Philos Trans R Soc Lond B Biol Sci. 360: 1747–1767). Alloreactive donor T cells are critical for causing GVHD (Fowler. 2006. Crit Rev Oncol Hematol. 57: 225–244 and Ferrara and Reddy. 2006. Semin Hematol. 43: 3–10), whereas recent data demonstrated a significant role for the naturally occurring thymic-derived donor CD4+CD25+Foxp3+ regulatory T cells (Tregs) (Bluestone and Abbas. 2003. Nat Rev Immunol. 3: 253–257 and Shevach. 2006. Immunity. 25: 195–201) in suppressing experimental GVHD after bone marrow transplantation (Blazar and Taylor. 2005. Biol Blood Marrow Transpl. 11: 46–49 and Joffe and van Meerwijk. 2006. Semin Immunol. 18: 128–135). Host APCs are required for induction of GVHD by the conventional donor T cells. However, it is not known whether they are also obligatory for donor Treg-mediated suppression of GVHD. Using multiple clinically relevant MHC-matched and -mismatched murine models of GVHD, we investigated the role of host APCs in the suppression of GVHD by donor Tregs. We found that alloantigen expression by the host APCs is necessary and sufficient for induction of GVHD protection by donor Tregs. This requirement was independent of their effect on the maintenance of Treg numbers and the production of IL-10 or IDO by the host APCs. PMID:20810991

Outcomes of matched sibling donor bone marrow transplantation in children using single-agent calcineurin inhibitors as prophylaxis for graft versus host disease.

PubMed

Elgarten, Caitlin W; Arnold, Danielle E; Bunin, Nancy J; Seif, Alix E

2018-01-01

Optimal graft versus host disease (GVHD) prophylaxis prevents severe manifestations without excess immunosuppression. Standard prophylaxis includes a calcineurin inhibitor (CNI) with low-dose methotrexate. However, single-agent CNI may be sufficient prophylaxis for a defined group of patients. Single-agent CNI has been used for GVHD prophylaxis for human leukocyte antigen (HLA)-matched sibling donor (MSD) bone marrow transplants (BMTs) in young patients at the Children's Hospital of Philadelphia for over 20 years. Here, we describe outcomes using this prophylactic strategy in a recent cohort. We performed a single-institution chart review and retrospective analysis of consecutive children undergoing MSD BMT who received single-agent CNI for GVHD prophylaxis between January 2002 and December 2014. Fifty-two children with a median age of 6.1 years (interquartile range [IQR] 2.5-8.3) and donor age of 6 years (IQR 3-10), with malignant and nonmalignant diseases (n = 35 and 17, respectively) were evaluated. Forty-three (82.6%) received oral prophylaxis with single-agent tacrolimus after initial intravenous therapy. Rates of GVHD were consistent with reported rates on dual prophylaxis: the overall incidence of grades 2-4 acute GVHD was 25.5%, grades 3-4 GVHD 9.8%, and chronic GVHD 10.4%. The cumulative incidence of relapse among children with malignancy was 20% at a median of 237 days (IQR 194-318) post-transplant. Two-year overall survival was 82.7% (95% confidence interval [CI]: 69.4-90.6%) and event-free survival was 78.9% (95% CI: 65.1-87.7%). No patient experienced graft failure. Single-agent CNI is a safe, effective approach to GVHD prophylaxis in young patients undergoing HLA-identical sibling BMT. Additionally, single-agent oral tacrolimus is a reasonable alternative to cyclosporine in this population. © 2017 Wiley Periodicals, Inc.

Acute and chronic graft-versus-host disease after allogeneic peripheral-blood stem-cell and bone marrow transplantation: a meta-analysis.

PubMed

Cutler, C; Giri, S; Jeyapalan, S; Paniagua, D; Viswanathan, A; Antin, J H

2001-08-15

Controversy exists as to whether the incidence of graft-versus-host disease (GVHD) is increased after peripheral-blood stem-cell transplantation (PBSCT) when compared with bone marrow transplantation (BMT). We performed a meta-analysis of all trials comparing the incidence of acute and chronic GVHD after PBSCT and BMT reported as of June, 2000. Secondary analyses examined relapse rates after the two procedures. An extensive MEDLINE search of the literature was undertaken. Primary authors were contacted for clarification and completion of missing information. A review of cited references was also undertaken. Sixteen studies (five randomized controlled trials and 11 cohort studies) were included in this analysis. Data was extracted by two pairs of reviewers and analyzed for the outcomes of interest. Meta-analyses, regression analyses, and assessments of publication bias were performed. Using a random effects model, the pooled relative risk (RR) for acute GVHD after PBSCT was 1.16 (95% confidence interval [CI], 1.04 to 1.28; P=.006) when compared with traditional BMT. The pooled RR for chronic GVHD after PBSCT was 1.53 (95% CI, 1.25 to 1.88; P <.001) when compared with BMT. The RR of developing clinically extensive chronic GVHD was 1.66 (95% CI, 1.35 to 2.05; P <.001). The excess risk of chronic GVHD was explained by differences in the T-cell dose delivered with the graft in a meta-regression model that did not reach statistical significance. There was a trend towards a decrease in the rate of relapse after PBSCT (RR = 0.81; 95% CI, 0.62 to 1.05). Both acute and chronic GVHD are more common after PBSCT than BMT, and this may be associated with lower rates of malignant relapse. The magnitude of the transfused T-cell load may explain the differences in chronic GVHD risk.

Interleukin 7 Plays a Role in T Lymphocyte Apoptosis Inhibition Driven by Mesenchymal Stem Cell without Favoring Proliferation and Cytokines Secretion

PubMed Central

Normanton, Marilia; Alvarenga, Heliene; Hamerschlak, Nelson; Ribeiro, Andreza; Kondo, Andrea; Rizzo, Luiz Vicente; Marti, Luciana Cavalheiro

2014-01-01

Since 2004, when a case report describing the use of human mesenchymal stem cells (hMSCs) infusion as a therapy for GVHD after bone marrow transplantation, a new perspective in MSC function emerged. Since then hMSCs immunomodulatory potential became the target of several studies. Although great progress has been made in our understanding of hMSCs, their effect on T cell remains obscure. Our study has confirmed the already described effect of hMSCs on lymphocytes proliferation and survival. We also show that the impairment of lymphocyte proliferation and apoptosis is contact-independent and occurs in a prostaglandin-independent manner. A potential correlation between IL-7 and hMSCs effect is suggested, as we observed an increase in IL-7 receptors (CD127) on lymphocyte membrane in MSC presence. Additionally, blocking IL-7 in hMSCs-lymphocytes co-cultures increased lymphocytes apoptosis and we also have demonstrated that hMSCs are able to produce this interleukin. Moreover, we found that during Th1/Th17 differentiation in vitro, hMSCs presence leads to Th1/Th17 cells with reduced capacity of INF-y and IL-17 secretion respectively, regardless of having several pro-inflammatory cytokines in culture. We did not confirm an increment of Treg in these cultures, but a reduced percentage of INF-y/IL-17 secreting cells was observed, suggesting that the ratio between anti and pro-inflammatory cells changed. This changed ratio is very important to GvHD therapy and links hMSCs to an anti-inflammatory role. Taken together, our findings provide important preliminary results on the lymphocyte pathway modulated by MSCs and may contribute for developing novel treatments and therapeutic targets for GvHD and others autoimmune diseases. PMID:25184791

Foucault on targets.

PubMed

Lynch, John

2004-01-01

This paper seeks to gain an insight into the behavior of a large NHS trust, in its attempt to meet a 90 percent patient access target, in a week long national audit in March 2003. Why did individuals act in dramatically different ways to their norm over this period. The work of Michel Foucault is used to explore these issues. The discourses of power, knowledge, discipline and governmentality are identified as key foucaudian themes that offer an alternative interpretation of how individuals behave in their place of work. The importance of the historical context of discourse within the NHS cannot be underestimated in shaping the behavior of individuals and groups today. Power and knowledge permeate NHS organizations through disciplinary practices and dressage. Governmentality seeks to maintain the status quo through disciplinary processes such as national healthcare targets. The natural response of NHS organizations is therefore, to seek order and conformity rather than disorder and conflict.

The Role of Intestinal Microbiota in Acute Graft-versus-Host Disease

PubMed Central

Chen, Yuanyuan; Zhao, Ye; Cheng, Qiao; Wu, Depei; Liu, Haiyan

2015-01-01

The mammalian intestinal microbiota is a complex ecosystem that plays an important role in host immune responses. Recent studies have demonstrated that alterations in intestinal microbiota composition are linked to multiple inflammatory diseases in humans, including acute graft-versus-host disease (aGVHD). aGVHD is one of the major obstacles in allogeneic hematopoietic stem cell transplantation (allo-HSCT), characterized by tissue damage in the gastrointestinal (GI) tract, liver, lung, and skin. Here, we review the current understanding of the role of intestinal microbiota in the control of immune responses during aGVHD. Additionally, the possibility of using probiotic strains for potential treatment or prevention of aGVHD will be discussed. PMID:26090477

Synthesis of a biofuel target through conventional organic chemistry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Page, Jordan P.; Robinson, Joshua W.; Albrecht, Karl O.

In this work, the biofuel target compound 2-ethyl-5,5-dimethylcyclopenta-1,3-diene (1) and its exo isomers (9a and 9b), were successfully synthesized via two different pathways from the common intermediate 4,4-dimethylcyclopent-2-ene-1-one (2). The first pathway produced the endocyclic product as a pure isomer via a triflate intermediate obtained from the ketone 2 in 60% yield, followed by copper catalyzed coupling with ethyl magnesium bromide in 63% yield. The second pathway employed a Grignard reaction with ketone 2, which generated an alcohol that was immediately subjected to mild acid catalyzed elimination upon workup of the previous step to yield a primarily a mixture ofmore » exo diastereomers 9a and 9b in 77% yield. These targets had their fuel properties characterized in a separate study.« less

Metabolic syndrome indicators and target organ damage in urban active coping African and Caucasian men: the SABPA study.

