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Sample records for active antibody-mediated rejection

  1. Activation of the transcription factor c-Jun in acute cellular and antibody-mediated rejection after kidney transplantation.

    PubMed

    Kobayashi, Akimitsu; Takahashi, Takamune; Horita, Shigeru; Yamamoto, Izumi; Yamamoto, Hiroyasu; Teraoka, Satoshi; Tanabe, Kazunari; Hosoya, Tatsuo; Yamaguchi, Yutaka

    2010-12-01

    c-Jun is a transcription factor that belongs to the activator protein-1 family of proteins. In human kidney disease, c-Jun is activated in glomerular and tubular cells and plays a major role in renal pathophysiology. However, the contribution of this pathway to renal allograft rejection has not been determined. We investigated whether c-Jun is activated in acute allograft rejection. c-Jun activation was assessed with immunohistochemistry using phospho-specific c-Jun antibodies in control human renal tissue and renal tissue from patients with acute cellular rejection, acute antibody-mediated rejection, and no rejection in the month after transplantation. In patients with acute cellular rejection, c-Jun activation was observed primarily in infiltrated T cells associated with tubulitis, interstitial cell infiltration, and endarteritis. The number of infiltrated phosphorylated c-Jun-positive cells in the tubules and interstitium was correlated with the Banff classification "t" and "i" scores. In patients with acute antibody-mediated rejection, c-Jun activation was observed in injured endothelial cells as well as in infiltrated cells, including macrophages, in the glomerular and peritubular capillaries. Furthermore, the serum creatinine levels and changes in serum creatinine from the previous year were significantly correlated with the total tubulointerstitial phosphorylated c-Jun-positive score (representing the number of positive nuclei in the tubules, interstitium, and peritubular capillaries). In conclusion, c-Jun was activated in acute antibody-mediated rejection and acute cellular rejection and was associated with reduced graft function. These findings suggest that c-Jun plays a key role in pathological events and may represent a novel therapeutic target in acute renal allograft rejection.

  2. Antibody-Mediated Lung Transplant Rejection

    PubMed Central

    Hachem, Ramsey

    2012-01-01

    Antibody-mediated rejection after lung transplantation remains enigmatic. However, emerging evidence over the past several years suggests that humoral immunity plays an important role in allograft rejection. Indeed, the development of donor-specific antibodies after transplantation has been identified as an independent risk factor for acute cellular rejection and bronchiolitis obliterans syndrome. Furthermore, cases of acute antibody-mediated rejection resulting in severe allograft dysfunction have been reported, and these demonstrate that antibodies can directly injure the allograft. However, the incidence and toll of antibody-mediated rejection are unknown because there is no widely accepted definition and some cases may be unrecognized. Clearly, humoral immunity has become an important area for research and clinical investigation. PMID:23002428

  3. Antibody-Mediated Rejection: A Review

    PubMed Central

    Garces, Jorge Carlos; Giusti, Sixto; Staffeld-Coit, Catherine; Bohorquez, Humberto; Cohen, Ari J.; Loss, George E.

    2017-01-01

    Background: Chronic antibody injury is a serious threat to allograft outcomes and is therefore the center of active research. In the continuum of allograft rejection, the development of antibodies plays a critical role. In recent years, an increased recognition of molecular and histologic changes has provided a better understanding of antibody-mediated rejection (AMR), as well as potential therapeutic interventions. However, several pathways are still unknown, which accounts for the lack of efficacy of some of the currently available agents that are used to treat rejection. Methods: We review the current diagnostic criteria for AMR; AMR paradigms; and desensitization, treatment, and prevention strategies. Results: Chronic antibody-mediated endothelial injury results in transplant glomerulopathy, manifested as glomerular basement membrane duplication, double contouring, or splitting. Clinical manifestations of AMR include proteinuria and a rise in serum creatinine. Current strategies for the treatment of AMR include antibody depletion with plasmapheresis (PLEX), immunoadsorption (IA), immunomodulation with intravenous immunoglobulin (IVIG), and T cell– or B cell–depleting agents. Some treatment benefits have been found in using PLEX and IA, and some small nonrandomized trials have identified some benefits in using rituximab and the proteasome inhibitor-based therapy bortezomib. More recent histologic follow-ups of patients treated with bortezomib have not shown significant benefits in terms of allograft outcomes. Furthermore, no specific treatment approaches have been approved by the US Food and Drug Administration. Other agents used for more difficult rejections include bortezomib and eculizumab (an anti-C5 monoclonal antibody). Conclusion: AMR is a fascinating field with ample opportunities for research and progress in the future. Despite the use of advanced techniques for the detection of human leukocyte antigen (HLA) or non-HLA donor-specific antibodies

  4. Acute antibody-mediated rejection in kidney transplant recipients.

    PubMed

    Davis, Scott; Cooper, James E

    2017-01-01

    Antibody-mediated rejection has now been recognized as one of the most important causes of graft loss. Transplantation across HLA barriers and nonadherence can result in acute antibody-mediated rejection, which is associated with particularly worse graft outcomes. New technologies, including genomic studies and assays to detect and define donor-specific antibodies, have provided important insights into the pathophysiology and diagnosis of acute antibody-mediated rejection but have engendered many questions about the clinical application of these tests in the prognosis and prevention of this protean disease process. In this article, we review the pathophysiology of acute antibody-mediated rejection, the evolving diagnostic criteria, and specific challenges related to its prognosis, treatment, and prevention.

  5. Platelets in Early Antibody-Mediated Rejection of Renal Transplants

    PubMed Central

    Kuo, Hsiao-Hsuan; Fan, Ran; Dvorina, Nina; Chiesa-Vottero, Andres

    2015-01-01

    Antibody-mediated rejection is a major complication in renal transplantation. The pathologic manifestations of acute antibody-mediated rejection that has progressed to functional impairment of a renal transplant have been defined in clinical biopsy specimens. However, the initial stages of the process are difficult to resolve with the unavoidable variables of clinical studies. We devised a model of renal transplantation to elucidate the initial stages of humoral rejection. Kidneys were orthotopically allografted to immunodeficient mice. After perioperative inflammation subsided, donor-specific alloantibodies were passively transferred to the recipient. Within 1 hour after a single transfer of antibodies, C4d was deposited diffusely on capillaries, and von Willebrand factor released from endothelial cells coated intravascular platelet aggregates. Platelet-transported inflammatory mediators platelet factor 4 and serotonin accumulated in the graft at 100- to 1000-fold higher concentrations compared with other platelet-transported chemokines. Activated platelets that expressed P-selectin attached to vascular endothelium and macrophages. These intragraft inflammatory changes were accompanied by evidence of acute endothelial injury. Repeated transfers of alloantibodies over 1 week sustained high levels of platelet factor 4 and serotonin. Platelet depletion decreased platelet mediators and altered the accumulation of macrophages. These data indicate that platelets augment early inflammation in response to donor-specific antibodies and that platelet-derived mediators may be markers of evolving alloantibody responses. PMID:25145937

  6. The role of complement in antibody-mediated rejection in kidney transplantation.

    PubMed

    Stegall, Mark D; Chedid, Marcio F; Cornell, Lynn D

    2012-11-01

    Over the past decade, several studies have suggested that the complement system has an active role in both acute and chronic allograft rejection. These studies have been facilitated by improved techniques to detect antibody-mediated organ rejection, including immunohistological staining for C4d deposition in the allograft and solid-phase assays that identify donor-specific alloantibodies (DSAs) in the serum of transplant recipients. Studies with eculizumab, a humanized monoclonal antibody directed against complement component C5, have shown that activation of the terminal complement pathway is necessary for the development of acute antibody-mediated rejection in recipients of living-donor kidney allografts who have high levels of DSAs. The extent to which complement activation drives chronic antibody-mediated injury leading to organ rejection is less clear. In chronic antibody-mediated injury, early complement activation might facilitate chemotaxis of inflammatory cells into the allograft in a process that later becomes somewhat independent of DSA levels and complement factors. In this Review, we discuss the different roles that the complement system might have in antibody-mediated allograft rejection, with specific emphasis on renal transplantation.

  7. Reviewing the pathogenesis of antibody-mediated rejection and renal graft pathology after kidney transplantation.

    PubMed

    Morozumi, Kunio; Takeda, Asami; Otsuka, Yasuhiro; Horike, Keiji; Gotoh, Norihiko; Narumi, Shunji; Watarai, Yoshihiko; Kobayashi, Takaaki

    2016-07-01

    The clinicopathological context of rejection after kidney transplantation was well recognized. Banff conferences greatly contributed to elucidate the pathogenesis and to establish the pathologic criteria of rejection after kidney transplantation. The most important current problem of renal transplantation is de novo donor-specific antibody (DSA) production leading chronic rejection and graft loss. Microvascular inflammation is considered as a reliable pathological marker for antibody-mediated rejection (AMR) in the presence of DSA. Electron microscopic study allowed us to evaluate early changes in peritubular capillaries in T-lymphocyte mediated rejection and transition to antibody-mediated rejection. Severe endothelial injuries with edema and activated lymphocyte invaded into subendothelial space with early multi-layering of peritubular capillary basement membrane suggest T-lymphocyte mediated rejection induce an unbounded chain of antibody-mediated rejection. The risk factors of AMR after ABO-incompatible kidney transplantation are important issues. Anti-ABO blood type antibody titre of IgG excess 32-fold before transplant operation is the only predictable factor for acute AMR. Characteristics of chronic active antibody-mediated rejection (CAAMR) are one of the most important problems. Light microscopic findings and C4d stain of peritubular capillary and glomerular capillary are useful diagnostic criteria of CAAMR. Microvascular inflammation, double contour of glomerular capillary and thickening of peritubular capillary basement are good predictive factors of the presence of de novo DSA. C4d stain of linear glomerular capillary is a more sensitive marker for CAAMR than positive C4d of peritubular capillary. Early and sensitive diagnostic attempts of diagnosing CAAMR are pivotal to prevent chronic graft failure.

  8. Diagnostic criteria of antibody-mediated rejection in kidney transplants.

    PubMed

    Mosquera Reboredo, J M; Vázquez Martul, E

    2011-01-01

    The diagnosis and treatment of anti-donor antibody-mediated rejection or humoral rejection (ABMR) is one of the main discussions at the moment in kidney transplantation. The search for histopathological markers that help us to diagnose ABMR has been more problematic, in contrast to the histological expression of cellular or tubulointerstitial rejection. Although the relationship between post-transplant anti-donor antibodies and the allograft's prognosis has been a topic of discussion for a long time, led in the main by P.Terasaki, it was not until the beginning of 1990s when P. Halloran studied the humoral mechanisms of rejection in greater depth. Feutch described the importance of C4d deposits as a marker that shows a humoral mechanism of allograft rejection in 1993. As a result of many studies carried out, the Banff consensus group established some diagnostic histopathological criteria of acute (ABMR) in 2003. These have been modified slightly in later meetings of the group. Furthermore, in 2005 this same working group looked at the physiopathological mechanisms causing chronic allograft failure in more detail and established the criteria defining chronic humoral rejection. In this review, we are trying to update any useful histopathological criteria for diagnosing acute and chronic ABMR.

  9. Refinement of the criteria for ultrastructural peritubular capillary basement membrane multilayering in the diagnosis of chronic active/acute antibody-mediated rejection.

    PubMed

    Go, Heounjeong; Shin, Sung; Kim, Young Hoon; Han, Duck Jong; Cho, Yong Mee

    2017-04-01

    Chronic active/acute antibody-mediated rejection (cABMR) is the main cause of late renal allograft loss. Severe peritubular capillary basement membrane multilayering (PTCML) assessed on electron microscopy is one diagnostic feature of cABMR according to the Banff 2013 classification. We aimed to refine the PTCML criteria for an earlier diagnosis of cABMR. We retrospectively investigated ultrastructural features of 159 consecutive renal allografts and 44 nonallografts. The presence of serum donor-specific antibodies at the time of biopsy of allografts was also examined. Forty-three patients (27.0%) fulfilled the criteria of cABMR, regardless of PTCML, and comprised the cABMR group. Forty-one patients (25.8%) did not exhibit cABMR features and comprised the non-cABMR allograft control group. In addition, 15 zero-day wedge resections and 29 native kidney biopsies comprised the nonallograft control group. When the diagnostic accuracies of various PTCML features were assessed using the cABMR and non-cABMR allograft control groups, ≥4 PTCML, either circumferential or partial, in ≥2 peritubular capillaries of the three most affected capillaries exhibited the highest AUC value (0.885), greater than the Banff 2013 classification (0.640). None of the nonallograft control groups exhibited PTCML features. We suggest that ≥4 PTCML in ≥2 peritubular capillaries of the three most affected cortical capillaries represents the proper cutoff for cABMR.

  10. Antibody-Mediated Rejection of Human Orthotopic Liver Allografts

    PubMed Central

    Demetris, A. Jake; Jaffe, Ron; Tzakis, A.; Ramsey, Glenn; Todo, S.; Belle, Steven; Esquivel, Carlos; Shapiro, Ron; Markus, Bernd; Mroczek, Elizabeth; Van Thiel, D. H.; Sysyn, Greg; Gordon, Robert; Makowka, Leonard; Starzl, Tom

    1988-01-01

    A clinicopathologic analysis of liver transplantation across major ABO blood group barriers was carried out 1) to determine if antibody-mediated (humoral) rejection was a cause of graft failure and if humoral rejection can be identified, 2) to propose criteria for establishing the diagnosis, and 3) to describe the clinical and pathologic features of humoral rejection. A total of 51 (24 primary) ABO-incompatible (ABO-I) liver grafts were transplanted into 49 recipients. There was a 46% graft failure rate during the first 30 days for primary ABO-I grafts compared with an 11% graft failure rate for primary ABO compatible (ABO-C), crossmatch negative, age, sex and priority-matched control patients (P < 0.02). A similarly high early graft failure rate (60%) was seen for nonprimary ABO-I grafts during the first 30 days. Clinically, the patients experienced a relentless rise in serum transaminases, hepatic failure, and coagulopathy during the first weeks after transplant. Pathologic examination of ABO-I grafts that failed early demonstrated widespread areas of geographic hemorrhagic necrosis with diffuse intraorgan coagulation. Prominent arterial deposition of antibody and complement components was demonstrated by immunoflourescent staining. Elution studies confirmed the presence of tissue-bound, donor-specific isoagglutinins within the grafts. No such deposition was seen in control cases. These studies confirm that antibody mediated rejection of the liver occurs and allows for the development of criteria for establishing the diagnosis. ImagesFigure 1Figure 2Figure 3Figure 4Figure 5Figure 6 PMID:3046369

  11. Treatment Options and Strategies for Antibody Mediated Rejection after Renal Transplantation

    PubMed Central

    Levine, Matthew H.