PubMed

de Kock, A; Malan, L; Potgieter, J C; Steenekamp, W; van der Merwe, M T

2012-05-01

Psychosocial stress relating to an urban environment or acculturation increases the prevalence of metabolic syndrome (MetS). The objectives of this study were firstly to indicate and compare differences regarding appraisal of stress or active coping responses in urban African (n=88) and Caucasian (n=101) male teachers of South Africa, in accord with the prevalence of MetS indicators. And secondly to investigate the extent to which utilisation of active coping responses, together with MetS indicators, predict target organ damage, in these men. The Coping Strategy Indicator determined high and low active coping responses in male teachers from the Sympathetic Activity and Ambulatory Blood Pressure in Africans (SABPA) study. SABPA inclusion and exclusion criteria were used. Additionally, diabetic medication users (n=8), and participants with renal impairment (n=2) or HIV positive (n=13), were excluded. MetS indicators included glucose, triglyceride, high-density lipoprotein cholesterol, blood pressure, and waist circumference, independent of confounders (age, physical activity, gamma glutamyl transferase). Microalbuminuria and carotid intima-media thickness indicated target organ damage. More MetS indicators exceeded the IDF cut-off points in high active coping African men (14.71%) than in their Caucasian counterparts (3.33%), as determined from χ² analyses. Furthermore, stepwise regressions indicated that more MetS indicators predicted endothelial dysfunction, especially in the high active coping African men. High active coping African men showed more manifestation of MetS, compared to their Caucasian counterparts, and revealed progress towards endothelial dysfunction. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.

MicroRNAs as biomarkers for graft-versus-host disease following allogeneic stem cell transplantation.

PubMed

Tomuleasa, Ciprian; Fuji, Shigeo; Cucuianu, Andrei; Kapp, Markus; Pileczki, Valentina; Petrushev, Bobe; Selicean, Sonia; Tanase, Alina; Dima, Delia; Berindan-Neagoe, Ioana; Irimie, Alexandru; Einsele, Hermann

2015-07-01

Allogeneic hematopoietic stem cell transplantation (HCT) is a well-established treatment for many malignant and non-malignant hematological disorders. As frequent complication in up to 50 % of all patients, graft-versus-host disease (GVHD) is still the main cause for morbidity and non-relapse mortality. Diagnosis of GVHD is usually done clinically, even though confirmation by pathology is often used to support the clinical findings. Effective treatment requires intensified immunosuppression as early as possible. Although several promising biomarkers have been proposed for an early diagnosis, no internationally recognized consensus has yet been established. Here, microRNAs (miRs) represent an interesting tool since miRs have been recently reported to be an important regulator of various cells, including immune cells such as T cells. Therefore, we could assume that miRs play a key role in the pathogenesis of acute GVHD, and their detection might be an interesting possibility in the early diagnosis and monitoring of acute GVHD. Recent studies additionally demonstrated the implication of miRs in the pathogenesis of acute GVHD. In this review, we aim to summarize the previous reports of miRs, focusing on the pathogenesis of acute GVHD and possible implications in diagnostic approaches.

USGS aerial resolution targets.

USGS Publications Warehouse

Salamonowicz, P.H.

1982-01-01

It is necessary to measure the achievable resolution of any airborne sensor that is to be used for metric purposes. Laboratory calibration facilities may be inadequate or inappropriate for determining the resolution of non-photographic sensors such as optical-mechanical scanners, television imaging tubes, and linear arrays. However, large target arrays imaged in the field can be used in testing such systems. The USGS has constructed an array of resolution targets in order to permit field testing of a variety of airborne sensing systems. The target array permits any interested organization with an airborne sensing system to accurately determine the operational resolution of its system. -from Author

Investigating an organ-targeting platform based on hydroxyapatite nanoparticles using a novel in situ method of radioactive ¹²⁵Iodine labeling.

PubMed

Ignjatović, Nenad; Vranješ Djurić, Sanja; Mitić, Zarko; Janković, Drina; Uskoković, Dragan

2014-10-01

In this study, we have investigated the synthesis of nanoparticles of hydroxyapatite (HAp) and hydroxyapatite coated with chitosan (HAp/Ch) and the chitosan-poly-d,l-lactide-co-glycolide polymer blend (HAp/Ch-PLGA) as an organ-targeting system. We have examined and defined the final destination, as well as the dynamics and the pathways of the synthesized particles following intravenous administration in vivo. The XRD, ZP, FT-IR and SEM analyses have confirmed that the hydroxyapatite nanoparticles with d50=72 nm are coated with polymers. Radioactive 125-Iodine ((125)I), a low energy gamma emitter, was used to develop a novel in situ method for the radiolabeling of particles and investigation of their biodistribution. (125)I-labeled particles exhibited high stability in saline and serum over the second day, which justified their use in the following in vivo studies. The biodistribution of (125)I-labeled particles after intravenous injection in rats differed significantly: HAp particles mostly targeted the liver, HAp/Ch the spleen and the liver, while HAp/Ch-PLGA targeted the lungs. Twenty-four hours post injection, HAp particles were excreted completely, while both (125)I-HAp/Ch and (125)I-HAp/Ch-PLGA were retained in the body for a prolonged period of time with more than 20% of radioactivity still found in different organs. Copyright © 2014 Elsevier B.V. All rights reserved.

Recent Developments in Cellular Immunotherapy for HSCT-Associated Complications

PubMed Central

Reis, Monica; Ogonek, Justyna; Qesari, Marsela; Borges, Nuno M.; Nicholson, Lindsay; Preußner, Liane; Dickinson, Anne Mary; Wang, Xiao-nong; Weissinger, Eva M.; Richter, Anne

2016-01-01

Allogeneic hematopoietic stem cell transplantation is associated with serious complications, and improvement of the overall clinical outcome of patients with hematological malignancies is necessary. During the last decades, posttransplant donor-derived adoptive cellular immunotherapeutic strategies have been progressively developed for the treatment of graft-versus-host disease (GvHD), infectious complications, and tumor relapses. To date, the common challenge of all these cell-based approaches is their implementation for clinical application. Establishing an appropriate manufacturing process, to guarantee safe and effective therapeutics with simultaneous consideration of economic requirements is one of the most critical hurdles. In this review, we will discuss the recent scientific findings, clinical experiences, and technological advances for cell processing toward the application of mesenchymal stromal cells as a therapy for treatment of severe GvHD, virus-specific T cells for targeting life-threating infections, and of chimeric antigen receptors-engineered T cells to treat relapsed leukemia. PMID:27895644

Formulation of multifunctional oil-in-water nanosized emulsions for active and passive targeting of drugs to otherwise inaccessible internal organs of the human body.

PubMed

Tamilvanan, Shunmugaperumal

2009-10-20

Oil-in-water (o/w) type nanosized emulsions (NE) have been widely investigated as vehicles/carrier for the formulation and delivery of drugs with a broad range of applications. A comprehensive summary is presented on how to formulate the multifunctional o/w NE for active and passive targeting of drugs to otherwise inaccessible internal organs of the human body. The NE is classified into three generations based on its development over the last couple of decades to make ultimately a better colloidal carrier for a target site within the internal and external organs/parts of the body, thus allowing site-specific drug delivery and/or enhanced drug absorption. The third generation NE has tremendous application for drug absorption enhancement and for 'ferrying' compounds across cell membranes in comparison to its first and second generation counterparts. Furthermore, the third generation NE provides an interesting opportunity for use as drug delivery vehicles for numerous therapeutics that can range in size from small molecules to macromolecules.

Radar Imaging for Moving Targets

DTIC Science & Technology

2009-06-01

MOVING TARGETS by Teo Beng Koon William June 2009 Thesis Advisor: Brett H. Borden Second Reader: Donald L. Walters THIS PAGE...Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and to the Office of Management and Budget, Paperwork Reduction Project...TITLE AND SUBTITLE Radar Imaging for Moving Targets 6. AUTHOR(S) Teo Beng Koon William 5. FUNDING NUMBERS 7. PERFORMING ORGANIZATION NAME(S

Nursing challenges caring for bone marrow transplantation patients with graft versus host disease.

PubMed

Neumann, Joyce

2017-12-01

Nursing care of blood and marrow transplantation (BMT) patients is complicated. Nursing considerations of BMT patients with GVHD require an additional set of skills and knowledge that include side effects, both expected and less common, assessment skills, treatment administration, both standard and novel, and acute or intensive care. Nursing care of BMT patients with skin GVHD will be determined by the degree of skin alteration with distinct decisions made about hygiene, both topical and systemic treatment, infection prevention, relief of discomfort, functional ability (ADL) and body image alteration. The nurse needs to have knowledge about assessment criteria for acute and chronic (NIH) assessment with special attention to skin (presence of rash, texture, mobility), joint mobility, mouth care, dressings, and skin care products. Nursing consideration of gastrointestinal GVHD includes importance of accurate intake and output, obtaining culture, fluid and electrolyte imbalance, nutrition, treatment, and skin care. Complication of GVHD treatment, namely effects of steroids require experts from many disciplines to provide comprehensive care. Caring and advocating for GVHD patients may include preparing for outcomes that are undesirable and impact the patient's quality of life and mortality. BMT survivorship programs are a major source of patient education about chronic GVHD for patients after treatment. Caring for BMT patients, especially those experiencing GVHD, takes a knowledgeable, committed, and caring team of healthcare providers. Workshops like this are vital in providing information and networking to keep providers around the region and globe engaged in this critical work. Copyright © 2017. Published by Elsevier B.V.

Safety and efficacy of an intra-oral electrostimulator for the relief of dry mouth in patients with chronic graft versus host disease: Case series.

PubMed

Zadik, Yehuda; Zeevi, Itai; Luboshitz-Shon, Noa; Dakwar, Nasri; Wolff, Andy; Shapira, Michael Y; Or, Reuven; Elad, Sharon

2014-05-01

Patients with chronic graft-versus-host disease (cGVHD) often suffer from dry mouth and oral mucosal lesions. The primary objective of this study was to investigate the safety of an intra-oral electrostimulator (GenNarino) in symptomatic cGVHD patients. The secondary objective was to study the impact on the salivary gland involvement of cGVHD patients. This paper presents a case series. The study included patients treated for 4 weeks, randomly assigned to the active device and then crossed-over to a sham-device or vice versa. The patients and clinicians were blind to the treatment delivered. Data regarding oral mucosal and salivary gland involvement were collected. Six patients were included in this series. Most of the intraoral areas with manifestations of cGVHD were not in contact with the GenNarino device. Two patients developed mild mucosal lesions in areas in contact with the GenNarino during the study. However, only one of them had a change in the National Institutes of Health (NIH) score for oral cGVHD. The unstimulated and stimulated salivary flow rate increased in 4 out of the 5 patients included in this analysis. Symptoms of dry mouth and general oral comfort improved. This study suggests that GenNarino is safe in cGVHD patients with respect to oral tissues. Furthermore the use of GenNarino resulted in subjective and objective improvements in dry mouth symptoms. A large scale study is needed to confirm the impact and safety of GenNarino on systemic cGVHD.

OSI-027 modulates acute graft-versus-host disease after liver transplantation in a rat model.

PubMed

Zhi, Xiao; Xue, Fei; Chen, Wei; Liang, Chao; Liu, Hao; Ma, Tao; Xia, Xuefeng; Hu, Liqiang; Bai, Xueli; Liang, Tingbo

2017-09-01

Despite its rarity (1%-2%), acute graft-versus-host disease after liver transplantation (LT-aGVHD) has a high mortality rate (85%). A gradual decrease in regulatory T cells (Tregs) correlates with disease progression in a rat LT-GVHD model, and treatments which increase Tregs exert therapeutic effects on LT-aGVHD. In this study, LT-aGVHD model rats were treated with rapamycin (RAPA), OSI-027, or an equal quantity of vehicle. Rats treated with OSI-027 survived longer (>100 days) than those in the RAPA (70 ± 8 days) or control (24 ± 3 days) groups. Flow cytometric analysis showed that the Treg ratios in peripheral blood mononuclear cells in the OSI-027 group were higher than those in the RAPA or control groups. The proportions of donor-derived lymphocytes in the OSI-027 group were lower than those in the RAPA or control groups. Hematoxylin-eosin staining of skin tissue demonstrated less severe lymphocyte infiltration in the OSI-027 group than that in the RAPA or control groups. In vitro, OSI-027 induced differentiation of CD4 + CD25 - T cells into CD4 + CD25 + forkhead box P3 + Tregs. Furthermore, injection of OSI-027-induced donor-derived CD4 + CD25 + T cells into the peripheral blood of LT-aGVHD model rats prevented LT-aGVHD. Thus, OSI-027 is implicated as a novel method for the treatment of LT-aGVHD. Liver Transplantation 23 1186-1198 2017 AASLD. © 2017 by the American Association for the Study of Liver Diseases.

CMV antigenemia following bone marrow transplantation: risk factors and outcomes.

PubMed

Osarogiagbon, R U; Defor, T E; Weisdorf, M A; Erice, A; Weisdorf, D J

2000-01-01

Cytomegalovirus (CMV) infection remains a major problem in blood and bone marrow transplant (BMT) recipients. Recent efforts have been directed at prevention, early diagnosis, and treatment of CMV disease following BMT. Assay for CMV early antigen pp65 on circulating leukocytes has been shown to be sensitive, and specific in detecting early CMV infection. We examined the frequency, risk factors, and outcomes of a positive CMV antigen assay in 118 consecutive BMT patients. Forty-three (36%) of the 118 patients developed CMV antigenemia a median of 26 days post-BMT (range, -6 to 209 days). The incidence of antigenemia in autologous, related donor, and unrelated donor BMT recipients was 15%, 50%, and 48%, respectively (P < .01) and was lower in CMV-seronegative patients (19% versus 51% in seropositive patients; P < .01). Patients with grade II to IV acute graft-versus-host disease (GVHD) had 2.2 times the risk of antigenemia of patients with no or only limited GVHD (P = .03). Age at transplantation, underlying disease, CMV prophylaxis regimen, and GVHD prophylaxis regimen did not affect the risk of CMV antigenemia. Ten of the 43 antigenemic patients, all CMV-seropositive allogeneic BMT (alloBMT) recipients, developed CMV organ disease a median of 101 days (range, 28-283 daya) post-BMT. These data suggest that CMV-seropositive alloBMT patients are at highest risk for CMV antigenemia and for organ disease as well. CMV disease may occur before antigenemia is detectable in leukopenic patients and may also develop late post-BMT, even in patients still receiving antiviral prophylaxis. In high-risk groups, intensive surveillance continuing for more than 6 months after BMT may be indicated.

Synthesis of a biofuel target through conventional organic chemistry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Page, Jordan P.; Robinson, Joshua W.; Albrecht, Karl O.

Here in this work, the biofuel target compound 2-ethyl-5,5-dimethylcyclopenta-1,3-diene (1) and its exo isomers (9a and 9b), were successfully synthesized via two different pathways from the common intermediate 4,4-dimethylcyclopent-2-ene-1-one (2). The first pathway produced the endocyclic product as a pure isomer via a triflate intermediate obtained from ketone 2 in 60% yield, followed by copper-catalyzed coupling with ethyl magnesium bromide in 63% yield. The second pathway employed a Grignard reaction with ketone 2, which generated an alcohol that was immediately subjected to mild acid-catalyzed elimination to yield primarily a mixture of exo isomers 9a and 9b in 46% yield. Themore » preparation method developed by this work allowed for the production of a sufficient quantity of these targets to evaluate their fuel properties, which will be reported in a separate study.« less

Synthesis of a biofuel target through conventional organic chemistry

DOE PAGES

Page, Jordan P.; Robinson, Joshua W.; Albrecht, Karl O.; ...

2018-02-28

Here in this work, the biofuel target compound 2-ethyl-5,5-dimethylcyclopenta-1,3-diene (1) and its exo isomers (9a and 9b), were successfully synthesized via two different pathways from the common intermediate 4,4-dimethylcyclopent-2-ene-1-one (2). The first pathway produced the endocyclic product as a pure isomer via a triflate intermediate obtained from ketone 2 in 60% yield, followed by copper-catalyzed coupling with ethyl magnesium bromide in 63% yield. The second pathway employed a Grignard reaction with ketone 2, which generated an alcohol that was immediately subjected to mild acid-catalyzed elimination to yield primarily a mixture of exo isomers 9a and 9b in 46% yield. Themore » preparation method developed by this work allowed for the production of a sufficient quantity of these targets to evaluate their fuel properties, which will be reported in a separate study.« less

Oral Chronic Graft-versus-Host Disease: Current Pathogenesis, Therapy, and Research

PubMed Central

Mays, JW; Fassil, H; Edwards, DA; Pavletic, SZ; Bassim, CW

2012-01-01

Optimal management of complex autoimmune diseases requires a multidisciplinary medical team including dentists to care for lesions of the oral cavity. In this review, we discuss the presentation, prevalence, diagnosis and treatment of oral manifestations in chronic Graft-versus-Host Disease (cGVHD) which is a major late complication in patients treated by allogeneic hematopoietic stem cell transplantation. We assess current general knowledge of systemic and oral cGVHD, and present general treatment recommendations based on literature review and our clinical experience. Additionally, we review areas where the understanding of oral cGVHD could be improved by further research, and address tools with which to accomplish the long-term goal of providing better health and quality-of-life to patients with cGVHD. PMID:23107104

Are leaves that fall from imidacloprid-treated maple trees to control Asian longhorned beetles toxic to non-target decomposer organisms?

PubMed

Kreutzweiser, David P; Good, Kevin P; Chartrand, Derek T; Scarr, Taylor A; Thompson, Dean G

2008-01-01

The systemic insecticide imidacloprid may be applied to deciduous trees for control of the Asian longhorned beetle, an invasive wood-boring insect. Senescent leaves falling from systemically treated trees contain imidacloprid concentrations that could pose a risk to natural decomposer organisms. We examined the effects of foliar imidacloprid concentrations on decomposer organisms by adding leaves from imidacloprid-treated sugar maple trees to aquatic and terrestrial microcosms under controlled laboratory conditions. Imidacloprid in maple leaves at realistic field concentrations (3-11 mg kg(-1)) did not affect survival of aquatic leaf-shredding insects or litter-dwelling earthworms. However, adverse sublethal effects at these concentrations were detected. Feeding rates by aquatic insects and earthworms were reduced, leaf decomposition (mass loss) was decreased, measurable weight losses occurred among earthworms, and aquatic and terrestrial microbial decomposition activity was significantly inhibited. Results of this study suggest that sugar maple trees systemically treated with imidacloprid to control Asian longhorned beetles may yield senescent leaves with residue levels sufficient to reduce natural decomposition processes in aquatic and terrestrial environments through adverse effects on non-target decomposer organisms.

Cancer-linked targets modulated by curcumin

PubMed Central

Hasima, Noor; Aggarwal, Bharat B

2012-01-01

In spite of major advances in oncology, the World Health Organization predicts that cancer incidence will double within the next two decades. Although it is well understood that cancer is a hyperproliferative disorder mediated through dysregulation of multiple cell signaling pathways, most cancer drug development remains focused on modulation of specific targets, mostly one at a time, with agents referred to as “targeted therapies,” “smart drugs,” or “magic bullets.” How many cancer targets there are is not known, and how many targets must be attacked to control cancer growth is not well understood. Although more than 90% of cancer-linked deaths are due to metastasis of the tumor to vital organs, most drug targeting is focused on killing the primary tumor. Besides lacking specificity, the targeted drugs induce toxicity and side effects that sometimes are greater problems than the disease itself. Furthermore, the cost of some of these drugs is so high that most people cannot afford them. The present report describes the potential anticancer properties of curcumin, a component of the Indian spice turmeric (Curcuma longa), known for its safety and low cost. Curcumin can selectively modulate multiple cell signaling pathways linked to inflammation and to survival, growth, invasion, angiogenesis, and metastasis of cancer cells. More clinical trials of curcumin are needed to prove its usefulness in the cancer setting. PMID:23301199

[Prevalence of target organ damage and factors associated with cardiovascular events in subjects with refractory hypertension].

PubMed

Armario, Pedro; Oliveras, Anna; Hernández Del Rey, Raquel; Poch, Esteban; Larrouse, María; Roca-Cusachs, Alex; de la Sierra, Alejandro

2009-06-27

To asses the prevalence of target organ damage (TOD) and factors associated with cardiovascular events in subjects with refractory hypertension. Cross-sectional study of 146 patients with clinical diagnosis of refractory hypertension. TOD was defined as the presence of microalbuminuria (MA), renal failure (RF), left ventricular hypertrophy (LVH) or left atrial enlargement (LAE). Cardiovascular events were defined as the antecedent of stroke, coronary heart disease, heart failure or peripheral arterial disease. 24-h ambulatory blood pressure monitoring was (ABPM) performed with a validated Spacelabs 90207. The prevalence of LVH was 62.3%, and LAE was observed in 27.7% of the subjects. The prevalence of RF was 28.1% and MA was found in 41,4%. An association between MA and LVH was observed. After adjusting by age, the urinary albumin excretion (UAE) correlated with clinical blood pressure (BP) and BP during 24-h ABPM, whereas LVMI correlated with ambulatory BP but not with clinical BP. The prevalence of previous cardiovascular events was 22% and in the multivariate regression analysis, UAE was the only independent factor associated with the antecedent of cardiovascular events. In subjects with refractory hypertension, the prevalence of TOD was high, and an association between heart and renal organ damage was observed. UAE was independently associated with the antecedent of cardiovascular disease.

Cell-free DNA characteristics and chimerism analysis in patients after allogeneic cell transplantation.