    2011-01-01

    Antibody mediated rejection is a significant clinical problem encountered in a subset of renal transplant recipients. This type of rejection has a variable pathogenesis from the presence of donor specific antibodies with no overt disease to immediate hyperacute rejection and many variations between. Antibody mediated rejection is more common in human leukocyte antigen sensitized patients. In general, transplant graft survival after antibody mediated rejection is jeopardized, with less than 50% graft survival 5 years after this diagnosis. A variety of agents have been utilized singly and in combinations to treat antibody mediated rejection with differing results and significant research efforts are being placed on developing new targets for intervention. These same agents have been used in desensitization protocols with some success. In this review, we describe the biology of antibody mediated rejection, review the available agents to treat this form of rejection, and highlight areas of ongoing and future research into this difficult clinical problem. PMID:21940179

  12. Expression of MMP-2 and TIMP-1 in Renal Tissue of Patients with Chronic Active Antibody-mediated Renal Graft Rejection

    PubMed Central

    2012-01-01

    Objective To investigate the expression of matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metallopropteinase-1 (TIMP-1) in the renal allografts of patients with chronic active antibody-mediated rejection (AMR), and to explore their role in the pathogenesis of AMR. Methods Immunohistochemistry assay and computer-assisted image analysis were used to detect the expression of MMP-2 and TIMP-1 in the renal allografts with interstitial fibrosis and tubular atrophy (IF/TA) in 46 transplant recipients and 15 normal renal tissue specimens as the controls. The association of the expression level of either MMP-2 or TIMP-1 with the pathological grade of IF/TA in AMR was analyzed. Results The expression of either MMP-2 or TIMP-1 was significantly increased in the renal allografts of the recipients as compared with the normal renal tissue (P < 0.05). MMP-2 expression tended to decrease, while TIMP-1 and serum creatinine increased along with the increase of pathological grade of IF/TA (P < 0.05). In IF/TA groups, the expression of TIMP-1 was positively correlated to serum creatinine level (r = 0.718, P < 0.05). Conclusions It is suggested by the results that abnormal expressions of MMP-2 and TIMP-1 might play roles in the development of renal fibrosis in chronic AMR. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1128474926172838 PMID:23057632

  13. Acute antibody-mediated rejection after intestinal transplantation

    PubMed Central

    Wu, Guo-Sheng; Cruz Jr, Ruy J; Cai, Jun-Chao

    2016-01-01

    AIM To investigate the incidence, risk factors and clinical outcomes of acute antibody-mediated rejection (ABMR) after intestinal transplantation (ITx). METHODS A retrospective single-center analysis was performed to identify cases of acute ABMR after ITx, based on the presence of donor-specific antibody (DSA), acute tissue damage, C4d deposition, and allograft dysfunction. RESULTS Acute ABMR was identified in 18 (10.3%) out of 175 intestinal allografts with an average occurrence of 10 d (range, 4-162) after ITx. All acute ABMR cases were presensitized to donor human leukocyte antigens class I and/or II antigens with a detectable DSA. A positive cross-match was seen in 14 (77.8%) cases and twelve of 18 patients (66.7%) produced newly-formed DSA following ITx. Histological characteristics of acute ABMR include endothelial C4d deposits, interstitial hemorrhage, and severe congestion with focal fibrin thrombin in the lamina propria capillaries. Multivariate analysis identified a liver-free graft and high level of panel reactive antibody as a significant independent risk factor. Despite initial improvement after therapy, eleven recipients (61.1%) lost transplant secondary to rejection. Of those, 9 (50%) underwent graft removal and 4 (22.2%) received second transplantation following acute ABMR. At an average follow-up of 32.3 mo (range, 13.3-76.4), 8 (44.4%) recipients died. CONCLUSION Our results indicate that acute ABMR is an important cause of intestine graft dysfunction, particularly in a liver-exclusive graft and survivors are at an increased risk of developing refractory acute rejection and chronic rejection. More effective strategies to prevent and manage acute ABMR are needed to improve outcomes. PMID:28058223

  14. Acute and chronic antibody-mediated rejection in pediatric kidney transplantation.

    PubMed

    Pape, Lars; Becker, Jan U; Immenschuh, Stephan; Ahlenstiel, Thurid

    2015-03-01

    Acute antibody-mediated rejection is a diagnostic challenge in renal transplantation medicine. However, it is an important diagnosis to make, since chronic antibody-mediated rejection (CAMR) is the main cause of long-term graft loss. Antibody-mediated rejection is diagnosed by detecting donor-specific antibodies (DSAs) in the blood in combination with observing typical histomorphological signs in kidney biopsy, as described in the Banff classification. Therapy is based on the removal of DSAs by administering intravenous immunoglobulins (IVIGs), plasmapheresis, or immunoadsorption. Reoccurrence of antibodies is diminished by the use of rituximab, increased immunosuppression, and in some cases additional experimental substances. A combination of these techniques has been shown to be successful in the majority of cases of acute and chronic antibody-mediated rejection. Routine DSA monitoring is warranted for early detection of antibody-mediated rejection.

  15. Post-Transplant Membranous Nephropathy Associated with Chronic Active Antibody-Mediated Rejection and Hepatitis C Infection after Deceased Donor Renal Transplantation.

    PubMed

    Doke, Tomohito; Sato, Waichi; Takahashi, Kazuo; Hayashi, Hiroki; Koide, Sigehisa; Sasaki, Hitomi; Kusaka, Mamoru; Shiroki, Ryoichi; Hoshinaga, Kiyotaka; Takeda, Asami; Yuzawa, Yukio; Hasegawa, Midori

    2016-01-01

    A 53-year-old woman who had undergone deceased donor kidney transplantation twice, at 35 and 43 years of age, presented with renal impairment. She was infected with hepatitis C virus (HCV). The histology of the graft kidney revealed post-transplant membranous nephropathy (MN) with podocytic infolding and antibody-mediated rejection (AMR). IgG subclass staining showed fine granular deposits of IgG1 and IgG3, but not IgG4, in the glomerular capillary walls. Panel reactive antibody scores for human leukocyte antigen class I and class II were 92.67% and 66.68%, respectively. Thus, this case of post-transplanted MN was considered to be associated with AMR and HCV infection.

  16. Identifying Subphenotypes of Antibody-Mediated Rejection in Kidney Transplants.

    PubMed

    Halloran, P F; Merino Lopez, M; Barreto Pereira, A

    2016-03-01

    The key lesions in antibody-mediated kidney transplant rejection (ABMR) are microcirculation inflammation (peritubular capillaritis and/or glomerulitis lesions, abbreviated "pg") and glomerular double contours (cg lesions). We used these features to explore subphenotypes in 164 indication biopsies with ABMR-related diagnoses: 137 ABMR (109 pure and 28 mixed with T cell-mediated rejection [TCMR]) and 27 transplant glomerulopathy (TG), identified from prospective multicenter studies. The lesions indicated three ABMR subphenotypes: pgABMR, cgABMR, and pgcgABMR. Principal component analysis confirmed these subphenotypes and showed that TG can be reclassified as pgcgABMR (n = 17) or cgABMR (n = 10). ABMR-related biopsies included 45 pgABMR, 90 pgcgABMR, and 25 cgABMR, with four unclassifiable. Dominating all time intervals was the subphenotype pgcgABMR. The pgABMR subphenotype presented earliest (median <2 years), frequently mixed with TCMR, and was most associated with nonadherence. The cgABMR subphenotype presented late (median 9 years). Subphenotypes differed in their molecular changes, with pgABMR having the most histologic-molecular discrepancies (i.e. potential errors). Donor-specific antibody (DSA) was not identified in 29% of pgcgABMR and 46% of cgABMR, but failure rates and molecular findings were similar to cases where DSA was known to be positive. Thus, ABMR presents distinct subphenotypes, early pg-dominant, late cg-dominant, and combined pgcg phenotype, differing in time, molecular features, accompanying TCMR, HLA antibody, and probability of nonadherence.

  17. Molecular diagnosis of antibody-mediated rejection in human kidney transplants.

    PubMed

    Sellarés, J; Reeve, J; Loupy, A; Mengel, M; Sis, B; Skene, A; de Freitas, D G; Kreepala, C; Hidalgo, L G; Famulski, K S; Halloran, P F

    2013-04-01

    Antibody-mediated rejection is the major cause of kidney transplant failure, but the histology-based diagnostic system misses most cases due to its requirement for C4d positivity. We hypothesized that gene expression data could be used to test biopsies for the presence of antibody-mediated rejection. To develop a molecular test, we prospectively assigned diagnoses, including C4d-negative antibody-mediated rejection, to 403 indication biopsies from 315 patients, based on histology (microcirculation lesions) and donor-specific HLA antibody. We then used microarray data to develop classifiers that assigned antibody-mediated rejection scores to each biopsy. The transcripts distinguishing antibody-mediated rejection from other conditions were mostly expressed in endothelial cells or NK cells, or were IFNG-inducible. The scores correlated with the presence of microcirculation lesions and donor-specific antibody. Of 45 biopsies with scores>0.5, 39 had been diagnosed as antibody-mediated rejection on the basis of histology and donor-specific antibody. High scores were also associated with unanimity among pathologists that antibody-mediated rejection was present. The molecular score also strongly predicted future graft loss in Cox regression analysis. We conclude that microarray assessment of gene expression can assign a probability of ABMR to transplant biopsies without knowledge of HLA antibody status, histology, or C4d staining, and predicts future failure.

  18. Soluble BAFF Cytokine Levels and Antibody-Mediated Rejection of the Kidney Allograft.

    PubMed

    Slavcev, Antonij; Brozova, Jitka; Slatinska, Janka; Sekerkova, Zuzana; Honsova, Eva; Skibova, Jelena; Striz, Ilja; Viklicky, Ondrej

    2016-12-01

    The B-cell activating factor (BAFF) cytokine has important functions for the survival and maturation of B lymphocytes, which implies that this cytokine might play a role in the development of antibody-mediated rejection (AMR) after kidney transplantation. In our study, we compared the concentrations of the soluble BAFF cytokine in kidney graft recipients with AMR and patients without rejection with the goal of testing the hypothesis whether BAFF level measurement might be useful as a diagnostic marker of AMR. The study included a cohort of 19 high-risk patients with diagnosed AMR and 17 control patients free of rejection. BAFF was measured in all patients before transplantation, during the rejection episodes, and three months after transplantation in patients free of rejection using the Luminex technique. Before transplantation, the serum concentrations of BAFF in patients with AMR and kidney recipients without rejection did not significantly differ. After transplantation, however, BAFF levels were significantly lower in patients with AMR and also in patients with concurrent humoral and cellular rejection compared with patients without rejection (p < 0.05 and p < 0.01, respectively). No correlation was found between BAFF and the production of donor-specific antibodies (DSA) before and after transplantation. Patients experiencing AMR and simultaneous cellular and AMR had significantly lower concentrations of BAFF in comparison with patients free of rejection.

  19. Quantifying renal allograft loss following early antibody-mediated rejection.

    PubMed

    Orandi, B J; Chow, E H K; Hsu, A; Gupta, N; Van Arendonk, K J; Garonzik-Wang, J M; Montgomery, J R; Wickliffe, C; Lonze, B E; Bagnasco, S M; Alachkar, N; Kraus, E S; Jackson, A M; Montgomery, R A; Segev, D L

    2015-02-01

    Unlike antibody-mediated rejection (AMR) with clinical features, it remains unclear whether subclinical AMR should be treated, as its effect on allograft loss is unknown. It is also uncertain if AMR's effect is homogeneous across donor (deceased/live) and (HLA/ABO) antibody types. We compared 219 patients with AMR (77 subclinical, 142 clinical) to controls matched on HLA/ABO-compatibility, donor type, prior transplant, panel reactive antibody (PRA), age and year. One and 5-year graft survival in subclinical AMR was 95.9% and 75.7%, compared to 96.8% and 88.4% in matched controls (p = 0.0097). Subclinical AMR was independently associated with a 2.15-fold increased risk of graft loss (95% CI: 1.19-3.91; p = 0.012) compared to matched controls, but not different from clinical AMR (p = 0.13). Fifty three point two percent of subclinical AMR patients were treated with plasmapheresis within 3 days of their AMR-defining biopsy. Treated subclinical AMR patients had no difference in graft loss compared to matched controls (HR 1.73; 95% CI: 0.73-4.05; p = 0.21), but untreated subclinical AMR patients did (HR 3.34; 95% CI: 1.37-8.11; p = 0.008). AMR's effect on graft loss was heterogeneous when stratified by compatible deceased donor (HR = 4.73; 95% CI: 1.57-14.26; p = 0.006), HLA-incompatible deceased donor (HR = 2.39; 95% CI: 1.10-5.19; p = 0.028), compatible live donor (no AMR patients experienced graft loss), ABO-incompatible live donor (HR = 6.13; 95% CI: 0.55-67.70; p = 0.14) and HLA-incompatible live donor (HR = 6.29; 95% CI: 3.81-10.39; p < 0.001) transplant. Subclinical AMR substantially increases graft loss, and treatment seems warranted.

  20. Late Failing Heart Allografts: Pathology of Cardiac Allograft Vasculopathy and Association With Antibody-Mediated Rejection.

    PubMed

    Loupy, A; Toquet, C; Rouvier, P; Beuscart, T; Bories, M C; Varnous, S; Guillemain, R; Pattier, S; Suberbielle, C; Leprince, P; Lefaucheur, C; Jouven, X; Bruneval, P; Duong Van Huyen, J P

    2016-01-01

    In heart transplantation, there is a lack of robust evidence of the specific causes of late allograft failure. We hypothesized that a substantial fraction of failing heart allografts may be associated with antibody-mediated injury and immune-mediated coronary arteriosclerosis. We included all patients undergoing a retransplantation for late terminal heart allograft failure in three referral centers. We performed an integrative strategy of heart allograft phenotyping by assessing the heart vascular tree including histopathology and immunohistochemistry together with circulating donor-specific antibodies. The main analysis included 40 explanted heart allografts patients and 402 endomyocardial biopsies performed before allograft loss. Overall, antibody-mediated rejection was observed in 19 (47.5%) failing heart allografts including 16 patients (40%) in whom unrecognized previous episodes of subclinical antibody-mediated rejection occurred 4.5 ± 3.5 years before allograft loss. Explanted allografts with evidence of antibody-mediated rejection demonstrated higher endothelitis and microvascular inflammation scores (0.89 ± 0.26 and 2.25 ± 0.28, respectively) compared with explanted allografts without antibody-mediated rejection (0.42 ± 0.11 and 0.36 ± 0.09, p = 0.046 and p < 0.0001, respectively). Antibody-mediated injury was observed in 62.1% of failing allografts with pure coronary arteriosclerosis and mixed (arteriosclerosis and atherosclerosis) pattern, while it was not observed in patients with pure coronary atherosclerosis (p = 0.0076). We demonstrate that antibody-mediated rejection is operating in a substantial fraction of failing heart allografts and is associated with severe coronary arteriosclerosis. Unrecognized subclinical antibody-mediated rejection episodes may be observed years before allograft failure.