PubMed

Duque-Afonso, Jesus; Waterhouse, Miguel; Pfeifer, Dietmar; Follo, Marie; Duyster, Justus; Bertz, Hartmut; Finke, Jürgen

2018-02-01

Cell-free DNA (cfDNA) isolated from plasma or serum has received increasing interest for diagnostic applications in pregnancy, solid tumors and solid organ transplantation. The reported clinical usefulness of cfDNA obtained from plasma or serum in patients undergoing allogeneic cell transplantation (alloHSCT) is scarce. To analyze the potential clinical utility of cfDNA chimerism analysis after alloHSCT. A total of 196 samples obtained from 110 patients were investigated for their chimeric status both in peripheral blood and plasma using standard PCR for microsatellite amplification. Plasma DNA size distribution was analyzed using capillary electrophoresis. The mean cfDNA concentration in the transplanted patients was 469ng/ml (range: 50-10,700ng/ml). The size range of almost 80% of the analyzed fragments was between 80 and 200bp. In 41 out of the 110 patients included in the study a mixture of donor and recipient plasma cfDNA was detected. There was a statistically significant difference in the percentage of plasma mixed chimerism between the patients without transplant related complications and the patients with either GvHD (p<0.05) or relapse (p<0.01). In those patients who showed improvement of GvHD also displayed a decrease in the observable percentage of recipient cfDNA during GvHD treatment. In patients without improvement or even with worsening of acute GvHD, stable or increasing levels of recipient cfDNA were detected. cfDNA in combination with peripheral blood and bone marrow cell chimerism analysis might improve its utility in the clinic in particular in those patients with clinical complications after alloHSCT. Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Central blood pressure variability is increased in hypertensive patients with target organ damage.

PubMed

de la Sierra, Alejandro; Pareja, Julia; Yun, Sergi; Acosta, Eva; Aiello, Francesco; Oliveras, Anna; Vázquez, Susana; Armario, Pedro; Blanch, Pedro; Sierra, Cristina; Calero, Francesca; Fernández-Llama, Patricia

2018-02-01

We aimed to evaluate the association of aortic and brachial short-term blood pressure variability (BPV) with the presence of target organ damage (TOD) in hypertensive patients. One-hundred seventy-eight patients, aged 57 ± 12 years, 33% women were studied. TOD was defined by the presence of left ventricular hypertrophy on echocardiogram, microalbuminuria, reduced glomerular filtration rate, or increased aortic pulse wave velocity. Aortic and brachial BPV was assessed by 24-hour ambulatory BP monitoring (Mobil-O-Graph). TOD was present in 92 patients (51.7%). Compared to those without evidence of TOD, they had increased night-to-day ratios of systolic and diastolic BP (both aortic and brachial) and heart rate. They also had significant increased systolic BPV, as measured by both aortic and brachial daytime and 24-hours standard deviations and coefficients of variation, as well as for average real variability. Circadian patterns and short-term variability measures were very similar for aortic and brachial BP. We conclude that BPV is increased in hypertensive-related TOD. Aortic BPV does not add relevant information in comparison to brachial BPV. ©2018 Wiley Periodicals, Inc.

New and emerging therapies for acute and chronic graft versus host disease

PubMed Central

Hill, LaQuisa; Alousi, Amin; Kebriaei, Partow; Mehta, Rohtesh; Rezvani, Katayoun; Shpall, Elizabeth

2017-01-01

Graft versus host disease (GVHD) remains a major cause of morbidity and mortality following allogeneic hematopoietic stem-cell transplantation (HSCT). Despite the use of prophylactic GVHD regimens, a significant proportion of transplant recipients will develop acute or chronic GVHD following HSCT. Corticosteroids are standard first-line therapy, but are only effective in roughly half of all cases with ~50% of patients going on to develop steroid-refractory disease, which increases the risk of nonrelapse mortality. While progress has been made with improvements in survival outcomes over time, corticosteroids are associated with significant toxicities, and many currently available salvage therapies are associated with increased immunosuppression, infectious complications, and potential loss of the graft versus leukemia (GVL) effect. Thus, there is an unmet need for development of newer treatment strategies for both acute and chronic GVHD to improve long-term post-transplant outcomes and quality of life for HSCT recipients. Here, we provide a concise review of major emerging therapies currently being studied in the treatment of acute and chronic GVHD. PMID:29317998

Level of Granzyme B-positive T-regulatory cells is a strong predictor biomarker of acute Graft-versus-host disease after day +30 after allo-HSCT.

PubMed

Drokov, Mikhail Y; Davydova, Julia O; Kuzmina, Larisa A; Galtseva, Irina V; Kapranov, Nikolay M; Vasilyeva, Vera A; Dubnyak, Darya S; Koroleva, Olga M; Mikhalcova, Ekaterina D; Popova, Natalia N; Parovichnikova, Elena N; Savchenko, Valery G

2017-03-01

Acute Graft-versus-host-disease (aGVHD), the major complication and one of the main causes of poor outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Nowadays there are no widely accepted cell, plasma or another biomarker that can be used for aGVHD prediction. We hypothesized that a level of Granzyme B-positive T regulatory (GZMB-positive Treg) cells on day+30 after allo-HSCT could be the measure of immune response suppression and could predict aGVHD development after day +30. We applied a widespread and easy-to-perform method of multicolor flow cytometry to measure level of GZMB-positive Treg cells. Levels of GZMB-positive Tregs on day +30 after allo-HSCT were significantly higher in those patients who never developed aGVHD in comparison with the other group of patient with aGVHD after day +30 (p=0.0229). We conclude that the level of GZMB-positive Treg cells is a strong predictor of acute Graft-versus-host disease after day +30 after allo-HSCT. Copyright © 2017 Elsevier Ltd. All rights reserved.

Acute graft-versus-host disease: a bench-to-bedside update.

PubMed

Holtan, Shernan G; Pasquini, Marcelo; Weisdorf, Daniel J

2014-07-17

Over the past 5 years, many novel approaches to early diagnosis, prevention, and treatment of acute graft-versus-host disease (aGVHD) have been translated from the bench to the bedside. In this review, we highlight recent discoveries in the context of current aGVHD care. The most significant innovations that have already reached the clinic are prophylaxis strategies based upon a refinement of our understanding of key sensors, effectors, suppressors of the immune alloreactive response, and the resultant tissue damage from the aGVHD inflammatory cascade. In the near future, aGVHD prevention and treatment will likely involve multiple modalities, including small molecules regulating immunologic checkpoints, enhancement of suppressor cytokines and cellular subsets, modulation of the microbiota, graft manipulation, and other donor-based prophylaxis strategies. Despite long-term efforts, major challenges in treatment of established aGVHD still remain. Resolution of inflammation and facilitation of rapid immune reconstitution in those with only a limited response to corticosteroids is a research arena that remains rife with opportunity and urgent clinical need. © 2014 by The American Society of Hematology.

Vitamin D levels and their associations with survival and major disease outcomes in a large cohort of patients with chronic graft-vs-host disease

PubMed Central

Katić, Mašenjka; Pirsl, Filip; Steinberg, Seth M.; Dobbin, Marnie; Curtis, Lauren M.; Pulanić, Dražen; Desnica, Lana; Titarenko, Irina; Pavletic, Steven Z.

2016-01-01

Aim To identify the factors associated with vitamin D status in patients with chronic graft-vs-host disease (cGVHD) and evaluate the association between serum vitamin D (25(OH)D) levels and cGVHD characteristics and clinical outcomes defined by the National Institutes of Health (NIH) criteria. Methods 310 cGVHD patients enrolled in the NIH cGVHD natural history study (clinicaltrials.gov: NCT00092235) were analyzed. Univariate analysis and multiple logistic regression were used to determine the associations between various parameters and 25(OH)D levels, dichotomized into categorical variables: ≤20 and >20 ng/mL, and as a continuous parameter. Multiple logistic regression was used to develop a predictive model for low vitamin D. Survival analysis and association between cGVHD outcomes and 25(OH)D as a continuous as well as categorical variable: ≤20 and >20 ng/mL; <50 and ≥50 ng/mL, and among three ordered categories: ≤20, 20-50, and ≥50 ng/mL, was performed. PMID:27374829

Control of Aedes albopictus with attractive toxic sugar baits (ATSB) and potential impact on non-target organisms in St. Augustine, Florida

PubMed Central

Revay, Edita E.; Müller, Gunter C.; Qualls, Whitney A.; Kline, Daniel; Naranjo, Diana P.; Arheart, Kristopher L.; Kravchenko, Vasiliy D.; Yfremova, Zoya; Hausmann, Axel; Beier, John C.; Schlein, Yosef; Xue, Rui-De

2013-01-01

The purpose of this study was to test the efficacy of bait stations and foliar applications containing attractive toxic sugar baits (ATSB) and eugenol to control Aedes albopictus. At the same time the potential impact of these control methods was evaluated on non-target organisms. The study was conducted at five tire sites in St. Augustine, Florida. Aedes albopictus populations were significantly reduced with ATSB-eugenol applications applied directly to non-flowering vegetation and as bait stations compared with non-attractive sugar baits and control. The application of ATSB made to non-flowering vegetation resulted in more significant reductions of mosquito populations compared to the application of ATSB presented in a bait station. Over 5.5% of the non-targets were stained in the flowering vegetation application site. However, when the attractive sugar bait application was made to non-flowering vegetation or presented in bait stations the impact on non-target insects was very low for all non-target orders as only 0.6% of the individual insects were stained with the dye from the sugar solutions, respectively. There were no significant differences between the staining of mosquitoes collected in flowering vegetation (206/1000) or non-flowering vegetation (242/1000) sites during the non-target evaluation. Our field studies support the use of eugenol as an active ingredient for controlling the dengue vector Ae. albopictus when used as an ATSB toxin and demonstrates potential use in sub-tropical and tropical environments for dengue control. PMID:24122115

Low immunosuppressive burden after HLA-matched related or unrelated BMT using posttransplantation cyclophosphamide.

PubMed

Kanakry, Christopher G; Bolaños-Meade, Javier; Kasamon, Yvette L; Zahurak, Marianna; Durakovic, Nadira; Furlong, Terry; Mielcarek, Marco; Medeot, Marta; Gojo, Ivana; Smith, B Douglas; Kanakry, Jennifer A; Borrello, Ivan M; Brodsky, Robert A; Gladstone, Douglas E; Huff, Carol Ann; Matsui, William H; Swinnen, Lode J; Cooke, Kenneth R; Ambinder, Richard F; Fuchs, Ephraim J; de Lima, Marcos J; Andersson, Borje S; Varadhan, Ravi; O'Donnell, Paul V; Jones, Richard J; Luznik, Leo

2017-03-09

The intensive and prolonged immunosuppressive therapy required to prevent or treat graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (alloBMT) puts patients at substantial risk for life-threatening infections, organ toxicity, and disease relapse. Posttransplantation cyclophosphamide (PTCy) can function as single-agent GVHD prophylaxis after myeloablative, HLA-matched related (MRD), or HLA-matched unrelated (MUD) donor T-cell-replete bone marrow allografting, obviating the need for additional prophylactic immunosuppression. However, patients who develop GVHD require supplemental treatment. We assessed the longitudinal requirement for immunosuppressive therapy in 339 patients treated with this transplantation platform: 247 receiving busulfan/cyclophosphamide (BuCy) conditioning (data collected retrospectively) and 92 receiving busulfan/fludarabine (BuFlu) conditioning (data collected prospectively). Approximately 50% of MRD patients and 30% of MUD patients never required immunosuppression beyond PTCy. In patients requiring further immunosuppression, typically only 1 to 2 agents were required, and the median durations of systemic pharmacologic immunosuppression for the BuCy MRD, BuFlu MRD, BuCy MUD, and BuFlu MUD groups all were 4.5 to 5 months. For these 4 groups, 1-year probabilities of being alive and off all systemic immunosuppression were 61%, 53%, 53%, and 51% and 3-year probabilities were 53%, 48%, 49%, and 56%, respectively. These data suggest that PTCy minimizes the global immunosuppressive burden experienced by patients undergoing HLA-matched alloBMT.

High day 28 ST2 levels predict for acute graft-versus-host disease and transplant-related mortality after cord blood transplantation.

PubMed

Ponce, Doris M; Hilden, Patrick; Mumaw, Christen; Devlin, Sean M; Lubin, Marissa; Giralt, Sergio; Goldberg, Jenna D; Hanash, Alan; Hsu, Katharine; Jenq, Robert; Perales, Miguel-Angel; Sauter, Craig; van den Brink, Marcel R M; Young, James W; Brentjens, Renier; Kernan, Nancy A; Prockop, Susan E; O'Reilly, Richard J; Scaradavou, Andromachi; Paczesny, Sophie; Barker, Juliet N

2015-01-01

While cord blood transplantation (CBT) is an effective therapy for hematologic malignancies, acute graft-versus-host disease (aGVHD) is a leading cause of transplant-related mortality (TRM). We investigated if biomarkers could predict aGVHD and TRM after day 28 in CBT recipients. Day 28 samples from 113 CBT patients were analyzed. Suppressor of tumorigenicity 2 (ST2) was the only biomarker associated with grades II-IV and III-IV aGVHD and TRM. Day 180 grade III-IV aGVHD in patients with high ST2 levels was 30% (95% confidence interval [CI], 18-43) vs 13% (95% CI, 5-23) in patients with low levels (P = .024). The adverse effect of elevated ST2 was independent of HLA match. Moreover, high day 28 ST2 levels were associated with increased TRM with day 180 estimates of 23% (95% CI, 13-35) vs 5% (95% CI, 1-13) if levels were low (P = .001). GVHD was the most common cause of death in high ST2 patients. High concentrations of tumor necrosis factor receptor-1, interleukin-8, and regenerating islet-derived protein 3-α were also associated with TRM. Our results are consistent with those of adult donor allografts and warrant further prospective evaluation to facilitate future therapeutic intervention to ameliorate severe aGVHD and further improve survival after CBT. © 2015 by The American Society of Hematology.

Single-Nucleotide Polymorphisms Within the Thrombomodulin Gene (THBD) Predict Mortality in Patients With Graft-Versus-Host Disease.

PubMed

Rachakonda, Sivaramakrishna P; Penack, Olaf; Dietrich, Sascha; Blau, Olga; Blau, Igor Wolfgang; Radujkovic, Aleksandar; Isermann, Berend; Ho, Anthony D; Uharek, Lutz; Dreger, Peter; Kumar, Rajiv; Luft, Thomas

2014-10-20

Steroid-refractory graft-versus-host disease (GVHD) is a major and often fatal complication after allogeneic stem-cell transplantation (alloSCT). Although the pathophysiology of steroid refractoriness is not fully understood, evidence is accumulating that endothelial cell stress is involved, and endothelial thrombomodulin (THBD) plays a role in this process. Here we assess whether single-nucleotide polymorphisms (SNPs) within the THBD gene predict outcome after alloSCT. Seven SNPs within the THBD gene were studied (rs1962, rs1042579, rs1042580, rs3176123, rs3176124, rs3176126, and rs3176134) in a training cohort of 306 patients. The relevant genotypes were then validated in an independent cohort (n = 321). In the training cohort, an increased risk of nonrelapse mortality (NRM) was associated with three of seven SNPs tested: rs1962, rs1042579 (in linkage disequilibrium with rs3176123), and rs1042580. When patients were divided into risk groups (one v no high-risk SNP), a strong correlation with NRM was observed (hazard ratio [HR], 2.31; 95% CI, 1.36 to 3.95; P = .002). More specifically, NRM was predicted by THBD SNPs in patients who later developed GVHD (HR, 3.03; 95% CI, 1.61 to 5.68; P < .001) but not in patients without GVHD. In contrast, THBD SNPs did not predict incidence of acute GVHD. Multivariable analyses adjusting for clinical variables confirmed the independent effect of THBD SNPs on NRM. All findings could be reproduced in the validation cohort. THBD SNPs predict mortality of manifest GVHD but not the risk of acquiring GVHD, supporting the hypothesis that endothelial vulnerability contributes to GVHD refractoriness. © 2014 by American Society of Clinical Oncology.

Safety and efficacy of an intra-oral electrostimulator for the relief of dry mouth in patients with chronic graft versus host disease: Case Series

PubMed Central

Zadik, Yehuda; Zeevi, Itai; Luboshitz-Shon, Noa; Dakwar, Nasri; Wolff, Andy; Shapira, Michael Y.; Or, Reuven

2014-01-01

Objectives: Patients with chronic graft-versus-host disease (cGVHD) often suffer from dry mouth and oral mucosal lesions. The primary objective of this study was to investigate the safety of an intra-oral electrostimulator (GenNarino) in symptomatic cGVHD patients. The secondary objective was to study the impact on the salivary gland involvement of cGVHD patients. Study Design: This paper presents a case series. The study included patients treated for 4 weeks, randomly assigned to the active device and then crossed-over to a sham-device or vice versa. The patients and clinicians were blind to the treatment delivered. Data regarding oral mucosal and salivary gland involvement were collected. Results: Six patients were included in this series. Most of the intraoral areas with manifestations of cGVHD were not in contact with the GenNarino device. Two patients developed mild mucosal lesions in areas in contact with the GenNarino during the study. However, only one of them had a change in the National Institutes of Health (NIH) score for oral cGVHD. The unstimulated and stimulated salivary flow rate increased in 4 out of the 5 patients included in this analysis. Symptoms of dry mouth and general oral comfort improved. Conclusion: This study suggests that GenNarino is safe in cGVHD patients with respect to oral tissues. Furthermore the use of GenNarino resulted in subjective and objective improvements in dry mouth symptoms. A large scale study is needed to confirm the impact and safety of GenNarino on systemic cGVHD. Key words:Dry mouth, graft versus host disease, electrostimulation, oral mucosa, hematopoietic stem cell transplantation. PMID:24121920

Effect of HLA mismatch on acute graft-versus-host disease.

PubMed

Kanda, Junya

2013-09-01

HLA matching between donors and recipients is the most important factor associated with acute graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation. With improvements in GVHD prophylaxis and supportive care, transplantations from HLA mismatched donors are performed increasingly frequently, drawing greater attention to the effects of HLA mismatch. In related transplantation, HLA 1-antigen mismatch at the HLA-A, HLA-B, and HLA-DR loci is considered acceptable, but the incidence of severe acute GVHD under standard prophylaxis is higher than that for matched related and unrelated transplantation, highlighting the need for a modification of GVHD prophylaxis. Development of new GVHD prophylaxes has now made HLA 2-3-antigen mismatched related transplantation feasible, and has almost overcome the HLA barrier. In unrelated bone marrow or peripheral blood stem cell transplantation, donors matched for HLA-A, HLA-B, HLA-C, and HLA-DRB1 alleles are the most preferable. The impact of allele or antigen mismatch has been evaluated in a number of studies, but the results of these have not been consistent, partly due to differences in race and HLA distribution. The effects of HLA mismatch may differ depending on the year of transplantation and the form of GVHD prophylaxis administered. In cord blood transplantation, successful transplantation can be achieved with up to two HLA mismatches. In children, compared to the use of HLA mismatched units, the use of HLA-matched units is associated with a lower risk of acute GVHD and mortality, while in adults HLA mismatches may have a lower impact on outcome. Thus, the effect of HLA matching should be evaluated separately for different stem cell sources.

Wireless capsule endoscopy for diagnosis of acute intestinal graft-versus-host disease.

PubMed

Neumann, Susanne; Schoppmeyer, Konrad; Lange, Thoralf; Wiedmann, Marcus; Golsong, Johannes; Tannapfel, Andrea; Mossner, Joachim; Niederwieser, Dietger; Caca, Karel

2007-03-01

The small intestine is the most common location of intestinal graft-versus-host disease (GVHD). EGD with duodenal biopsies yields the highest diagnostic sensitivity, but the jejunum and ileum are not accessible by regular endoscopy. In contrast, wireless capsule endoscopy (WCE) is a noninvasive imaging procedure offering complete evaluation of the small intestine. The objective was to compare the diagnostic value of EGD, including biopsies, with the results of WCE in patients with acute intestinal symptoms who received allogeneic blood stem cell transplantation and to analyze the appearance and distribution of acute intestinal GVHD lesions in these patients. An investigator-blinded, single-center prospective study. Patients with acute intestinal symptoms after allogeneic stem cell transplantation underwent both EGD and WCE within 24 hours. Clinical data were recorded during 2 months of follow-up. Fourteen consecutive patients with clinical symptoms of acute intestinal GVHD were recruited. In 1 patient, the capsule remained in the stomach and was removed endoscopically. In 7 of 13 patients who could be evaluated, acute intestinal GVHD was diagnosed by EGD with biopsies, but 3 of these would have been missed by EGD alone. In all 7 patients with histologically confirmed acute intestinal GVHD, WCE revealed typical signs of GVHD. Lesions were scattered throughout the small intestine, but were most accentuated in the ileum. This study had a small number of patients. WCE, which is less invasive than EGD with biopsies, showed a comparable sensitivity and a high negative predictive value for diagnosing acute intestinal GVHD. It may be helpful to avoid repeated endoscopic procedures in patients who have undergone stem cell transplantation.

CD19+CD21low B cells and CD4+CD45RA+CD31+ T cells correlate with first diagnosis of chronic graft-versus-host disease.