  1. Preformed donor HLA-DP-specific antibodies mediate acute and chronic antibody-mediated rejection following renal transplantation.

    PubMed

    Jolly, E C; Key, T; Rasheed, H; Morgan, H; Butler, A; Pritchard, N; Taylor, C J; Clatworthy, M R

    2012-10-01

    Donor-specific HLA alloantibodies may cause acute and chronic antibody-mediated rejection (AMR) and significantly compromise allograft survival. The clinical relevance of antibodies directed against some HLA class II antigens, particularly HLA-DP, is less clear with conflicting reports on their pathogenicity. We report two patients with high levels of pretransplant donor-specific HLA-DP antibodies who subsequently developed recurrent acute AMR and graft failure. In both cases, there were no other donor-specific HLA alloantibodies, suggesting that the HLA-DP-specific antibodies may be directly pathogenic.

  2. [Antibody-mediated rejection of renal allograft and the update Banff classification 2013].

    PubMed

    Honsová, Eva

    2015-01-01

    The view on the role of donor-specific antibodies in organ transplantation has been changed during the last several decades. Today, it is considered that the majority of cases of the late renal allograft dysfunction and loss are caused by the presence of donor-specific antibodies to HLA antigens. The real breakthrough in the diagnosis of antibody-mediated rejection was represented by the discovery of C4d, which enabled the determination of the diagnostic criteria of acute and later chronic antibody-mediated rejection. Although detection of C4d has been the cornerstone in the diagnosis of antibody-mediated rejection for over 10 years, it has become clear that some cases with similar morphological and clinical features do not have detectable C4d. Outcomes of key studies concerning presence of donor specific antibodies and morphological features in the graft biopsy samples resulted in the modification of Banff classification of 2013, which includes integrating C4d negative antibody-mediated rejection and also that acute vascular rejection (v1, v2) can be a part of the antibody-mediated rejection.

  3. Bortezomib-based treatment of acute antibody-mediated rejection: a case report.

    PubMed

    Wang, Q; Li, X L; Xu, X G; Shi, B Y; Zhang, Z M; Li, Z L; Han, Y; Zhou, W Q; Chen, C Q; Cai, M; Zhang, X

    2015-12-22

    Antibody-mediated rejection (AMR) is an important factor affecting survival after renal transplantation. A highly selective proteasome inhibitor, bortezomib, clears activated plasma cells from the body and has important therapeutic effect on AMR. We investigated the effects of bortezomib on AMR in a patient after a second renal transplant. Biopsy confirmed the diagnosis of mixed cellular rejection and AMR. Bortezomib was administered on day 1 (1.3 mg/m(2)), day 4 (1.0 mg/m(2)), and day 8 (1.0 mg/m(2)). On the same days, 250 mg methylprednisolone was administered once, and cyclosporine dose (5 mg·kg(-1)·day(-1)) was reduced by 50%. Oral mycophenolate mofetil and steroid were withdrawn on day 1 of bortezomib treatment. Intermittent double-filtration plasmapheresis was also performed. We monitored parameters, including T lymphocyte subsets, CD139 and CD19 expression, panel reactive antibody (PRA), and serum creatinine concentration. At follow-up 6 months after bortezomib treatment, we observed: 1) serum creatinine stabilized at 130 μM from a peak level of 337 μM; 2) PRA decreased from a maximum of 66.7 to 0%; 3) blood plasma cell percentage rebounded after significantly decreasing following the first dose of bortezomib; 4) in renal allograft biopsy, immunohistochemical staining for C4d shifted from strongly positive to negative, and cellular rejection shifted from type IIA to borderline; and 5) adverse effects such as platelet suppression, hypotension, and grade 3 peripheral neuropathy emerged. Bortezomib effectively treated antibody-mediated renal transplantation rejection in this case study, but clinical trials with large sample sizes are still needed to explore clinical safety and tolerability.

  4. B cells display an abnormal distribution and an impaired suppressive function in patients with chronic antibody-mediated rejection.

    PubMed

    Nouël, Alexandre; Ségalen, Isabelle; Jamin, Christophe; Doucet, Laurent; Caillard, Sophie; Renaudineau, Yves; Pers, Jacques-Olivier; Le Meur, Yannick; Hillion, Sophie

    2014-03-01

    In kidney transplantation, the composition of the B-cell compartment is increasingly identified as an important determinant for graft outcome. Whereas naive and transitional B cells have been associated with long-term allograft survival and operational tolerance, memory B cells have been linked to graft rejection and graft loss. Chronic antibody-mediated rejection now represents a major complication in transplantation and is a challenge in current therapeutics. Here, we show that patients with chronic antibody-mediated rejection display a unique B-cell phenotype with a reduced ratio of activated to memory B cells associated with an impaired immunosuppressive activity. The regulatory functions of the B cells depended on their maturation status. Thus, phenotypic and functional analyses of the B-cell compartment may be indicated for appropriate follow-up after transplantation and drive therapy in the establishment of transplant tolerance processes.

  5. Treatment of simultaneous acute antibody-mediated rejection and acute cellular rejection with alemtuzumab in kidney transplantation: a case report.

    PubMed

    Jirasiritham, S; Khunprakant, R; Techawathanawanna, N; Jirasiritham, Si; Mavichak, V

    2010-04-01

    This is a case report of a living related donor kidney transplantation using basiliximab induction and maintenance immunosuppression with cyclosporine, mycophenolate sodium, and steroid. On the second posttransplant day, the patient developed acute antibody-mediated rejection, which was treated with plasmapheresis and intravenous immunoglobulin (IVIG). Five days later, the graft had still not responded to the treatment. Another biopsy revealed additional acute cellular rejection (Banff IIA). As alemtuzumab can rapidly deplete T and B lymphocytes, monocytes, and natural killer cells, the patient was treated with alemtuzumab (30 mg subcutaneously) together with methylprednisolone (500 mg) and two more plasmaphereses. The kidney graft responded within 48 hours, producing more than 4 L of urine per day. The total lymphocyte decreased from 530/microL to 50/microL remaining in the 50 to 220/microL range. The patient received valgancyclovir and cotrimoxazole as infection prophylaxis. The kidney graft responded well to the rescue treatment and the patient was discharged with a serum creatinine of 1.1 mg/mL and has been uneventfully followed in the outpatient clinic for 8 months. Today, with the potent, effective, and selective immunosuppressive regimens, the rate and severity of acute cellular rejection in kidney transplantation has decreased in most centers. However, the rate of acute antibody-mediated rejection has increased to levels greater than those of acute cellular rejection in many centers. Acute antibody-mediated rejection is more difficult and expensive to treat successfully. The treatment of acute antibody-mediated rejection included plasmapheresis and IVIG. Herein we have reported a case of kidney transplantation simultaneously developing acute antibody-mediated and acute cellular rejection; the patient was successfully treated with alemtuzumab.

  6. Antibody-mediated rejection in kidney transplantation: a review of pathophysiology, diagnosis, and treatment options.

    PubMed

    Kim, Miae; Martin, Spencer T; Townsend, Keri R; Gabardi, Steven

    2014-07-01

    Antibody-mediated rejection (AMR), also known as B-cell-mediated or humoral rejection, is a significant complication after kidney transplantation that carries a poor prognosis. Although fewer than 10% of kidney transplant patients experience AMR, as many as 30% of these patients experience graft loss as a consequence. Although AMR is mediated by antibodies against an allograft and results in histologic changes in allograft vasculature that differ from cellular rejection, it has not been recognized as a separate disease process until recently. With an improved understanding about the importance of the development of antibodies against allografts as well as complement activation, significant advances have occurred in the treatment of AMR. The standard of care for AMR includes plasmapheresis and intravenous immunoglobulin that remove and neutralize antibodies, respectively. Agents targeting B cells (rituximab and alemtuzumab), plasma cells (bortezomib), and the complement system (eculizumab) have also been used successfully to treat AMR in kidney transplant recipients. However, the high cost of these medications, their use for unlabeled indications, and a lack of prospective studies evaluating their efficacy and safety limit the routine use of these agents in the treatment of AMR in kidney transplant recipients.

  7. [Immunosuppressive treatment after kidney transplant: the frontier of chronic antibody-mediated rejection].

    PubMed

    Biancone, Luigi; Lavacca, Antonio; Beltramo, Silvia; Ariaudo, Claudia; Gallo, Ester; Segoloni, Giuseppe Paolo

    2012-01-01

    The recognition of antibody-mediated rejection as an important factor in the reduction of long-term renal graft survival represents a new challenge to the immunosuppressive strategies of recent years, which have been quite successful in reducing the acute rejection rates as well as the side effects of pharmacological immunosuppression. The search for an effective treatment of chronic anti-donor antibody disease has been pursued mostly through limited single-center experiences and therefore in a dispersed fashion, without leading to the definition of a consolidated approach. The most frequently used pharmacological approaches stem from the experience of antibody-mediated acute rejection. In this review we will critically analyze the results reported so far of various intervention strategies and we will discuss future pharmacological novelties targeting the humoral immune response.

  8. Complement inhibition as potential new therapy for antibody-mediated rejection.

    PubMed

    Eskandary, Farsad; Wahrmann, Markus; Mühlbacher, Jakob; Böhmig, Georg A

    2016-04-01

    Antibody-mediated rejection (ABMR) is a leading cause of kidney allograft failure. While the exact mechanisms contributing to donor-specific antibody (DSA)-triggered tissue injury are still incompletely understood, complement activation via the classical pathway is believed to be one of the key players. There is now growing interest in complement blockade as an antirejection treatment. One attractive strategy may be inhibition of terminal complex formation using anti-C5 antibody eculizumab. Anecdotal reports, case series, and a unique cohort of flow crossmatch-positive live donor kidney transplant recipients subjected to eculizumab-based desensitization have demonstrated successful prevention and reversal of acute clinical ABMR. Nevertheless, maybe due to complement activation steps proximal of C5 or even complement-independent mechanisms, subclinical rejection processes that might culminate in chronic injury were found to escape inhibition. Larger studies designed to clarify the actual clinical value of terminal complement inhibition as an antirejection treatment are currently underway. In addition, alternative concepts, such as therapies that target key component C1, are currently under development, and we will see in the near future whether new strategies in the pipeline will have the potential to beneficially impact clinical practice.

  9. A case of chronic antibody-mediated rejection in the making.

    PubMed

    Bravou, Vasiliki; Galliford, Jack; McLean, Adam; Willicombe, Michelle; Taube, David; Cook, Herbert T; Roufosse, Candice

    2013-10-01

    A kidney transplant recipient developed chronic antibody-mediated rejection (ABMR) with clinically significant transplant glomerulopathy while under careful clinical monitoring. The patient developed a de novo donor-specific antibody (DSA) posttransplantation, and a protocol renal biopsy showed C4d deposition with no histological evidence of rejection. Subsequently he developed peritubular capillary basement membrane multilayering, with negative C4d and DSA. Finally, he developed proteinuria and transplant glomerulopathy, with reappearance of DSA and C4d. Despite having a de novo antibody and progressive antibody-mediated damage, this patient under close histological and serological surveillance did not fulfill Banff criteria for acute or chronic ABMR until his disease was advanced. This case illustrates the limitations of current Banff criteria in this setting, due to the fluctuating nature of DSA and C4d staining.

  10. Expanding the antibody-mediated component of plasma cell-rich acute rejection: A case series

    PubMed Central

    Uppin, M. S.; Gudithi, S.; Taduri, G.; Prayaga, A. K.; Raju, S. B.

    2016-01-01

    Renal allograft rejection is mediated by T-cells (T-cell mediated rejection) or by donor-specific antibodies (DSAs) (antibody mediated rejection, ABMR). Plasma cell-rich acute rejection (PCAR) is a unique entity due to its peculiar morphology and poor prognostic behavior. All allograft biopsies done at our center from January 2013 to October 2014 were reviewed, and seven were identified with a diagnosis of PCAR with antibody mediated rejection (ABMR). The allograft biopsies were classified as per the Banff 2007 schema. Immunohistochemistry with C4d, SV 40, CD3, CD20, CD138, kappa and lambda light chain was performed. Total 210 allograft biopsies were performed in the study period of which seven biopsies (3.3%) were diagnosed as PCAR with ABMR. All these were late ABMRs (more than 6 months) with median posttransplant duration of 17 months. The allograft biopsy showed features of PCAR along with glomerulitis, peritubular capillaritis, and positive C4d. DSA was positive in six patients. All the patients were treated with standard therapeutic measures of acute cellular rejection (ACR) and ABMR including steroids, plasma exchange, rituximab and intravenous immunoglobulins. All the patients had persistent graft dysfunction or graft loss on follow-up. PMID:27194831

  11. Challenges inherent to the diagnosis of antibody-mediated rejection in lung transplantation

    PubMed Central

    Chin, Nicholas; Westall, Glen; Paraskeva, Miranda; Ciciulla, John; Cantwell, Linda; Snell, Greg

    2015-01-01

    A bilateral sequential lung transplant was performed on a young female with cystic fibrosis-related bronchiectasis. She had negative prospective T- and B-cell crossmatch, and no known donor-specific antibodies. Post-transplantation, she developed bilateral pulmonary infiltrates of uncertain etiology, compounded by persistent tachycardia and questionable medication adherence. Despite aggressive intervention for suspected cellular rejection with high-dose intravenous corticosteroid, immunoglobulin, and anti-thymocyte globulin, her condition deteriorated to ultimately require ventilatory support. The eventual discovery of eplet donor-recipient mismatches on related DQB1 alleles raised the diagnosis of antibody-mediated rejection. Before plasmapheresis could be instituted, the patient rapidly succumbed to respiratory failure. Postmortem examination confirmed features of atypical allograft rejection, without evidence of classic acute cellular rejection. This is an unconventional case of antibody-mediated lung allograft rejection – an entity that is currently a difficult diagnostic and therapeutic challenge. Prevention of donor-specific antibodies by correct donor-recipient matching, and optimizing adherence post-transplantation are most important. PMID:25802749

  12. Better understanding of transplant glomerulopathy secondary to chronic antibody-mediated rejection.

    PubMed

    Remport, Adam; Ivanyi, Bela; Mathe, Zoltan; Tinckam, Kathryn; Mucsi, Istvan; Molnar, Miklos Z

    2015-11-01

    Transplant glomerulopathy (TG) is generally accepted to result from repeated episodes of endothelial activation, injury and repair, leading to pathological abnormalities of double contouring or multi-layering of the glomerular basement membrane. TG is a major sequel of chronic active antibody-mediated rejection (cABMR), from pre-existing or de novo anti-HLA antibodies. Hepatitis C infection, thrombotic microangiopathy or other factors may also contribute to TG development. TG prevalence is 5-20% in most series, reaching 55%, in some high-risk cohorts, and is associated with worse allograft outcomes. Despite its prevalence and clinical significance, few well-studied treatment options have been proposed. Similar to desensitization protocols, plasmapheresis with or without immunoabsorption, high-dose intravenous immunoglobulin, rituximab, bortezomib and eculizumab have been proposed in the treatment of TG due to cABMR individually or in various combinations. Robust clinical trials are urgently needed to address this major cause of allograft loss. This review summarizes the current knowledge of the epidemiology, etiology, pathology, and the preventive and treatment options for TG secondary to cABMR.