PubMed

Greinix, Hildegard T; Kuzmina, Zoya; Weigl, Roman; Körmoczi, Ulrike; Rottal, Arno; Wolff, Daniel; Kralj, Mateja; Kalhs, Peter; Mitterbauer, Margit; Rabitsch, Werner; Edinger, Matthias; Holler, Ernst; Pickl, Winfried F

2015-02-01

Chronic graft-versus-host disease (cGVHD) is a serious and frequent complication of allogeneic hematopoietic stem cell transplantation (HCT). Currently, no biomarkers for prediction and diagnosis of cGVHD are available. We performed a large prospective study focusing on noninvasive biomarkers for National Institutes of Health-defined cGVHD patients (n = 163) in comparison to time-matched HCT recipients who never experienced cGVHD (n = 64), analyzed from day 100 after HCT. In logistic regression analysis, CD19(+)CD21(low) B cells (P = .002; hazard ratio [HR], 3.31; 95% confidence interval [CI], 1.53 to 7.17) and CD4(+)CD45RA(+)CD31(+) T cells (P < .001; HR, 3.88; 95% CI, 1.88 to 7.99) assessed on day 100 after HCT were significantly associated with subsequent development of cGVHD, independent of clinical parameters. A significant association with diagnosis of cGVHD was only observed for CD19(+)CD21(low) B cells (P = .008; HR, 3.00; 95% CI, 1.33 to 6.75) and CD4(+)CD45RA(+)CD31(+) T cells (P = .017; HR, 2.80; 95% CI, 1.19 to 6.55). CD19(+)CD21(low) B cells were found to have the highest discriminatory value with an area under the receiver operating curve of .77 (95% CI, .64 to .90). Our results demonstrate that CD19(+)CD21(low) B cells and CD4(+)CD45RA(+)CD31(+) T cells are significantly elevated in patients with newly diagnosed cGVHD. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Impact of Donor Epstein-Barr Virus Serostatus on the Incidence of Graft-Versus-Host Disease in Patients With Acute Leukemia After Hematopoietic Stem-Cell Transplantation: A Study From the Acute Leukemia and Infectious Diseases Working Parties of the European Society for Blood and Marrow Transplantation.

PubMed

Styczynski, Jan; Tridello, Gloria; Gil, Lidia; Ljungman, Per; Hoek, Jennifer; Iacobelli, Simona; Ward, Katherine N; Cordonnier, Catherine; Einsele, Hermann; Socie, Gerard; Milpied, Noel; Veelken, Hendrik; Chevallier, Patrice; Yakoub-Agha, Ibrahim; Maertens, Johan; Blaise, Didier; Cornelissen, Jan; Michallet, Mauricette; Daguindau, Etienne; Petersen, Eefke; Passweg, Jakob; Greinix, Hildegard; Duarte, Rafael F; Kröger, Nicolaus; Dreger, Peter; Mohty, Mohamad; Nagler, Arnon; Cesaro, Simone

2016-07-01

We investigated the effect of Epstein-Barr virus (EBV) serostatus on the overall outcome of allogeneic hematopoietic stem-cell transplantation (allo-HSCT). The study included 11,364 patients who underwent allogeneic peripheral-blood or bone marrow transplantation for acute leukemia between 1997 and 2012. We analyzed the impact of donor and recipient EBV serologic status on overall survival, relapse-free survival, relapse incidence, nonrelapse mortality, and incidence of graft-versus-host disease (GVHD) after allo-HSCT. Patients receiving grafts from EBV-seropositive donors had the same overall survival as patients who received grafts from EBV-seronegative donors (hazard ratio [HR], 1.05; 95% CI, 0.97 to 1.12; P = .23). Seropositive donors also had no influence on relapse-free survival (HR, 1.04; 95% CI, 0.97 to 1.11; P = 0.31), relapse incidence (HR, 1.03; 95% CI, 0.94 to 1.12; P = .58), and nonrelapse mortality (HR, 1.05; 95% CI, 0.94 to 1.17; P = .37). However, in univariate analysis, recipients receiving grafts from seropositive donors had a higher risk of chronic GVHD than those with seronegative donors (40.8% v 31.0%, respectively; P < .001; HR, 1.42; 95% CI, 1.30 to 1.56). When adjusting for confounders, higher risk was identified for both acute and chronic GVHD. In seronegative patients with seropositive donors, the HR for chronic GVHD was 1.30 (95% CI, 1.06 to 1.59; P = .039). In seropositive patients with seropositive donors, the HR was 1.24 (95% CI, 1.07 to 1.45; P = .016) for acute GVHD and 1.43 (95% CI, 1.23 to 1.67; P < .001) for chronic GVHD. Seropositive patients with seronegative donors did not have an increased risk of GVHD. Our data suggest that donor EBV status significantly influences development of acute and chronic GVHD after allo-HSCT. © 2016 by American Society of Clinical Oncology.

Immunomodulation effects of mesenchymal stromal cells on acute graft-versus-host disease after hematopoietic stem cell transplantation.

PubMed

Zhao, Ke; Lou, Rui; Huang, Fen; Peng, Yanwen; Jiang, Zujun; Huang, Ke; Wu, Xiuli; Zhang, Yu; Fan, Zhiping; Zhou, Hongsheng; Liu, Can; Xiao, Yang; Sun, Jing; Li, Yangqiu; Xiang, Peng; Liu, Qifa

2015-01-01

Refractory acute graft-versus-host disease (aGVHD) is a major cause of death after allogeneic hematopoietic stem cell transplantation. This study evaluated the immunomodulation effects of mesenchymal stromal cells (MSCs) from bone marrow of a third-party donor for refractory aGVHD. Forty-seven patients with refractory aGVHD were enrolled: 28 patients receiving MSC and 19 patients without MSC treatment. MSCs were given at a median dose of 1 × 10(6) cells/kg weekly until patients got complete response or received 8 doses of MSCs. After 125 doses of MSCs were administered, with a median of 4 doses (range, 2 to 8) per patient, overall response rate was 75% in the MSC group compared with 42.1% in the non-MSC group (P = .023). The incidence of cytomegalovirus, Epstein-Barr virus infections, and tumor relapse was not different between the 2 groups during aGVHD treatment and follow-up. The incidence and severity of chronic GVHD in the MSC group were lower than those in the non-MSC group (P = .045 and P = .005). The ratio of CD3(+)CD4(+)/CD3(+)CD8(+) T cells, the frequencies of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs), and the levels of signal joint T cell-receptor excision DNA circles (sjTRECs) after MSCs treatment were higher than those pretreatment. MSC-treated patients exhibited higher Tregs frequencies and sjTRECs levels than those in the non-MSC group at 8 and 12 weeks after treatment. MSCs derived from bone marrow of a third-party donor are effective to refractory aGVHD. It might reduce the incidence and severity of chronic GVHD in aGVHD patients by improving thymic function and induction of Tregs but not increase the risks of infections and tumor relapse. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Mesenchymal stem cells transplantation in hematological patients with acute graft-versus-host disease: characteristics and risk factors for infectious complications.

PubMed

Stoma, Igor; Karpov, Igor; Krivenko, Svetlana; Iskrov, Igor; Milanovich, Natalia; Koritko, Alla; Uss, Anatoly

2018-05-01

The role of MSCs in infection prevention and treatment is still discussed in transplant and hematological patients. The spectrum and risk factors for infections after MSCs transplantation in patients with acute GVHD have not been studied before. To determine the risk factors and spectrum of infectious complications in patients received mesenchymal stem cell transplantation as a treatment for acute GVHD. A prospective observational study was performed to evaluate the risk factors and characteristics of infectious complications after MSCs transplantation in adult patients having acute GVHD. Thirty-four episodes of MSCs transplantation in patients with acute GVHD after allogeneic HSCT were enrolled in the study. MSCs were given at a median dose of 1.32 (interquartile range 0.87-2.16) mln cells/kg per infusion at 91 days (interquartile range 31-131 days) after HSCT. Data relating to age, gender, date, and type of transplantation, characteristics of MSCs, infectious agents, and antimicrobial therapy and prevention regimens were prospectively collected in all of the enrolled patients. The episode of proven infectious complication was set as a primary outcome. There were totally 68 patients with acute GVHD in the study; among them there were 34 cases of MSCs transplantation performed. Among the registered infectious episodes were viral infections (CMV-associated disease, EBV-associated disease), invasive pulmonary aspergillosis, bacterial bloodstream infections, and pneumonia. MSCs transplantation has shown no statistically significant association with risk of infectious complications in patients with acute GVHD in a performed multivariate analysis. Among the most frequent infections in acute GVHD, we have described CMV, invasive aspergillosis, and bacterial infections (bloodstream infections or pneumonia). Among risk factors for infectious complications in patients with acute GVHD with/without MSCs transplantation are progression of main disease and neutropenia below

Targeting Terrorist Leaders: A Case Study

DTIC Science & Technology

2011-03-01

PRESSURE .................................38 IV. STATISTICAL ANALYSIS ON ISRAELI LEADERSHIP TARGETING ...43 V. CONCLUSION: HAVE ISRAELI ATTEMPTS TO...organization. D. POTENTIAL WEAKNESSES The use of one case to evaluate the efficacy of the terrorist-leadership targeting model is problematic...times who was in charge. In addition, the literature on Hamas is widely split on the role that inspirational leaders had on operational matters

Graft-versus-host disease

MedlinePlus

GVHD; Bone marrow transplant - graft-versus-host disease; Stem cell transplant - graft-versus-host disease; Allogeneic transplant - ... GVHD may occur after a bone marrow, or stem cell, transplant in which someone receives bone marrow ...

The development of organized visual search

PubMed Central

Woods, Adam J.; Goksun, Tilbe; Chatterjee, Anjan; Zelonis, Sarah; Mehta, Anika; Smith, Sabrina E.

2013-01-01

Visual search plays an important role in guiding behavior. Children have more difficulty performing conjunction search tasks than adults. The present research evaluates whether developmental differences in children's ability to organize serial visual search (i.e., search organization skills) contribute to performance limitations in a typical conjunction search task. We evaluated 134 children between the ages of 2 and 17 on separate tasks measuring search for targets defined by a conjunction of features or by distinct features. Our results demonstrated that children organize their visual search better as they get older. As children's skills at organizing visual search improve they become more accurate at locating targets with conjunction of features amongst distractors, but not for targets with distinct features. Developmental limitations in children's abilities to organize their visual search of the environment are an important component of poor conjunction search in young children. In addition, our findings provide preliminary evidence that, like other visuospatial tasks, exposure to reading may influence children's spatial orientation to the visual environment when performing a visual search. PMID:23584560

[Impact of HLA mismatch on transplant outcomes].