  13. Endothelial Cells in Antibody-Mediated Rejection of Kidney Transplantation: Pathogenesis Mechanisms and Therapeutic Implications

    PubMed Central

    Wang, Shuo; Wang, Jina; Yang, Cheng; Xu, Ming

    2017-01-01

    Antibody-mediated rejection (AMR) has been identified as a main obstacle for stable immune tolerance and long survival of kidney allografts. In spite of new insights into the underlying mechanisms of AMR, accurate diagnosis and efficient treatment are still challenges in clinical practice. Endothelium is the first barrier between recipients' immune systems and grafts in vascularized organ transplants. Considering that endothelial cells express a number of antigens that can be attacked by various allo- and autoantibodies, endothelial cells act as main targets for the recipients' humoral immune responses. Importantly, emerging evidence has shown that endothelial cells in transplants could also initiate protective mechanisms in response to immune injuries. A better understanding of the role of endothelial cells during the pathogenesis of AMR might provide novel therapeutic targets. In the present review, we summarize the antigens expressed by endothelial cells and also discuss the activation and accommodation of endothelial cells as well as their clinical implications. Collectively, the progress discussed in this review indicates endothelial cells as promising targets to improve current diagnosis and therapeutic regimens for AMR. PMID:28255564

  14. Atypical HUS associated with severe, unexpected antibody-mediated rejection post kidney transplant.

    PubMed

    Stevenson, Sarah; Mallett, Andrew; Oliver, Kimberley; Hyland, Valentine; Hawley, Carmel; Malmanche, Theo; Isbel, Nicole

    2014-04-01

    We present a case of an unsensitized patient with end-stage kidney disease secondary to atypical haemolytic uremic syndrome (aHUS) with mutations in CD46/MCP and CFH who developed severe, intractable antibody-mediated rejection (ABMR) unresponsive to therapy post kidney transplantation. There were no haematological features of thrombotic microangiopathy. The patient received standard induction therapy and after an initial fall in serum creatinine, severe ABMR developed in the setting of urosepsis. Despite maximal therapy with thymoglobulin, plasma exchange and methylprednisolone, rapid graft loss resulted and transplant nephrectomy was performed. Luminex at 4 weeks showed a new DSA and when repeated after nephrectomy showed antibodies to each of the 5 mismatched antigens with high MFI. The rate of recurrence of disease in patients with aHUS referred for transplantation is 50% and is associated with a high rate of graft loss. It is dependent in part on the nature of the mutation with circulating factors CFH and CFI more likely to cause recurrent disease than MCP which is highly expressed in the kidney. There is increasing interest in the role of complement in the development and propagation of ABMR via terminal complement activation. This case suggesting that dysregulation of the alternative complement pathway within the transplant kidney may have contributed to the severe AMR. Very little is known about the impact of complement dysregulation and the development of anti HLA antibodies however the strength of HLA antibody formation was prominent in this case.

  15. Endothelial Cells in Antibody-Mediated Rejection of Kidney Transplantation: Pathogenesis Mechanisms and Therapeutic Implications.

    PubMed

    Wang, Shuo; Zhang, Chao; Wang, Jina; Yang, Cheng; Xu, Ming; Rong, Ruiming; Zhu, Tongyu; Zhu, Dong

    2017-01-01

    Antibody-mediated rejection (AMR) has been identified as a main obstacle for stable immune tolerance and long survival of kidney allografts. In spite of new insights into the underlying mechanisms of AMR, accurate diagnosis and efficient treatment are still challenges in clinical practice. Endothelium is the first barrier between recipients' immune systems and grafts in vascularized organ transplants. Considering that endothelial cells express a number of antigens that can be attacked by various allo- and autoantibodies, endothelial cells act as main targets for the recipients' humoral immune responses. Importantly, emerging evidence has shown that endothelial cells in transplants could also initiate protective mechanisms in response to immune injuries. A better understanding of the role of endothelial cells during the pathogenesis of AMR might provide novel therapeutic targets. In the present review, we summarize the antigens expressed by endothelial cells and also discuss the activation and accommodation of endothelial cells as well as their clinical implications. Collectively, the progress discussed in this review indicates endothelial cells as promising targets to improve current diagnosis and therapeutic regimens for AMR.

  16. Not All Antibodies Are Created Equal: Factors That Influence Antibody Mediated Rejection

    PubMed Central

    Butler, Carrie L.; Valenzuela, Nicole M.; Thomas, Kimberly A.

    2017-01-01

    Consistent with Dr. Paul Terasaki's “humoral theory of rejection” numerous studies have shown that HLA antibodies can cause acute and chronic antibody mediated rejection (AMR) and decreased graft survival. New evidence also supports a role for antibodies to non-HLA antigens in AMR and allograft injury. Despite the remarkable efforts by leaders in the field who pioneered single antigen bead technology for detection of donor specific antibodies, a considerable amount of work is still needed to better define the antibody attributes that are associated with AMR pathology. This review highlights what is currently known about the clinical context of pre and posttransplant antibodies, antibody characteristics that influence AMR, and the paths after donor specific antibody production (no rejection, subclinical rejection, and clinical dysfunction with AMR). PMID:28373996

  17. Effective therapy for acute antibody-mediated rejection with mild chronic changes: case report and review of the literature.

    PubMed

    Gheith, Osama; Al-Otaibi, Torki; Nampoory, Narayanan; Halim, Medhat; Nair, Prasad; Saied, Tarek; Al-Waheeb, Salah; Muzeirei, Ibraheem; Ibraheim, Mona

    2012-08-01

    To reduce the long-term toxicities of immunosuppressant drugs, corticosteroid-sparing and calcineurin-inhibitor-sparing immunosuppression protocols have become increasingly popular in managing kidney transplant recipients. The most vexing clinical condition caused by antibodies in organ transplants is antibody-mediated rejection. Limitations of the current antibody-mediated rejection therapies include (1) antibody-mediated rejection reversal tends to be gradual rather than prompt, (2) expense, (3) rejection reversal rates below 80%, (4) common appearance of chronic rejection after antibody-mediated rejection treatment, and (5) long-term persistence of donor specific antibodies after therapy. Because these limitations may be due to a lack of effects on mature plasma cells, the effects of bortezomib on mature plasma cells may represent a quantum advance in antihumoral therapy. Our experiences represent the first clinical use of bortezomib as an antihumoral agent in renal allograft recipients in Kuwait. We present 2 cases with resistant-acute antibody-mediated rejection to the standard therapies that were managed successfully with bortezomib.

  18. Complement Inhibition for Prevention and Treatment of Antibody-Mediated Rejection in Renal Allograft Recipients.

    PubMed

    Jordan, S C; Choi, J; Kahwaji, J; Vo, A

    2016-04-01

    Therapeutic interventions aimed at the human complement system are recognized as potentially important strategies for the treatment of inflammatory and autoimmune diseases because there is often evidence of complement-mediated injury according to pathologic assessments. In addition, there are a large number of potential targets, both soluble and cell bound, that might offer potential for new drug development, but progress in this area has met with significant challenges. Currently, 2 drugs are approved aimed at inhibition of complement activation. The first option is eculizumab (anti-C5), which is approved for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Eculizumab has also been studied in human transplantation for the treatment and prevention of antibody-mediated rejection (ABMR). Initial data from uncontrolled studies suggested a significant benefit of eculizumab for the prevention of ABMR in highly HLA-sensitized patients, but a subsequent randomized, placebo-controlled trial failed to meet its primary endpoint. Anecdotal data, primarily from case studies, showed benefits in treating complement-mediated ABMR. A second approved complement-inhibiting therapy is C1 esterase inhibitor (C1-INH), which is approved for use in patients with hereditary angioedema, a condition caused by mutations in the gene that codes for C1-INH. A recent placebo-controlled trial of C1-INH for prevention of ABMR in HLA-sensitized patients found that the drug was safe, with evidence for inhibition of systemic complement activation and complement-activating donor-specific antibodies. Other drugs are now under development.

  19. Acute antibody-mediated rejection after ABO-incompatible kidney transplantation treated successfully with antigen-specific immunoadsorption.

    PubMed

    Just, Søren Andreas; Marcussen, Niels; Sprogøe, Ulrik; Koefoed-Nielsen, Pernille; Bistrup, Claus

    2010-01-01

    ABO-incompatible kidney transplantation is possible after pre-treatment with rituximab, intravenous immunoglobulin and basiliximab combined with tacrolimus, mycophenolate mofetil and prednisolone. We report on the first patient treated with this protocol who developed acute antibody-mediated rejection (Banff grade II with IgG deposits) caused by ABO antibodies (anti-B). Anti-rejection treatment with anti-B-specific immunoadsorption, intravenous immunoglobulin and methylprednisolone efficiently cleared deposited IgG from the kidney allograft and re-established normal kidney function. We suggest that ABO-incompatible kidney transplantation complicated by acute antibody-mediated rejection, caused by ABO antibodies, may successfully be treated with this regime.

  20. A severe Mycoplasma pneumoniae pneumonia inducing an acute antibody-mediated pulmonary graft rejection

    PubMed Central

    Démir, Sarah; Saison, Julien; Sénéchal, Agathe; Mornex, Jean-Francois

    2017-01-01

    A 40-year-old cystic fibrosis woman with a history of double-lung transplantation 2 years previously was admitted for a progressive respiratory distress. Physical examination revealed fever (39°C) and diffuse bilateral lung crackles. Laboratory findings included severe hypoxemia and inflammatory syndrome. Bronchoalveolar lavage and serological test were positive for mycoplasma pneumonia. As the patient did not improve after 3 days of antibiotics and donor-specific HLA antibodies had been detected, an acute antibody-mediated graft rejection was treated with high-dose corticosteroids, plasma exchange, intravenous immunoglobulin, and rituximab. The patient rapidly improved. Unfortunately, 6 months after this episode, she developed a bronchiolitis obliterans syndrome with a dependence to noninvasive ventilator leading to the indication of retransplantation. This case illustrates the possible relationship between infection and humoral rejection. These two diagnoses should be promptly investigated and systematically treated in lung transplant recipients. PMID:28144069

  1. A type I interferon signature characterizes chronic antibody-mediated rejection in kidney transplantation.

    PubMed

    Rascio, Federica; Pontrelli, Paola; Accetturo, Matteo; Oranger, Annarita; Gigante, Margherita; Castellano, Giuseppe; Gigante, Maddalena; Zito, Anna; Zaza, Gianluigi; Lupo, Antonio; Ranieri, Elena; Stallone, Giovanni; Gesualdo, Loreto; Grandaliano, Giuseppe

    2015-09-01

    Chronic antibody-mediated rejection (CAMR) represents the main cause of kidney graft loss. To uncover the molecular mechanisms underlying this condition, we characterized the molecular signature of peripheral blood mononuclear cells (PBMCs) and, separately, of CD4(+) T lymphocytes isolated from CAMR patients, compared to kidney transplant recipients with normal graft function and histology. We enrolled 29 patients with biopsy-proven CAMR, 29 stable transplant recipients (controls), and 8 transplant recipients with clinical and histological evidence of interstitial fibrosis/tubular atrophy. Messenger RNA and microRNA profiling of PBMCs and CD4(+) T lymphocytes was performed using Agilent microarrays in eight randomly selected patients per group from CAMR and control subjects. Results were evaluated statistically and by functional pathway analysis (Ingenuity Pathway Analysis) and validated in the remaining subjects. In PBMCs, 45 genes were differentially expressed between the two groups, most of which were up-regulated in CAMR and were involved in type I interferon signalling. In the same patients, 16 microRNAs were down-regulated in CAMR subjects compared to controls: four were predicted modulators of six mRNAs identified in the transcriptional analysis. In silico functional analysis supported the involvement of type I interferon signalling. To further confirm this result, we investigated the transcriptomic profiles of CD4(+) T lymphocytes in an independent group of patients, observing that the activation of type I interferon signalling was a specific hallmark of CAMR. In addition, in CAMR patients, we detected a reduction of circulating BDCA2(+) dendritic cells, the natural type I interferon-producing cells, and their recruitment into the graft along with increased expression of MXA, a type I interferon-induced protein, at the tubulointerstitial and vascular level. Finally, interferon alpha mRNA expression was significantly increased in CAMR compared to control

  2. Morphologic and immunohistochemical findings in antibody-mediated rejection of the cardiac allograft.

    PubMed

    Fishbein, Gregory A; Fishbein, Michael C

    2012-12-01

    The recognition and acceptance of the entity of antibody-mediated rejection (AMR) of solid organs has been slow to develop. Greatest acceptance and most information relates to cardiac transplantation. AMR is thought to represent antibody/complement mediated injury to the microvasculature of the graft that can result in allograft dysfunction, allograft loss, accelerated graft vasculopathy, and increased mortality. The morphologic hallmark is microvascular injury with immunoglobulin and complement deposition in capillaries, accumulation of intravascular macrophages, and in more severe cases, microvascular hemorrhage and thrombosis, with inflammation and edema of the affected organ. Understanding of the pathogenesis of AMR, criteria and methods for diagnosis, and treatment strategies are still in evolution, and will be addressed in this review.

  3. Current and future challenges in therapy for antibody-mediated rejection.

    PubMed

    Nair, Nandini; Ball, Timothy; Uber, Patricia A; Mehra, Mandeep R

    2011-06-01

    Antibody-mediated rejection (AMR) continues to present a challenge for the survival of the cardiac allograft. AMR appears to be on the rise, likely secondary to changing trends in clinical practice, including selection of patients for transplantation on mechanical circulatory support and development of more effective combinations of immunosuppressive drugs against acute cellular rejection. Most current strategies are aimed at treating acute AMR, but the treatment of chronic AMR is still not well defined. Clinically, AMR can often be more severe than cellular rejection and more difficult to treat, often not responding to typical protocols of increased immunosuppression. Complex steps involved in the antibody response allows for several potential targets for therapeutic intervention, including suppression of T and B cells, elimination of circulating antibodies, and inhibition of residual antibodies. Existing evidence suggests a multiregimen approach is the best option. Sustenance of accommodation and induction of tolerance could be viewed as viable options if adequate immune surveillance can be achieved in this setting. This review discusses the challenges in treating AMR and provides a critical analysis of current and possible future therapies.

  4. Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence.

    PubMed

    Sellarés, J; de Freitas, D G; Mengel, M; Reeve, J; Einecke, G; Sis, B; Hidalgo, L G; Famulski, K; Matas, A; Halloran, P F

    2012-02-01

    We prospectively studied kidney transplants that progressed to failure after a biopsy for clinical indications, aiming to assign a cause to every failure. We followed 315 allograft recipients who underwent indication biopsies at 6 days to 32 years posttransplant. Sixty kidneys progressed to failure in the follow-up period (median 31.4 months). Failure was rare after T-cell-mediated rejection and acute kidney injury and common after antibody-mediated rejection or glomerulonephritis. We developed rules for using biopsy diagnoses, HLA antibody and clinical data to explain each failure. Excluding four with missing information, 56 failures were attributed to four causes: rejection 36 (64%), glomerulonephritis 10 (18%), polyoma virus nephropathy 4 (7%) and intercurrent events 6 (11%). Every rejection loss had evidence of antibody-mediated rejection by the time of failure. Among rejection losses, 17 of 36 (47%) had been independently identified as nonadherent by attending clinicians. Nonadherence was more frequent in patients who progressed to failure (32%) versus those who survived (3%). Pure T-cell-mediated rejection, acute kidney injury, drug toxicity and unexplained progressive fibrosis were not causes of loss. This prospective cohort indicates that many actual failures after indication biopsies manifest phenotypic features of antibody-mediated or mixed rejection and also underscores the major role of nonadherence.

  5. Disappearance of T Cell-Mediated Rejection Despite Continued Antibody-Mediated Rejection in Late Kidney Transplant Recipients.

    PubMed

    Halloran, Philip F; Chang, Jessica; Famulski, Konrad; Hidalgo, Luis G; Salazar, Israel D R; Merino Lopez, Maribel; Matas, Arthur; Picton, Michael; de Freitas, Declan; Bromberg, Jonathan; Serón, Daniel; Sellarés, Joana; Einecke, Gunilla; Reeve, Jeff

    2015-07-01

    The prevalent renal transplant population presents an opportunity to observe the adaptive changes in the alloimmune response over time, but such studies have been limited by uncertainties in the conventional biopsy diagnosis of T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR). To circumvent these limitations, we used microarrays and conventional methods to investigate rejection in 703 unselected biopsies taken 3 days to 35 years post-transplant from North American and European centers. Using conventional methods, we diagnosed rejection in 205 biopsy specimens (28%): 67 pure TCMR, 110 pure ABMR, and 28 mixed (89 designated borderline). Using microarrays, we diagnosed rejection in 228 biopsy specimens (32%): 76 pure TCMR, 124 pure ABMR, and 28 mixed (no borderline). Molecular assessment confirmed most conventional diagnoses (agreement was 90% for TCMR and 83% for ABMR) but revealed some errors, particularly in mixed rejection, and improved prediction of failure. ABMR was strongly associated with increased graft loss, but TCMR was not. ABMR became common in biopsy specimens obtained >1 year post-transplant and continued to appear in all subsequent intervals. TCMR was common early but progressively disappeared over time. In 108 biopsy specimens obtained 10.2-35 years post-transplant, TCMR defined by molecular and conventional features was never observed. We conclude that the main cause of kidney transplant failure is ABMR, which can present even decades after transplantation. In contrast, TCMR disappears by 10 years post-transplant, implying that a state of partial adaptive tolerance emerges over time in the kidney transplant population.

  6. Successful Salvage Treatment of Resistant Acute Antibody-Mediated Kidney Transplant Rejection with Eculizumab.

    PubMed

    Khan, Saif A; Al-Riyami, Dawood; Al-Mula Abed, Yasser W; Mohammed, Saja; Al-Riyami, Marwa; Al-Lawati, Nabil M

    2016-08-01

    Antibody-mediated rejection (ABMR) jeopardises short- and long-term transplant survival and remains a challenge in the field of organ transplantation. We report the first use of the anticomplement agent eculizumab in Oman in the treatment of a 61-year-old female patient with ABMR following a living unrelated kidney transplant. The patient was admitted to the Sultan Qaboos University Hospital in Muscat, Oman, in 2013 on the eighth day post-transplantation with serum creatinine (Cr) levels of 400 µmol/L which continued to rise, necessitating haemodialysis. A biopsy indicated ABMR with acute cellular rejection. No improvement was observed following standard ABMR treatment and she continued to require dialysis. Five doses of eculizumab were administered over six weeks with a subsequent dramatic improvement in renal function. The patient became dialysis-free with serum Cr levels of 119 µmol/L within four months. This case report indicates that eculizumab is a promising agent in the treatment of ABMR.

  7. Microarray diagnosis of antibody-mediated rejection in kidney transplant biopsies: an international prospective study (INTERCOM).

    PubMed

    Halloran, P F; Pereira, A B; Chang, J; Matas, A; Picton, M; De Freitas, D; Bromberg, J; Serón, D; Sellarés, J; Einecke, G; Reeve, J

    2013-11-01

    In a reference set of 403 kidney transplant biopsies, we recently developed a microarray-based test that diagnoses antibody-mediated rejection (ABMR) by assigning an ABMR score. To validate the ABMR score and assess its potential impact on practice, we performed the present prospective INTERCOM study (clinicaltrials.gov NCT01299168) in 300 new biopsies (264 patients) from six centers: Baltimore, Barcelona, Edmonton, Hannover, Manchester and Minneapolis. We assigned ABMR scores using the classifier created in the reference set and compared it to conventional assessment as documented in the pathology reports. INTERCOM documented uncertainty in conventional assessment: In 41% of biopsies where ABMR features were noted, the recorded diagnoses did not mention ABMR. The ABMR score correlated with ABMR histologic lesions and donor-specific antibodies, but not with T cell-mediated rejection lesions. The agreement between ABMR scores and conventional assessment was identical to that in the reference set (accuracy 85%). The ABMR score was more strongly associated with failure than conventional assessment, and when the ABMR score and conventional assessment disagreed, only the ABMR score was associated with early progression to failure. INTERCOM confirms the need to reduce uncertainty in the diagnosis of ABMR, and demonstrates the potential of the ABMR score to impact practice.

  8. Key role for CD4 T cells during mixed antibody mediated rejection of renal allografts

    PubMed Central

    Gaughan, A.; Wang, J.; Pelletier, R.P.; Nadasdy, T.; Brodsky, S.; Roy, S.; Lodder, M.; Bobek, D.; Mofatt-Bruce, S.; Fairchild, R.L.; Henry, M.L.; Hadley, G.A.

    2014-01-01

    We utilized mouse models to elucidate the immunologic mechanisms of functional graft loss during mixed antibody mediated rejection of renal allografts (mixed AMR), in which humoral and cellular responses to the graft occur concomitantly. Although the majority of T cells in the graft at the time of rejection were CD8 T cells with only a minor population of CD4 T cells, depletion of CD4 but not CD8 cells prevented acute graft loss during mixed AMR. CD4 depletion eliminated anti-donor alloantibodies and conferred protection from destruction of renal allografts. ELISPOT revealed that CD4 T effectors responded to donor alloantigens by both the direct and indirect pathways of allorecognition. In transfer studies, CD4 T effectors primed to donor alloantigens were highly effective at promoting acute graft dysfunction, and exhibited the attributes of effector T cells. Laser capture microdissection and confirmatory immunostaining studies revealed that CD4 T cells infiltrating the graft produced effector molecules with graft destructive potential. Bioluminescent imaging confirmed that CD4 T effectors traffic to the graft site in immune replete hosts. These data document that host CD4 T cells can promote acute dysfunction of renal allografts by directly mediating graft injury in addition to facilitating anti-donor alloantibody responses. PMID:24410909

  9. Characterization of transfusion-elicited acute antibody-mediated rejection in a rat model of kidney transplantation.

    PubMed

    Huang, G; Wilson, N A; Reese, S R; Jacobson, L M; Zhong, W; Djamali, A

    2014-05-01

    Animal models of antibody-mediated rejection (ABMR) may provide important evidence supporting proof of concept. We elicited donor-specific antibodies (DSA) by transfusion of donor blood (Brown Norway RT1(n) ) into a complete mismatch recipient (Lewis RT1(l) ) 3 weeks prior to kidney transplantation. Sensitized recipients had increased anti-donor splenocyte IgG1, IgG2b and IgG2c DSA 1 week after transplantation. Histopathology was consistent with ABMR characterized by diffuse peritubular capillary C4d and moderate microvascular inflammation with peritubular capillaritis + glomerulitis > 2. Immunofluorescence studies of kidney allograft tissue demonstrated a greater CD68/CD3 ratio in sensitized animals, primarily of the M1 (pro-inflammatory) phenotype, consistent with cytokine gene analyses that demonstrated a predominant T helper (TH )1 (interferon-γ, IL-2) profile. Immunoblot analyses confirmed the activation of the M1 macrophage phenotype as interferon regulatory factor 5, inducible nitric oxide synthase and phagocytic NADPH oxidase 2 were significantly up-regulated. Clinical biopsy samples in sensitized patients with acute ABMR confirmed the dominance of M1 macrophage phenotype in humans. Despite the absence of tubulitis, we were unable to exclude the effects of T cell-mediated rejection. These studies suggest that M1 macrophages and TH 1 cytokines play an important role in the pathogenesis of acute mixed rejection in sensitized allograft recipients.

  10. ABO-compatible Liver Allograft Antibody-mediated Rejection: an update

    PubMed Central

    Demetris, Anthony J.; Zeevi, Adriana; O’Leary, Jacqueline G.

    2015-01-01

    Purpose Liver allograft antibody-mediated rejection (AMR) studies have lagged behind parallel efforts in kidney and heart because of a comparative inherent hepatic resistance to AMR. Three developments, however, have increased interest: 1) solid phase antibody testing enabled more precise antibody characterization; 2) increased expectations for long-term, morbidity-free survival; and 3) immunosuppression minimization trials. Recent Findings Two overlapping liver allograft AMR phenotypic expressions are beginning to emerge: acute and chronic AMR. Acute AMR usually occurs within the several weeks after transplantation and characterized clinically by DSA persistence, allograft dysfunction, thrombocytopenia, and hypocomplementemia. Acute AMR appears histopathologically similar to acute AMR in other organs: diffuse microvascular endothelial cell hypertrophy, C4d deposits, neutrophilic, eosinophilic, and macrophage-mediated microvasculitis/capillaritis, along with liver-specific ductular reaction, centrilobular hepatocyte swelling and hepatocanalicular cholestasis often combined with T cell-mediated rejection (TCMR). Chronic AMR is less well-defined, but strongly linked to serum class II DSA and associated with late-onset acute TCMR, fibrosis, chronic rejection and decreased survival. Unlike acute AMR, chronic AMR is a slowly evolving insult with a number of potential manifestations, but most commonly appears as low-grade lymphoplasmacytic portal and perivenular inflammation accompanied by unusual fibrosis patterns and variable microvascular C4d deposition; capillaritis is more difficult to identify than in acute AMR. Summary More precise DSA characterization, increasing expectations for long-term survival, and immunosuppression weaning precipitated a re-emergence of liver allograft AMR interest. Pathophysiological similarities exist between heart, kidney, and liver allografts, but liver-specific considerations may prove critical to our ultimate understanding of all

  11. A Probabilistic Approach to Histologic Diagnosis of Antibody-Mediated Rejection in Kidney Transplant Biopsies.

    PubMed

    Halloran, P F; Famulski, K S; Chang, J

    2017-01-01

    Histologic diagnosis of antibody-mediated rejection (ABMR) in kidney transplant biopsies uses lesion score cutoffs such as 0 versus >0 rather than actual scores and requires donor-specific antibody (DSA); however, cutoffs lose information, and DSA is not always reliable. Using microarray-derived molecular ABMR scores as a histology-independent estimate of ABMR in 703 biopsies, we reassessed criteria for ABMR to determine relative importance of various lesions, the utility of equations using actual scores rather than cutoffs, and the potential for diagnosing ABMR when DSA is unknown or negative. We confirmed that the important features for ABMR diagnosis were peritubular capillaritis (ptc), glomerulitis (g), glomerular double contours, DSA and C4d staining, but we questioned some features: arterial fibrosis, vasculitis, acute tubular injury, and sum of ptc+g scores. Regression equations using lesion scores predicted molecular ABMR more accurately than score cutoffs (area under the curve 0.85-0.86 vs. 0.75). DSA positivity improved accuracy, but regression equations predicted ABMR with moderate accuracy when DSA was unknown. Some biopsies without detectable DSA had high probability of ABMR by regression, although most had HLA antibody. We concluded that regression equations using lesion scores plus DSA maximized diagnostic accuracy and can estimate probable ABMR when DSA is unknown or undetectable.