PubMed

Kanda, Junya

Human leukocyte antigen (HLA) mismatch increases the risk of severe graft-versus-host disease (GVHD) and transplant-related mortality. However, the variety of stem cell sources such as cord blood units or the improvements in GVHD prophylaxis makes the interpretation of HLA mismatch more complex. In unrelated transplantation, the locus of HLA mismatch has a great impact on the donor candidate selection, whereas in related transplantation, it has an impact on the intensity of GVHD prophylaxis because donor availability is limited. Anti-thymocyte globulin and post-transplant cyclophosphamide are attractive GVHD prophylactic agents to reduce the risk of immune-associated complications in HLA-mismatched transplantations. HLA mismatch has a reduced impact in adult cord blood transplantation. In this review article, the impact of HLA mismatch based on graft sources is discussed.

Intermediaries for youth: a vital target audience.

PubMed

1997-01-01

Worldwide, youth are recognized as a key target audience for HIV/STD awareness and prevention campaigns. Rural young people, who often have less access to information and prevention tools than urban youth, may be particularly vulnerable to HIV/STD infection. Many initiatives have been organized by nongovernmental organizations, governments, churches, and other organizations to help youth. However, parents, relatives, guardians, teachers, church and youth leaders, social workers, and other adults in a position to influence youth must also be helped to undertake the role of an intermediary between youth and HIV/STD interventions and other youth-oriented programs. In training adults to openly address sexual and reproductive health issues with adolescents, adults must first be encouraged to feel comfortable about discussing such issues among themselves. Intermediaries and how to target them are discussed.

Cortical Recruitment and Nuclear–Cytoplasmic Shuttling of Scd5p, a Protein Phosphatase-1-targeting Protein Involved in Actin Organization and EndocytosisD⃞

PubMed Central

Chang, Ji Suk; Henry, Kenneth; Geli, María Isabel; Lemmon, Sandra K.

2006-01-01

Scd5p regulates endocytosis and cortical actin organization as a targeting subunit for the Ser/Thr protein phosphatase-1 (PP1) in yeast. To identify localization signals in Scd5p required for cell surface recruitment, visualization of GFP-tagged Scd5 truncations and deletions was performed. Scd5p contains a PP1 binding site, a 3-repeat region of 20 amino acids (3R), and a 9-repeat region of 12 amino acids (9R). We found that the 9R is critical for cortical localization of Scd5p, but cortical recruitment is not essential for Scd5p's function in actin organization and endocytosis. We propose that Scd5p can target PP1 to endocytic factors in the cytoplasm that have been disassembled and/or inactivated by phosphorylation. We also found that Scd5p undergoes nuclear-cytoplasmic shuttling in a Crm1p-dependent manner. Scd5p-ΔCT lacking the 9R region and its nuclear export signal (NES) accumulates in the nucleus, causing cortical actin and endocytic defects. Cytoplasmic localization and function of Scd5p-ΔCT is restored by NES addition. However, removal of Scd5p's nuclear localization signal prevents nuclear entry, but endocytosis and actin organization remain relatively normal. These results indicate that nuclear-cytoplasmic shuttling is not required for regulation of Scd5p's cortical function and suggest that Scd5p has an independent nuclear function. PMID:16251346

Spatial organization of the cytoskeleton enhances cargo delivery to specific target areas on the plasma membrane of spherical cells.

PubMed

Hafner, Anne E; Rieger, Heiko

2016-11-15

Intracellular transport is vital for the proper functioning and survival of a cell. Cargo (proteins, vesicles, organelles, etc) is transferred from its place of creation to its target locations via molecular motor assisted transport along cytoskeletal filaments. The transport efficiency is strongly affected by the spatial organization of the cytoskeleton, which constitutes an inhomogeneous, complex network. In cells with a centrosome microtubules grow radially from the central microtubule organizing center towards the cell periphery whereas actin filaments form a dense meshwork, the actin cortex, underneath the cell membrane with a broad range of orientations. The emerging ballistic motion along filaments is frequently interrupted due to constricting intersection nodes or cycles of detachment and reattachment processes in the crowded cytoplasm. In order to investigate the efficiency of search strategies established by the cell's specific spatial organization of the cytoskeleton we formulate a random velocity model with intermittent arrest states. With extensive computer simulations we analyze the dependence of the mean first passage times for narrow escape problems on the structural characteristics of the cytoskeleton, the motor properties and the fraction of time spent in each state. We find that an inhomogeneous architecture with a small width of the actin cortex constitutes an efficient intracellular search strategy.

Spatial organization of the cytoskeleton enhances cargo delivery to specific target areas on the plasma membrane of spherical cells

NASA Astrophysics Data System (ADS)

Hafner, Anne E.; Rieger, Heiko

2016-12-01

Intracellular transport is vital for the proper functioning and survival of a cell. Cargo (proteins, vesicles, organelles, etc) is transferred from its place of creation to its target locations via molecular motor assisted transport along cytoskeletal filaments. The transport efficiency is strongly affected by the spatial organization of the cytoskeleton, which constitutes an inhomogeneous, complex network. In cells with a centrosome microtubules grow radially from the central microtubule organizing center towards the cell periphery whereas actin filaments form a dense meshwork, the actin cortex, underneath the cell membrane with a broad range of orientations. The emerging ballistic motion along filaments is frequently interrupted due to constricting intersection nodes or cycles of detachment and reattachment processes in the crowded cytoplasm. In order to investigate the efficiency of search strategies established by the cell’s specific spatial organization of the cytoskeleton we formulate a random velocity model with intermittent arrest states. With extensive computer simulations we analyze the dependence of the mean first passage times for narrow escape problems on the structural characteristics of the cytoskeleton, the motor properties and the fraction of time spent in each state. We find that an inhomogeneous architecture with a small width of the actin cortex constitutes an efficient intracellular search strategy.

Assessment of cardiovascular risk and target organ damage among adult patients with primary hypertension in Thika Level 5 Hospital, Kenya: a criteria-based clinical audit.

PubMed

Mwita, Clifford Chacha; Akello, Walter; Sisenda, Gloria; Ogoti, Evans; Tivey, David; Munn, Zachary; Mbogo, David

2013-06-01

Appropriate management of hypertension reduces the risk of death from stroke and cardiac disease and includes routine assessment for target organ damage and estimation of cardiovascular risk. However, implementation of evidence-based hypertension management guidelines is unsatisfactory. We explore the use of audit and feedback as a quality improvement (QI) strategy for reducing the knowledge practice gap in hypertension care in a resource poor setting. The aim of this study is to determine the level of compliance to evidence-based guidelines on assessment of cardiovascular risk and target organ damage among patients with hypertension in Thika Level 5 Hospital in central Kenya and to implement best practice with regard to evidence utilisation among clinicians in the hospital. A retrospective clinical audit done in three phases spread over 5 months. Phase one involved identifying five audit criteria on assessment of cardiovascular risk and target organ damage in patients with hypertension and conducting a baseline audit in which compliance to audit criteria, blood pressure control and drug prescription practices were assessed. Phase two involved identifying barriers to compliance to audit criteria and strategies to overcoming these barriers. The third phase was a follow-up audit. There was no use of a cardiovascular risk assessment tool in both audits (0% vs. 0%; P = 1.00). Testing urine for haematuria and proteinuria reduced from 13% to 8% (P = 0.230) while taking a blood sample for measuring blood glucose, electrolytes and creatinine levels improved from 11% to 17% (P = 0.401). Performance of fundoscopy and electrocardiography remained unchanged at 2% and 8%, respectively (P = 0.886 and P = 0.898). High patient load was identified as the biggest barrier to implementation of best practice. Blood pressure control improved from 33% to 70% (P ≤ 0.001), whereas the proportion of patients on two or more recommended antihypertensive drugs rose

Recipient Immune Modulation with Atorvastatin for Acute Graft-versus-Host Disease Prophylaxis after Allogeneic Transplantation.

PubMed

Kanate, Abraham S; Hari, Parameswaran N; Pasquini, Marcelo C; Visotcky, Alexis; Ahn, Kwang W; Boyd, Jennifer; Guru Murthy, Guru Subramanian; Rizzo, J Douglas; Saber, Wael; Drobyski, William; Michaelis, Laura; Atallah, Ehab; Carlson, Karen S; D'Souza, Anita; Fenske, Timothy S; Cumpston, Aaron; Bunner, Pamela; Craig, Michael; Horowitz, Mary M; Hamadani, Mehdi

2017-08-01

Atorvastatin administration to both the donors and recipients of matched related donor (MRD) allogeneic hematopoietic cell transplantation (allo-HCT) as acute graft-versus-host disease (GVHD) prophylaxis has been shown to be safe and effective. However, its efficacy as acute GVHD prophylaxis when given only to allo-HCT recipients is unknown. We conducted a phase II study to evaluate the safety and efficacy of atorvastatin-based acute GVHD prophylaxis given only to the recipients of MRD (n = 30) or matched unrelated donor (MUD) (n = 39) allo-HCT, enrolled in 2 separate cohorts. Atorvastatin (40 mg/day) was administered along with standard GVHD prophylaxis consisting of tacrolimus and methotrexate. All patients were evaluable for acute GVHD. The cumulative incidences of grade II to IV acute GVHD at day +100 in the MRD and MUD cohorts were 9.9% (95% confidence interval [CI], 0 to 20%) and 29.6% (95% CI,15.6% to 43.6%), respectively. The cumulative incidences of grade III and IV acute GVHD at day +100 in the MRD and MUD cohorts were 3.4% (95% CI, 0 to 9.7%) and 18.3% (95% CI, 6.3% to 30.4%), respectively. The corresponding rates of moderate/severe chronic GVHD at 1 year were 28.1% (95% CI, 11% to 45.2%) and 38.9% (95% CI, 20.9% to 57%), respectively. In the MRD cohort, the 1-year nonrelapse mortality, relapse rate, progression-free survival, and overall survival were 6.7% (95% CI, 0 to 15.4%), 43.3% (95% CI, 24.9% to 61.7%), 50% (95% CI, 32.1% to 67.9%), and 66.7% (95% CI, 49.8% to 83.6%), respectively. The respective figures for the MUD cohort were 10.3% (95% CI, 8% to 19.7%), 20.5% (95% CI, 7.9% to 33.1%), 69.2% (95% CI, 54.7% to 83.7%), and 79.5% (95% CI, 66.8% to 92.2%), respectively. No grade 4 toxicities attributable to atorvastatin were seen. In conclusion, the addition of atorvastatin to standard GVHD prophylaxis in only the recipients of MRD and MUD allo-HCT appears to be feasible and safe. The preliminary efficacy seen here warrants confirmation in

Sibling Donor and Recipient Immune Modulation With Atorvastatin for the Prophylaxis of Acute Graft-Versus-Host Disease

PubMed Central

Hamadani, Mehdi; Gibson, Laura F.; Remick, Scot C.; Wen, Sijin; Petros, William; Tse, William; Brundage, Kathleen M.; Vos, Jeffrey A.; Cumpston, Aaron; Bunner, Pamela; Craig, Michael D.

2013-01-01

Purpose Graft-versus-host disease (GVHD) is major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Atorvastatin is a potent immunomodulatory agent that holds promise as a novel and safe agent for acute GVHD prophylaxis. Patients and Methods We conducted a phase II trial to evaluate the safety and efficacy of atorvastatin administration for GVHD prophylaxis in both adult donors and recipients of matched sibling allogeneic HCT. Atorvastatin (40 mg per day orally) was administered to sibling donors, starting 14 to 28 days before the anticipated first day of stem-cell collection. In HCT recipients (n = 30), GVHD prophylaxis consisted of tacrolimus, short-course methotrexate, and atorvastatin (40 mg per day orally). Results Atorvastatin administration in healthy donors and recipients was not associated with any grade 3 to 4 adverse events. Cumulative incidence rates of grade 2 to 4 acute GVHD at days +100 and +180 were 3.3% (95% CI, 0.2% to 14.8%) and 11.1% (95% CI, 2.7% to 26.4%), respectively. One-year cumulative incidence of chronic GVHD was 52.3% (95% CI, 27.6% to 72.1%). Viral and fungal infections were infrequent. One-year cumulative incidences of nonrelapse mortality and relapse were 9.8% (95% CI, 1.4% to 28%) and 25.4% (95% CI, 10.9% to 42.9%), respectively. One-year overall survival and progression-free survival were 74% (95% CI, 58% to 96%) and 65% (95% CI, 48% to 87%), respectively. Compared with baseline, atorvastatin administration in sibling donors was associated with a trend toward increased mean plasma interleukin-10 concentrations (5.6 v 7.1 pg/mL; P = .06). Conclusion A novel two-pronged strategy of atorvastatin administration in both donors and recipients of matched sibling allogeneic HCT seems to be a feasible, safe, and potentially effective strategy to prevent acute GVHD. PMID:24166529

Comprehensive Analysis of the Activation and Proliferation Kinetics and Effector Functions of Human Lymphocytes, and Antigen Presentation Capacity of Antigen-Presenting Cells in Xenogeneic Graft-Versus-Host Disease.

PubMed

Kawasaki, Yasufumi; Sato, Kazuya; Hayakawa, Hiroko; Takayama, Norihito; Nakano, Hirofumi; Ito, Ryoji; Mashima, Kiyomi; Oh, Iekuni; Minakata, Daisuke; Yamasaki, Ryoko; Morita, Kaoru; Ashizawa, Masahiro; Yamamoto, Chihiro; Hatano, Kaoru; Fujiwara, Shin-Ichiro; Ohmine, Ken; Muroi, Kazuo; Kanda, Yoshinobu

2018-04-17

Xenogeneic graft-versus-host disease (GVHD) models in highly immunodeficient mice are currently being used worldwide to investigate human immune responses against foreign antigens in vivo. However, the individual roles of CD4 + and CD8 + T cells, and donor/host hematopoietic and nonhematopoietic antigen-presenting cells (APCs) in the induction and development of GVHD have not been fully investigated. In the present study, we comprehensively investigated the immune responses of human T cells and the antigen presentation capacity of donor/host hematopoietic and nonhematopoietic APCs in xenogeneic GVHD models using nonobese diabetic/Shi-scid-IL2rg null mice. CD4 + T cells and, to a lesser extent, CD8 + T cells individually mediated potentially lethal GVHD. In addition to inflammatory cytokine production, CD4 + T cells also supported the activation and proliferation of CD8 + T cells. Using bone marrow chimeras, we demonstrated that host hematopoietic, but not nonhematopoietic, APCs play a critical role in the development of CD4 + T cell-mediated GVHD. During early GVHD, we detected 2 distinct populations in memory CD4 + T cells. One population was highly activated and proliferated in major histocompatibility complex antigen (MHC) +/+ mice but not in MHC -/- mice, indicating alloreactive T cells. The other population showed a less activated and slowly proliferative status regardless of host MHC expression, and was associated with higher susceptibility to apoptosis, indicating nonalloreactive T cells in homeostasis-driven proliferation. These observations are clinically relevant to donor T cell response after allogeneic hematopoietic stem cell transplantation. Our findings provide a better understanding of the immunobiology of humanized mice and support the development of novel options for the prevention and treatment for GVHD. Copyright © 2018. Published by Elsevier Inc.

Antibodies against human cytomegalovirus late protein UL94 in the pathogenesis of scleroderma-like skin lesions in chronic graft-versus-host disease.

PubMed

Pastano, Rocco; Dell'Agnola, Chiara; Bason, Caterina; Gigli, Federica; Rabascio, Cristina; Puccetti, Antonio; Tinazzi, Elisa; Cetto, Gianluigi; Peccatori, Fedro; Martinelli, Giovanni; Lunardi, Claudio

2012-09-01

Human cytomegalovirus (hCMV) infection and its reactivation correlate both with the increased risk and with the worsening of graft-versus-host disease (GVHD). Because scleroderma-like skin lesions can occur in chronic GVHD (cGVHD) in allogeneic stem-cell transplant (HCT) patients and hCMV is relevant in the pathogenesis of systemic sclerosis (SSc), we evaluated the possible pathogenetic link between hCMV and skin cGVHD. Plasma from 18 HCT patients was tested for anti-UL94 and/or anti-NAG-2 antibodies, identified in SSc patients, by direct ELISA assays. Both donors and recipients were anti-hCMV IgG positive, without autoimmune diseases. Patients' purified anti-UL94 and anti-NAG-2 IgG binding to human umbilical endothelial cells (HUVECs) and fibroblasts was performed by FACS analysis and ELISA test. HUVECs apoptosis and fibroblasts proliferation induced by patients' anti-NAG-2 antibodies were measured by DNA fragmentation and cell viability, respectively. About 11/18 patients developed cGVHD and all of them showed skin involvement, ranging from diffuse SSc-like lesions to limited erythema. Eight of eleven cGVHD patients were positive for anti-UL94 and/or anti-NAG-2 antibodies. Remarkably, 4/5 patients who developed diffuse or limited SSc-like lesions had antibodies directed against both UL94 and NAG-2; their anti-NAG-2 IgG-bound HUVECs and fibroblasts induce both endothelial cell apoptosis and fibroblasts proliferation, similar to that induced by purified anti-UL94 and anti-NAG-2 antibodies obtained from SSc patients. In conclusion, our data suggest a pathogenetic link between hCMV infection and scleroderma-like skin cGVHD in HCT patients through a mechanism of molecular mimicry between UL94 viral protein and NAG-2 molecule, as observed in patients with SSc.

Genome-wide minor histocompatibility matching as related to the risk of graft-versus-host disease.

PubMed

Martin, Paul J; Levine, David M; Storer, Barry E; Warren, Edus H; Zheng, Xiuwen; Nelson, Sarah C; Smith, Anajane G; Mortensen, Bo K; Hansen, John A

2017-02-09

The risk of acute graft-versus-host disease (GVHD) is higher after allogeneic hematopoietic cell transplantation (HCT) from unrelated donors as compared with related donors. This difference has been explained by increased recipient mismatching for major histocompatibility antigens or minor histocompatibility antigens. In the current study, we used genome-wide arrays to enumerate single nucleotide polymorphisms (SNPs) that produce graft-versus-host (GVH) amino acid coding differences between recipients and donors. We then tested the hypothesis that higher degrees of genome-wide recipient GVH mismatching correlate with higher risks of GVHD after allogeneic HCT. In HLA-genotypically matched sibling recipients, the average recipient mismatching of coding SNPs was 9.35%. Each 1% increase in genome-wide recipient mismatching was associated with an estimated 20% increase in the hazard of grades III-IV GVHD (hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.05-1.37; P = .007) and an estimated 22% increase in the hazard of stage 2-4 acute gut GVHD (HR, 1.22; 95% CI, 1.02-1.45; P = .03). In HLA-A, B, C, DRB1, DQA1, DQB1, DPA1, DPB1-phenotypically matched unrelated recipients, the average recipient mismatching of coding SNPs was 17.3%. The estimated risks of GVHD-related outcomes in HLA-phenotypically matched unrelated recipients were low, relative to the large difference in genome-wide mismatching between the 2 groups. In contrast, the risks of GVHD-related outcomes were higher in HLA-DP GVH-mismatched unrelated recipients than in HLA-matched sibling recipients. Taken together, these results suggest that the increased GVHD risk after unrelated HCT is predominantly an effect of HLA-mismatching. © 2017 by The American Society of Hematology.

Donor Lymphocyte Infusions for Chronic Myeloid Leukemia Relapsing after Allogeneic Stem Cell Transplantation: May We Predict Graft-versus-Leukemia Without Graft-versus-Host Disease?

PubMed

Radujkovic, Aleksandar; Guglielmi, Cesare; Bergantini, Stefania; Iacobelli, Simona; van Biezen, Anja; Milojkovic, Dragana; Gratwohl, Alois; Schattenberg, Antonius V M B; Verdonck, Leo F; Niederwieser, Dietger W; de Witte, Theo; Kröger, Nicolaus; Olavarria, Eduardo

2015-07-01

Donor lymphocyte infusions (DLI) are an effective treatment for relapsed chronic myeloid leukemia (CML) after allogeneic stem cell transplantation (alloSCT). Leukemia resistance and secondary graft-versus-host disease (GVHD) are major obstacles to success with DLI. The aim of this study was to identify pre-DLI factors associated with prolonged survival in remission without secondary GVHD. We retrospectively analyzed 500 patients treated with DLI for CML relapse (16% molecular, 30% cytogenetic, and 54% hematological) after alloSCT. The overall probabilities of failure- and secondary GVHD-free survival (FGFS) were 29% and 27% at 5 and 10 years after DLI, respectively. The type of relapse was the major factor influencing FGFS (40% for molecular and/or cytogenetic relapse and 20% for hematological relapse at 5 years, P < .001). Chronic GVHD before DLI and an interval <1 year between alloSCT and first DLI were independently associated with inferior FGFS in patients with molecular and/or cytogenetic relapse. Consequently, FGFS was 13%, 35%, to 56% at 5 years in patients with 2, 1, and 0 adverse features, respectively. In patients with hematological relapse, independent adverse prognostic factors for FGFS were initial dose of CD3(+) cells ≥ 50 × 10(6)/kg, donor-recipient sex mismatch, and chronic GVHD before DLI. FGFS was 0%, 17%, 33%, to 37% in patients with 3, 2, 1, and 0 adverse features, respectively. The probability of survival in remission without secondary GVHD was highest (>50% at 5 years) when DLI were given beyond 1 year from alloSCT for molecular and/or cytogenetic CML relapse that was not preceded by chronic GVHD. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

An early-biomarker algorithm predicts lethal graft-versus-host disease and survival