  12. Eculizumab to treat antibody-mediated rejection in a 7-year-old kidney transplant recipient.

    PubMed

    Chehade, Hassib; Rotman, Samuel; Matter, Maurice; Girardin, Eric; Aubert, Vincent; Pascual, Manuel

    2015-02-01

    We report on successful early eculizumab administration to treat acute antibody-mediated rejection (ABMR) in a highly sensitized kidney transplant recipient. The recipient is a 7-year-old boy who received, 6 months after a desensitization protocol with monthly intravenous immunoglobulin infusion, a second kidney transplant in the presence of low donor-specific antibodies (DSAs). Both pretransplant lymphocytotoxic and flow cytometric crossmatch were negative. Allograft function recovered promptly, with excellent initial function. On postoperative day (POD) 4, the child developed significant proteinuria with an acute rise in serum creatinine. Allograft biopsy showed severe acute ABMR. Intravenous eculizumab (600 mg), preceded by a single session of plasmapheresis, was administered on POD 5 and 12 along with a 4-day thymoglobulin course. After the first dose of eculizumab, a strikingly rapid normalization of allograft function with a decrease in proteinuria occurred. However, because circulating DSA levels remained elevated, the child received 3 doses of intravenous immunoglobulin (POD 15, 16, and 17), with a significant subsequent decrease in DSA levels. At 9 months after transplant, the child continues to maintain excellent allograft function with undetectable circulating DSA levels. This unique case highlights the potential efficacy of using early eculizumab to rapidly reverse severe ABMR in pediatric transplantation, and therefore it suggests a novel therapeutic approach to treat acute ABMR.

  13. Asymptomatic Antibody-mediated Rejection After Heart Transplantation Predicts Poor Outcomes

    PubMed Central

    Wu, Grace W.; Kobashigawa, Jon A.; Fishbein, Michael C.; Patel, Jignesh K.; Kittleson, Michelle M.; Reed, Elaine F.; Kiyosaki, Krista K.; Ardehali, Abbas

    2013-01-01

    Background Antibody-mediated rejection (AMR) has been associated with poor outcome after heart transplantation. The diagnosis of AMR usually includes endomyocardial biopsy findings of endothelial cell swelling, intravascular macrophages, C4d+ staining, and associated left ventricular dysfunction. The significance of AMR findings in biopsy specimens of asymptomatic heart transplant patients (normal cardiac function and no symptoms of heart failure) is unclear. Methods Between July 1997 and September 2001, AMR was found in the biopsy specimens of 43 patients. Patients were divided into 2 groups: asymptomatic AMR (AsAMR, n = 21) and treated AMR (TxAMR with associated left ventricular dysfunction, n = 22). For comparison, a control group of 86 contemporaneous patients, without AMR, was matched for age, gender, and time from transplant. Outcomes included 5-year actuarial survival and development of cardiac allograft vasculopathy (CAV). Patients were considered to have AMR if they had ≥ 1 endomyocardial biopsy specimen positive for AMR. Results The 5-year actuarial survival for the AsAMR (86%), TxAMR (68%), and control groups (79%) was not significantly different (p = 0.41). Five-year freedom from CAV (≥ 30% stenosis in any vessel) was AsAMR, 52%; TxAMR, 68%; and control, 79%. Individually, freedom from CAV was significantly lower in the AsAMR group compared with the control group (p = 0.02). There was no significant difference between AsAMR vs TxAMR and TxAMR vs control for CAV. Conclusions Despite comparable 5-year survival with controls after heart transplantation, AsAMR rejection is associated with a greater risk of CAV. Trials to treat AsAMR to alter outcome are warranted. PMID:19416767

  14. Plasma cell-rich rejection accompanied by acute antibody-mediated rejection in a patient with ABO-incompatible kidney transplantation.

    PubMed

    Furuya, Maiko; Yamamoto, Izumi; Kobayashi, Akimitsu; Nakada, Yasuyuki; Sugano, Naoki; Tanno, Yudo; Ohkido, Ichiro; Tsuboi, Nobuo; Yamamoto, Hiroyasu; Yokoyama, Keitaro; Yokoo, Takashi

    2014-06-01

    We report a case of plasma cell-rich rejection accompanied by acute antibody-mediated rejection in a patient with ABO-incompatible kidney transplantation. A 33-year-old man was admitted for an episode biopsy; he had a serum creatinine (S-Cr) level of 5.7 mg/dL 1 year following primary kidney transplantation. Histological features included two distinct entities: (1) a focal, aggressive tubulointerstitial inflammatory cell (predominantly plasma cells) infiltration with moderate tubulitis; and (2) inflammatory cell infiltration (including neutrophils) in peritubular capillaries. Substantial laboratory examination showed that the patient had donor-specific antibodies for DQ4 and DQ6. Considering both the histological and laboratory findings, we diagnosed him with plasma cell-rich rejection accompanied by acute antibody-mediated rejection. We started 3 days of consecutive steroid pulse therapy three times every 2 weeks for the former and plasma exchange with intravenous immunoglobulin (IVIG) for the latter histological feature. One month after treatment, a second allograft biopsy showed excellent responses to treatment for plasma cell-rich rejection, but moderate, acute antibody-mediated rejection remained. Therefore, we added plasma exchange with IVIG again. After treatment, allograft function was stable, with an S-Cr level of 2.8 mg/dL. This case report demonstrates the difficulty of the diagnosis of, and treatment for, plasma cell-rich rejection accompanied by acute antibody-mediated rejection in a patient with ABO-incompatible kidney transplantation. We also include a review of the related literature.

  15. Eculizumab for Treatment of Refractory Antibody-Mediated Rejection in Kidney Transplant Patients: A Single-Center Experience.

    PubMed

    Yelken, B; Arpalı, E; Görcin, S; Kocak, B; Karatas, C; Demiralp, E; Turkmen, A

    2015-01-01

    Antibody-mediated rejection (AMR) is responsible for up to 20%-30% of acute rejection episodes after kidney transplantation. In several cases, conventional therapies including plasmapheresis, intravenous immunoglobulin, and anti-CD20 therapy can resolve AMR successfully. But in some cases the load of immunoglobulins that can activate complement cascade may submerge the routine desensitization therapy and result in the formation of membrane attack complexes. Eculizumab, a monoclonal antibody against C5, was reported to be an option in cases with severe AMR that are resistant to conventional therapy. Here, we present 8 cases that were resistant to conventional therapy and in which eculizumab was given as a salvage treatment. Given the bad prognosis for renal transplants displaying acute injury progressing rapidly to cortical necrosis on the biopsy, the prompt use of eculizumab could have the advantage of immediate effects by stopping cellular injury. This can provide a therapeutic window to allow conventional treatment modalities to be effective and prevent early graft loss.

  16. 2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection.

    PubMed

    Demetris, A J; Bellamy, C; Hübscher, S G; O'Leary, J; Randhawa, P S; Feng, S; Neil, D; Colvin, R B; McCaughan, G; Fung, J J; Del Bello, A; Reinholt, F P; Haga, H; Adeyi, O; Czaja, A J; Schiano, T; Fiel, M I; Smith, M L; Sebagh, M; Tanigawa, R Y; Yilmaz, F; Alexander, G; Baiocchi, L; Balasubramanian, M; Batal, I; Bhan, A K; Bucuvalas, J; Cerski, C T S; Charlotte, F; de Vera, M E; ElMonayeri, M; Fontes, P; Furth, E E; Gouw, A S H; Hafezi-Bakhtiari, S; Hart, J; Honsova, E; Ismail, W; Itoh, T; Jhala, N C; Khettry, U; Klintmalm, G B; Knechtle, S; Koshiba, T; Kozlowski, T; Lassman, C R; Lerut, J; Levitsky, J; Licini, L; Liotta, R; Mazariegos, G; Minervini, M I; Misdraji, J; Mohanakumar, T; Mölne, J; Nasser, I; Neuberger, J; O'Neil, M; Pappo, O; Petrovic, L; Ruiz, P; Sağol, Ö; Sanchez Fueyo, A; Sasatomi, E; Shaked, A; Shiller, M; Shimizu, T; Sis, B; Sonzogni, A; Stevenson, H L; Thung, S N; Tisone, G; Tsamandas, A C; Wernerson, A; Wu, T; Zeevi, A; Zen, Y

    2016-06-07

    The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.

  17. Severe antibody-mediated rejection following IVIG infusion in a kidney transplant recipient with BK-virus nephropathy.

    PubMed

    Mainra, R; Xu, Q; Chibbar, R; Hassan, A; Shoker, A

    2013-06-01

    Intravenous immune-globulin (IVIG) use in renal transplantation has increased, with common uses including desensitization, treatment of antibody mediated rejection and adjunctive therapy for BK virus nephropathy. Although considered generally safe, potential side effects can occur in up to 23% of patients including acute kidney injury. We present a case of an unexpected cause of acute kidney injury in a renal transplant recipient following IVIG infusion. A 48-year-old nonsensitized female with end stage renal disease secondary to polycystic kidney disease received a deceased donor kidney transplant. The initial post-transplant period was unremarkable however at three years post-transplant the patient develops BK virus nephropathy. Despite a reduction in immunosuppression, graft function worsened and IVIG infusion was commenced. Immediately following the IVIG infusion, the patient develops anuric acute kidney injury necessitating hemodialysis. Renal transplant biopsy performed before and after the IVIG infusion revealed the de novo development of acute antibody mediated rejection and donor specific antibodies in the serum. Anti-HLA and donor-specific antibodies were also confirmed in a diluted sample of the IVIG preparation. We argue that the anti-HLA antibodies present in the IVIG caused an acute antibody mediated rejection in this previously nonsensitized female.

  18. Treatment of Antibody-Mediated Renal Allograft Rejection: Improving Step by Step

    PubMed Central

    Duerr, Michael; Schönemann, Constanze; Pruß, Axel; Budde, Klemens; Waiser, Johannes

    2017-01-01

    Throughout the past years we stepwise modified our immunosuppressive treatment regimen for patients with antibody-mediated rejection (ABMR). Here, we describe three consecutive groups treated with different regimens. From 2005 until 2008, we treated all patients with biopsy-proven ABMR with rituximab (500 mg), low-dose (30 g) intravenous immunoglobulins (IVIG), and plasmapheresis (PPH, 6x) (group RLP, n = 12). Between 2009 and June 2010, patients received bortezomib (1.3 mg/m2, 4x) together with low-dose IVIG and PPH (group BLP, n = 11). In July 2010, we increased the IVIG dose and treated all subsequent patients with bortezomib, high-dose IVIG (1.5 g/kg), and PPH (group BHP, n = 11). Graft survival at three years after treatment was 73% in group BHP as compared to 45% in group BLP and 25% in group RLP. At six months after treatment median serum creatinine was 2.1 mg/dL, 2.9 mg/dL, and 4.2 mg/dL in groups BHP, BLP, and RLP, respectively (p = 0.02). Following treatment, a significant decrease of donor-specific HLA antibody (DSA) mean fluorescence intensity from 8467 ± 6876 to 5221 ± 4711 (p = 0.01) was observed in group BHP, but not in the other groups. Our results indicate that graft survival, graft function, and DSA levels could be improved along with stepwise modifications to our treatment regimen, that is, the introduction of bortezomib and high-dose IVIG treatment. PMID:28255562

  19. Treatment of acute antibody-mediated rejection using bortezomib: a case report.

    PubMed

    Sin, Yong-Hun; Kim, Yong-Jin; Oh, Joon Seok; Lee, Jin Ho; Kim, Seong Min; Kim, Joong Kyung

    2015-07-01

    Here we report the successful treatment of acute antibody-mediated rejection (AMR) with bortezomib. Bortezomib rescue treatment was administered after a 42-year-old woman failed to respond to steroid pulse and plasmapheresis with intravenous immunoglobulin (IVIG). The patient underwent a second renal transplantation with a deceased donor kidney. She was treated pre-operatively with rituximab (200 mg/body) and underwent plasmapheresis twice (day-1 and operation day) because ELISA screening revealed that her pre-operative peak panel reactive antibody (PRA) composition was 100% class I and 100% class II and 15 times of cross-match positive history during the waiting period for transplantation. The patients received induction therapy with Simulect (an IL-2-blocking agent). A 1-hour protocol biopsy revealed C4d-positivity and mild peritubular capillary inflammation. This was suggestive of early AMR-associated changes. After transplantation, the patient underwent plasmaphereses (nine times) with low-dose IVIG (2 mg/kg). Despite this treatment regimen, serum creatinine levels increased to 3.4 mg/dL on post-transplant day 15. A second graft biopsy was performed, which showed overt AMR with glomerulitis, peritubular capillary inflammation and no C4d deposition. On post-operative day (POD) 22, treatment with four doses of bortezomib (1.3 mg/m(2) ) was initiated with the patient's consent. On POD 55, renal function had recovered and serum creatinine was 1.5 mg/dL. In summary, bortezomib was administered as a rescue treatment for a patient who developed AMR that was refractory to a combination of plasmaphereses with low-dose IVIG and preemptive administration of rituximab.

  20. Antibody-mediated rejection in pediatric kidney transplantation: pathophysiology, diagnosis, and management.

    PubMed

    Ng, Yolanda W; Singh, Manpreet; Sarwal, Minnie M

    2015-04-01

    Kidney transplant is the preferred treatment of pediatric end-stage renal disease. One of the most challenging aspects of pediatric kidney transplant is the prevention and treatment of antibody-mediated rejection (ABMR), which is one of the main causes of graft dysfunction and early graft loss. Most challenges are similar to those faced in adult kidney transplants; however, factors unique to the pediatric realm include naivety of the immune system and the small number of studies and randomized controlled trials available when considering pharmacological treatment options. Here, we present a case of ABMR in a pediatric patient and a review of the pathophysiology, diagnosis, and management of ABMR. ABMR in pediatric kidney transplant continues to be a frustrating condition to treat because (1) there still remain many unidentified potential antigens leading to ABMR, (2) children and adults are at different stages of their immune system development, and, thus, (3) the full pathophysiology of alloimmunity is still not completely understood, and (4) the efficacy and safety of treatment in adults may not be directly translated to children. As we continue to gain a better understanding towards the precise alloimmune mechanism that drives a particular ABMR, we can also improve pharmacotherapeutic choices. With continued research, they will become more precise in treating a particular mechanism versus using a broad scope of immunosuppression such as steroids. However, there is much more to be uncovered, such as identifying more non-human leukocyte antigens and their role in alloimmunity, determining the exact mechanism of adults achieving complete operational tolerance, and understanding the difference between pediatric and adult transplant recipients. Making strides towards a better understanding of these mechanisms will lead to continued efficacy and safety in treatment of pediatric ABMR.

  1. Molecular microscope strategy to improve risk stratification in early antibody-mediated kidney allograft rejection.

    PubMed

    Loupy, Alexandre; Lefaucheur, Carmen; Vernerey, Dewi; Chang, Jessica; Hidalgo, Luis G; Beuscart, Thibaut; Verine, Jerome; Aubert, Olivier; Dubleumortier, Sébastien; Duong van Huyen, Jean-Paul; Jouven, Xavier; Glotz, Denis; Legendre, Christophe; Halloran, Philip F

    2014-10-01

    Antibody-mediated rejection (ABMR) is the leading cause of kidney allograft loss. We investigated whether the addition of gene expression measurements to conventional methods could serve as a molecular microscope to identify kidneys with ABMR that are at high risk for failure. We studied 939 consecutive kidney recipients at Necker Hospital (2004-2010; principal cohort) and 321 kidney recipients at Saint Louis Hospital (2006-2010; validation cohort) and assessed patients with ABMR in the first 1 year post-transplant. In addition to conventional features, we assessed microarray-based gene expression in transplant biopsy specimens using relevant molecular measurements: the ABMR Molecular Score and endothelial donor-specific antibody-selective transcript set. The main outcomes were kidney transplant loss and progression to chronic transplant injury. We identified 74 patients with ABMR in the principal cohort and 54 patients with ABMR in the validation cohort. Conventional features independently associated with failure were donor age and humoral histologic score (g+ptc+v+cg+C4d). Adjusting for conventional features, ABMR Molecular Score (hazard ratio [HR], 2.22; 95% confidence interval [95% CI], 1.37 to 3.58; P=0.001) and endothelial donor-specific antibody-selective transcripts (HR, 3.02; 95% CI, 1.00 to 9.16; P<0.05) independently associated with an increased risk of graft loss. The results were replicated in the independent validation group. Adding a gene expression assessment to a traditional risk model improved the stratification of patients at risk for graft failure (continuous net reclassification improvement, 1.01; 95% CI, 0.57 to 1.46; P<0.001; integrated discrimination improvement, 0.16; P<0.001). Compared with conventional assessment, the addition of gene expression measurement in kidney transplants with ABMR improves stratification of patients at high risk for graft loss.

  2. Presentation and Outcomes of C4d-Negative Antibody-Mediated Rejection After Kidney Transplantation.

    PubMed

    Orandi, B J; Alachkar, N; Kraus, E S; Naqvi, F; Lonze, B E; Lees, L; Van Arendonk, K J; Wickliffe, C; Bagnasco, S M; Zachary, A A; Segev, D L; Montgomery, R A

    2016-01-01

    The updated Banff classification allows for the diagnosis of antibody-mediated rejection (AMR) in the absence of peritubular capillary C4d staining. Our objective was to quantify allograft loss risk in patients with consistently C4d-negative AMR (n = 51) compared with C4d-positive AMR patients (n = 156) and matched control subjects without AMR. All first-year posttransplant biopsy results from January 2004 through June 2014 were reviewed and correlated with the presence of donor-specific antibody (DSA). C4d-negative AMR patients were not different from C4d-positive AMR patients on any baseline characteristics, including immunologic risk factors (panel reactive antibody, prior transplant, HLA mismatch, donor type, DSA class, and anti-HLA/ABO-incompatibility). C4d-positive AMR patients were significantly more likely to have a clinical presentation (85.3% vs. 54.9%, p < 0.001), and those patients presented substantially earlier posttransplantation (median 14 [interquartile range 8-32] days vs. 46 [interquartile range 20-191], p < 0.001) and were three times more common (7.8% vs 2.5%). One- and 2-year post-AMR-defining biopsy graft survival in C4d-negative AMR patients was 93.4% and 90.2% versus 86.8% and 82.6% in C4d-positive AMR patients, respectively (p = 0.4). C4d-negative AMR was associated with a 2.56-fold (95% confidence interval, 1.08-6.05, p = 0.033) increased risk of graft loss compared with AMR-free matched controls. No clinical characteristics were identified that reliably distinguished C4d-negative from C4d-positive AMR. However, both phenotypes are associated with increased graft loss and thus warrant consideration for intervention.

  3. Difference in outcomes after antibody-mediated rejection between abo-incompatible and positive cross-match transplantations.

    PubMed

    Couzi, Lionel; Manook, Miriam; Perera, Ranmith; Shaw, Olivia; Ahmed, Zubir; Kessaris, Nicos; Dorling, Anthony; Mamode, Nizam

    2015-10-01

    Graft survival seems to be worse in positive cross-match (HLAi) than in ABO-incompatible (ABOi) transplantation. However, it is not entirely clear why these differences exist. Sixty-nine ABOi, 27 HLAi and 10 combined ABOi+HLAi patients were included in this retrospective study, to determine whether the frequency, severity and the outcome of active antibody-mediated rejection (AMR) were different. Five-year death-censored graft survival was better in ABOi than in HLAi and ABOi+HLAi patients (99%, 69% and 64%, respectively, P = 0.0002). Features of AMR were found in 38%, 95% and 100% of ABOi, HLAi and ABOi+HLAi patients that had a biopsy, respectively (P = 0.0001 and P = 0.001). After active AMR, a declining eGFR and graft loss were observed more frequently in HLAi and HLAi+ABOi than in ABOi patients. The poorer prognosis after AMR in HLAi and ABOi+HLAi transplantations was not explained by a higher severity of histological lesions or by a less aggressive treatment. In conclusion, ABOi transplantation offers better results than HLAi transplantation, partly because AMR occurs less frequently but also because outcome after AMR is distinctly better. HLAi and combined ABOi+HLAi transplantations appear to have the same outcome, suggesting there is no synergistic effect between anti-A/B and anti-HLA antibodies.

  4. Probable C4d-negative accelerated acute antibody-mediated rejection due to non-HLA antibodies.

    PubMed

    Niikura, Takahito; Yamamoto, Izumi; Nakada, Yasuyuki; Kamejima, Sahoko; Katsumata, Haruki; Yamakawa, Takafumi; Furuya, Maiko; Mafune, Aki; Kobayashi, Akimitsu; Tanno, Yudo; Miki, Jun; Yamada, Hiroki; Ohkido, Ichiro; Tsuboi, Nobuo; Yamamoto, Hiroyasu; Yokoo, Takashi

    2015-07-01

    We report a case of probable C4d-negative accelerated acute antibody-mediated rejection due to non-HLA antibodies. A 44 year-old male was admitted to our hospital for a kidney transplant. The donor, his wife, was an ABO minor mismatch (blood type O to A) and had Gitelman syndrome. Graft function was delayed; his serum creatinine level was 10.1 mg/dL at 3 days after transplantation. Open biopsy was performed immediately; no venous thrombosis was observed during surgery. Histology revealed moderate peritubular capillaritis and mild glomerulitis without C4d immunoreactivity. Flow cytometric crossmatching was positive, but no panel-reactive antibodies against HLA or donor-specific antibodies (DSAbs) to major histocompatibility complex class I-related chain A (MICA) were detected. Taken together, we diagnosed him with probable C4d-negative accelerated antibody-mediated rejection due to non-HLA, non-MICA antibodies, the patient was treated with steroid pulse therapy (methylprednisolone 500 mg/day for 3 days), plasma exchange, intravenous immunoglobulin (40 g/body), and rituximab (200 mg/body) were performed. Biopsy at 58 days after transplantation, at which time S-Cr levels were 1.56 mg/dL, found no evidence of rejection. This case, presented with a review of relevant literature, demonstrates that probable C4d-negative accelerated acute AMR can result from non-HLA antibodies.

  5. Intravenous immunoglobulins and rituximab therapy for severe transplant glomerulopathy in chronic antibody-mediated rejection: a pilot study.

    PubMed

    Bachelet, Thomas; Nodimar, Celine; Taupin, Jean-Luc; Lepreux, Sebastien; Moreau, Karine; Morel, Delphine; Guidicelli, Gwendaline; Couzi, Lionel; Merville, Pierre

    2015-05-01

    Outcome of patients with transplant glomerulopathy (TG) is poor. Using B-cell targeting molecules represent a rational strategy to treat TG during chronic antibody-mediated rejection. In this pilot study, 21 patients with this diagnosis received four doses of intravenous immunoglobulins and two doses of rituximab (IVIG/RTX group). They were retrospectively compared with a untreated control group of 10 patients. At 24 months post-biopsy, graft survival was similar and poor between the treated and the untreated group, 47% vs. 40%, respectively, p = 0.69. This absence of response of IVIG/RTX treatment was observed, regardless the phenotype of TG. Baseline estimated glomerular filtration rate (eGFR) and decline in eGFR during the first six months after the treatment were risk factors associated with 24-month graft survival. The IVIG/RTX therapy had a modest effect on the kinetics of donor-specific alloantibodies at M24, compared to the untreated group, not associated with an improvement in graft survival. The mean number of adverse events per patient was higher in the IVIG/RTX group than in the control group (p = 0.03). Taken together, IVIG/RTX treatment for severe TG during chronic antibody-mediated rejection does not seem to change the natural history of TG and is associated with a high incidence of adverse events.

  6. The use of antibody to complement protein C5 for salvage treatment of severe antibody-mediated rejection.

    PubMed

    Locke, J E; Magro, C M; Singer, A L; Segev, D L; Haas, M; Hillel, A T; King, K E; Kraus, E; Lees, L M; Melancon, J K; Stewart, Z A; Warren, D S; Zachary, A A; Montgomery, R A

    2009-01-01

    Desensitized patients are at high risk of developing acute antibody-mediated rejection (AMR). In most cases, the rejection episodes are mild and respond to a short course of plasmapheresis (PP) / low-dose IVIg treatment. However, a subset of patients experience severe AMR associated with sudden onset oliguria. We previously described the utility of emergent splenectomy in rescuing allografts in patients with this type of severe AMR. However, not all patients are good candidates for splenectomy. Here we present a single case in which eculizumab, a complement protein C5 antibody that inhibits the formation of the membrane attack complex (MAC), was used combined with PP/IVIg to salvage a kidney undergoing severe AMR. We show a marked decrease in C5b-C9 (MAC) complex deposition in the kidney after the administration of eculizumab.

  7. Clinical outcome in patients with chronic antibody-mediated rejection treated with and without rituximab and intravenous immunoglobulin combination therapy.

    PubMed

    Chung, Byung Ha; Kim, Yaeni; Jeong, Hyeong Seok; Hong, Yu Ah; Choi, Bum Soon; Park, Cheol Whee; Choi, Yeong Jin; Kim, Yong-Soo; Yang, Chul Woo

    2014-09-01

    We previously reported that rituximab (RTX) and intravenous immunoglobulin (IVIg) combination therapy (RIT) is effective in treating patients with chronic active antibody-mediated rejection (CAMR), and the proteinuria level can determine the response to RIT. However, the results were not compared to those of patients who did not receive RIT. Fifty-nine patients with CAMR were divided into 2 groups: an RIT treated group (n = 25) and a historic control (HC) group who had not received RIT (n = 29). The RIT group was treated with RTX (375 mg/m(2)) and IVIg (0.4 g/kg) for 4 days. We compared the decline in glomerular filtration rate/month (ΔeGFR), RIT-related complications, and allograft survival rate in both groups. We also compared the allograft survival rate between patients with high proteinuria (spot urine protein/creatinine [PC] ratio > 3.5 g/g) and low proteinuria (PC ratio < 3.5 g/g). ΔeGFR was significantly decreased in the RIT group compared with the HC group after 6 months (P < 0.05). No serious complications were associated with RIT, and only one case of herpes zoster infection developed. The overall allograft survival rate in the RIT group was significantly higher than in the HC group. In both groups, patients with low proteinuria survived better than patients with heavy proteinuria (P < 0.05). The allograft survival rate was greater in the high proteinuria RIT group than that in the HC group. RIT treatment is recommended for delaying the progression of CAMR without serious complications, and is not limited by the presence of heavy proteinuria.

  8. Postoperative rebound of antiblood type antibodies and antibody-mediated rejection after ABO-incompatible living-related kidney transplantation.

    PubMed

    Ishida, Hideki; Kondo, Tsunenori; Shimizu, Tomokazu; Nozaki, Taiji; Tanabe, Kazunari

    2015-03-01

    The purpose of this study is to examine whether postoperative antiblood type antibody rebound is attributed to kidney allograft rejection in ABO blood type-incompatible (ABO-I) living-related kidney transplantation (KTx). A total of 191 ABO-I recipients who received ABO-I living-related KTx between 2001 and 2013 were divided into two groups: Group 1 consisted of low rebound [(≦1:32), N = 170] and Group 2 consisted of high rebound [(≧1:64), N = 21], according to the levels of the rebounded antiblood type antibodies within 1 year after transplantation. No prophylactic treatment for rejection was administered for elevated antiblood type antibodies, regardless of the levels of the rebounded antibodies. Within 1 year after transplantation, T-cell-mediated rejection was observed in 13 of 170 recipients (13/170, 8%) in Group 1 and in 2 of 21 recipients (2/21, 10%) in Group 2 (Groups 1 vs. 2, P = 0.432). Antibody-mediated rejection was observed in 15 of 170 recipients (15/170, 9%) and 2 of 21 recipients (2/21, 10%) in Groups 1 and 2, respectively (P = 0.898). In this study, we found no correlation between the postoperative antiblood type antibody rebound and the incidence of acute rejection. We concluded that no treatment is necessary for rebounded antiblood type antibodies.

  9. Molecular Assessment of Microcirculation Injury in Formalin-Fixed Human Cardiac Allograft Biopsies With Antibody-Mediated Rejection.

    PubMed

    Afzali, B; Chapman, E; Racapé, M; Adam, B; Bruneval, P; Gil, F; Kim, D; Hidalgo, L; Campbell, P; Sis, B; Duong Van Huyen, J P; Mengel, M

    2017-02-01

    Precise diagnosis of antibody-mediated rejection (AMR) in cardiac allograft endomyocardial biopsies (EMBs) remains challenging. This study assessed molecular diagnostics in human EMBs with AMR. A set of 34 endothelial, natural killer cell and inflammatory genes was quantified in 106 formalin-fixed, paraffin-embedded EMBs classified according to 2013 International Society for Heart and Lung Transplantation (ISHLT) criteria. The gene set expression was compared between ISHLT diagnoses and correlated with donor-specific antibody (DSA), endothelial injury by electron microscopy (EM) and prognosis. Findings were validated in an independent set of 57 EMBs. In the training set (n = 106), AMR cases (n = 70) showed higher gene set expression than acute cellular rejection (ACR; n = 21, p < 0.001) and controls (n = 15, p < 0.0001). Anti-HLA DSA positivity was associated with higher gene set expression (p = 0.01). Endothelial injury by electron microscopy strongly correlated with gene set expression, specifically in AMR cases (r = 0.62, p = 0.002). Receiver operating characteristic curve analysis for diagnosing AMR showed greater accuracy with gene set expression (area under the curve [AUC] = 79.88) than with DSA (AUC = 70.47) and C4d (AUC = 70.71). In AMR patients (n = 17) with sequential biopsies, increasing gene set expression was associated with inferior prognosis (p = 0.034). These findings were confirmed in the validation set. In conclusion, biopsy-based molecular assessment of antibody-mediated microcirculation injury has the potential to improve diagnosis of AMR in human cardiac transplants.

  10. Bortezomib in the treatment of antibody-mediated rejection in pediatric kidney transplant recipients: A multicenter Midwest Pediatric Nephrology Consortium study.

    PubMed

    Kizilbash, Sarah; Claes, Donna; Ashoor, Isa; Chen, Ashton; Jandeska, Sara; Matar, Raed Bou; Misurac, Jason; Sherbotie, Joseph; Twombley, Katherine; Verghese, Priya

    2017-05-01

    Antibody-mediated rejection leads to allograft loss after kidney transplantation. Bortezomib has been used in adults for the reversal of antibody-mediated rejection; however, pediatric data are limited. This retrospective study was conducted in collaboration with the Midwest Pediatric Nephrology Consortium. Pediatric kidney transplant recipients who received bortezomib for biopsy-proven antibody-mediated rejection between 2008 and 2015 were included. The objective was to characterize the use of bortezomib in pediatric kidney transplant recipients. Thirty-three patients received bortezomib for antibody-mediated rejection at nine pediatric kidney transplant centers. Ninety percent of patients received intravenous immunoglobulin, 78% received plasmapheresis, and 78% received rituximab. After a median follow-up of 15 months, 65% of patients had a functioning graft. The estimated glomerular filtration rate improved or stabilized in 61% and 36% of patients at 3 and 12 months post-bortezomib, respectively. The estimated glomerular filtration rate at diagnosis significantly predicted estimated glomerular filtration rate at 12 months after adjusting for chronic histologic changes (P .001). Fifty-six percent of patients showed an at least 25% reduction in the mean fluorescence intensity of the immune-dominant donor-specific antibody, 1-3 months after the first dose of bortezomib. Non-life-threatening side effects were documented in 21 of 33 patients. Pediatric kidney transplant recipients tolerated bortezomib without life-threatening side effects. Bortezomib may stabilize estimated glomerular filtration rate for 3-6 months in pediatric kidney transplant recipients with antibody-mediated rejection.

  11. [Effect of pre-transplant donor specific antibody on antibody-mediated rejection and graft dysfunction].

    PubMed

    Wang, Ning; Li, Wei; Zhang, Sheng

    2016-05-01

    目的:研究肾移植受者的术前供者特异性抗体(donor specific antibody,DSA)与其术后发生抗体介导的体液排斥反应(antibody-mediated rejection,AMR)及移植肾功能的关系。方法:选取符合要求的肾移植受者88例。术前采用Luminex流式法对肾移植受者进行DSA检测,并将受者分为DSA阳性组(n=20)与DSA阴性组(n=68)。随访时间为2年。术后参照Banff 2005标准对移植肾病理形态进行评估分级,并观察移植肾的情况。结果: DSA阳性组与阴性组AMR发生率分别为20.0%和1.5%,移植物丢失发生率分别为15.0%和1.5%,两组比较差异均有统计学意义(分别P<0.01,P<0.05);AMR受者最高DSA的荧光指数中值(mean fluorescence intensity,MFI)较非AMR受者差异明显(P<0.01);受试者工作特征(receiver operating characteristic,ROC)曲线显示肾移植术后受者发展为AMR的最高MFI阈值为7909.5。两组移植肾功能延迟回复的发生相比较,差异无统计学意义(P>0.05)。结论:肾移植术前检测DSA水平,可以预测AMR的发生风险和移植肾功能状态。最高DSA值的MFI截点(7909.5)能够预测AMR发生的风险。.

  12. Acute T cell-mediated rejection accompanied by C4d-negative acute antibody-mediated rejection and cell debris in tubulus: A case report.

    PubMed

    Takamura, Tsuyoshi; Yamamoto, Izumi; Nakada, Yasuyuki; Katsumata, Haruki; Yamakawa, Takafumi; Furuya, Maiko; Mafune, Aki; Kobayashi, Akimitsu; Tanno, Yudo; Miki, Jun; Ohkido, Ichiro; Tsuboi, Nobuo; Yamamoto, Hiroyasu; Yokoo, Takashi

    2015-07-01

    Herein, we report a complicated case of acute T-cell-mediated rejection (ACR) accompanied by C4d-negative acute antibody-mediated rejection (AMR) and cell debris in tubulus. A 32 year-old male was admitted for an episode biopsy with a serum creatinine (S-Cr) level of 1.83 mg/dL and pyuria (20-29 white blood cells per high power field) 49 days following kidney transplantation. Histological features included three distinct entities, mainly, in one of the three specimens: 1) focal aggressive tubulointerstitial inflammatory cell infiltration with moderate tubulitis, 2) inflammatory cell infiltration in peritubular capillaries (including neutrophils) and glomerular capillaries, and 3) cell debris consisting mainly of neutrophils in tubulus. Laboratory examination revealed evidence of non-human leukocyte antigen donor-specific antibodies. However, urinary culture and gram staining were negative. Considering both the histological and laboratory findings, the patient was diagnosed with ACR accompanied by C4d-negative AMR and suspicion of a urinary tract infection (UTI). The patient was treated for three consecutive days with steroid pulse therapy. The patient's S-Cr level decreased to ~1.5 mg/dL following treatment and did not increase thereafter. A second biopsy 133 days following kidney transplantation showed an excellent response to treatment and revealed no evidence of rejection. This case report demonstrates the difficulty in the diagnosis of, and therapy for, the complicated pathological findings of ACR, AMR and suspicion of a UTI.

  13. Impact of ABO Incompatibility on the Development of Acute Antibody-Mediated Rejection in Kidney Transplant Recipients Presensitized to HLA.

    PubMed

    Chung, Byung Ha; Joo, Yu Young; Lee, Jaesin; Kim, Hyung Duk; Kim, Ji-Il; Moon, In Sung; Choi, Bum Soon; Oh, Eun-Jee; Park, Cheol Whee; Kim, Yong-Soo; Yang, Chul Woo

    2015-01-01

    Whether the coexistence of anti-A/B antibody and donor specific anti-HLA antibody (HLA-DSA) has a synergistic impact on the development of acute antibody-mediated rejection (AAMR) in kidney transplant recipients (KTRs) is unclear. This study includes 92 KTRs who received a kidney from an ABO-incompatible (ABOi) donor or were presensitized to donor HLA (HLAs) and 292 controls (CONT). HLAs was defined as a crossmatch positivity or the presence of HLA-DSA. We compared the incidence of AAMR among ABOi (n = 58), ABOi+HLAs (n = 12), HLAs (n = 22), and CONT (n = 292) groups and evaluated the risk factors and antibody type (anti-A/B vs. HLA-DSA) responsible for AAMR. AAMR developed less frequently in ABOi and CONT than in the ABOi+HLAs or HLAs (P < 0.05 for all); however, there was no difference between the ABOi+HLAs and HLAs groups. AAMR developed more frequently with strong HLA-DSA at baseline; however, high baseline anti-A/B titer did not affect AAMR development. Strong baseline HLA-DSA was an independent predictor for AAMR, however the baseline anti-A/B titer was not. All four AAMR episodes in ABOi+HLAs were positive to HLA-DSA but not to anti-A/B. In conclusion, ABO incompatibility does not increase the risk for AAMR in HLAs KTRs.

  14. Risk of antibody-mediated rejection in kidney transplant recipients with anti-HLA-C donor-specific antibodies.

    PubMed

    Aubert, O; Bories, M-C; Suberbielle, C; Snanoudj, R; Anglicheau, D; Rabant, M; Martinez, F; Scemla, A; Legendre, C; Sberro-Soussan, R

    2014-06-01

    Anti-HLA donor-specific antibodies (DSAs) cause acute and chronic antibody-mediated rejection (AMR). However, the clinical relevance of anti-HLA-C antibodies remains unclear. We evaluated the clinical relevance of the presence of anti-HLA-C DSA at day 0 in renal transplant recipients. In this retrospective, case-controlled study, 608 patients who underwent kidney transplantation between August 2008 and March 2012 were screened for the presence of isolated anti-HLA-C DSA at day 0. A total of 22 renal transplant recipients were selected and followed for a period of 1 year. AMR was classified according to the Banff classification. The 22 patients were compared with 88 immunized patients. Acute AMR was diagnosed in six patients (27.3%). The median level of DSA at day 0 was 1179 (530-17,941). The mean fluorescence intensity in the anti-C group was 4966 (978-17,941) in the AMR group and 981 (530-8012) in the group of patients without AMR. Acute AMR was diagnosed less frequently in the 88 immunized individuals (9.1%) than in the DSA anti-C group (p = 0.033). The level of DSA at day 0 was predictive for AMR (p = 0.017). Patients with a high level of pretransplant anti-HLA-C DSAs are likely to develop acute AMR during the first year after transplantation.

  15. The molecular landscape of antibody-mediated kidney transplant rejection: evidence for NK involvement through CD16a Fc receptors.

    PubMed

    Venner, J M; Hidalgo, L G; Famulski, K S; Chang, J; Halloran, P F

    2015-05-01

    The recent recognition that antibody-mediated rejection (ABMR) is the major cause of kidney transplant loss creates strong interest in its pathogenesis. We used microarray analysis of kidney transplant biopsies to identify the changes in pure ABMR. We found that the ABMR transcript changes in the initial Discovery Set were strongly conserved in a subsequent Validation Set. In the Combined Set of 703 biopsies, 2603 transcripts were significantly changed (FDR < 0.05) in ABMR versus all other biopsies. In cultured cells, the transcripts strongly associated with ABMR were expressed in endothelial cells, e.g. cadherins CDH5 and CDH13; IFNG-treated endothelial cells, e.g. phospholipase PLA1A and chemokine CXCL11; or NK cells, e.g. cytotoxicity molecules granulysin (GNLY) and FGFBP2. Other ABMR transcripts were expressed in normal kidney but not cell lines, either increased e.g. Duffy chemokine receptor (DARC) or decreased e.g. sclerostin (SOST). Pathway analysis of ABMR transcripts identified angiogenesis, with roles for angiopoietin and vascular endothelial growth factors; leukocyte-endothelial interactions; and NK signaling, including evidence for CD16a Fc receptor signaling elements shared with T cells. These data support a model of ABMR involving injury-repair in the microcirculation induced by cognate recognition involving antibody and CD16a, triggering IFNG release and antibody-dependent NK cell-mediated cytotoxicity.

  16. Antibody-Mediated Rejection of Arterialised Venous Allografts Is Inhibited by Immunosuppression in Rats

    PubMed Central

    Varga, Martin; Oliverius, Martin; Kuhn, Stephanie; Feldbrügge, Linda; Krenzien, Felix; Hau, Hans-Michael; Wiltberger, Georg; Schmelzle, Moritz; Jonas, Sven

    2014-01-01

    Objectives and Design We determined in a rat model (1) the presence and dynamics of alloantibodies recognizing MHC complexes on quiescent Brown-Norway (BN) splenic cells in the sera of Lewis (LEW) recipients of Brown-Norway iliolumbar vein grafts under tacrolimus immunosuppression; and (2) the presence of immunoglobulins in the wall of acute rejected vein allografts. Materials and Methods Flow cytometry was used for the analysis of day 0, 14 and 30 sera obtained from Lewis recipients of isogeneic iliolumbar vein grafts (group A) or Brown-Norway grafts (group B, C) for the presence of donor specific anti-MHC class I and II antibodies. Tacrolimus 0.2 mg/kg daily was administered from day 1 to day 30 (group C). Histology was performed on day 30. Results Sera obtained preoperatively and on day 30 were compared in all groups. The statistically significant decrease of anti MHC class I and II antibody binding was observed only in allogenic non-immunosuppressed group B (splenocytes: MHC class I - day 0 (93%±7% ) vs day 30 (66%±7%), p = 0.02, MHC class II - day 0 (105%±3% ) vs day 30 (83%±5%), p = 0.003; B-cells: MHC class I - day 0 (83%±5%) vs day 30 (55%±6%), p = 0.003, MHC class II - day 0 (101%±1%) vs day 30 (79%±6%), p = 0.006; T-cells: MHC class I - day 0 (71%±7%) vs day 30 (49%±5%), p = 0.04). No free clusters of immunoglobulin G deposition were detected in any experimental group. Conclusion Arterialized venous allografts induce strong donor-specific anti-MHC class I and anti-MHC class II antibody production with subsequent immune-mediated destruction of these allografts with no evidence of immunoglobulin G deposition. Low-dose tacrolimus suppress the donor-specific antibody production. PMID:24618652

  17. Antibody-mediated rejection, T cell-mediated rejection, and the injury-repair response: new insights from the Genome Canada studies of kidney transplant biopsies.

    PubMed

    Halloran, Philip F; Reeve, Jeff P; Pereira, Andre B; Hidalgo, Luis G; Famulski, Konrad S

    2014-02-01

    Prospective studies of unselected indication biopsies from kidney transplants, combining conventional assessment with molecular analysis, have created a new understanding of transplant disease states and their outcomes. A large-scale Genome Canada grant permitted us to use conventional and molecular phenotypes to create a new disease classification. T cell-mediated rejection (TCMR), characterized histologically or molecularly, has little effect on outcomes. Antibody-mediated rejection (ABMR) manifests as microcirculation lesions and transcript changes reflecting endothelial injury, interferon-γ effects, and natural killer cells. ABMR is frequently C4d negative and has been greatly underestimated by conventional criteria. Indeed, ABMR, triggered in some cases by non-adherence, is the major disease causing failure. Progressive dysfunction is usually attributable to specific diseases, and pure calcineurin inhibitor toxicity rarely explains failure. The importance of ABMR argues against immunosuppressive drug minimization and stands as a barrier to tolerance induction. Microarrays also defined the transcripts induced by acute kidney injury (AKI), which correlate with reduced function, whereas histologic changes of acute tubular injury do not. AKI transcripts are induced in kidneys with late dysfunction, and are better predictors of failure than fibrosis and inflammation. Thus progression reflects ongoing parenchymal injury, usually from identifiable diseases such as ABMR, not destructive fibrosis.

  18. Natural killer cells play a critical role in mediating inflammation and graft failure during antibody-mediated rejection of kidney allografts.

    PubMed

    Kohei, Naoki; Tanaka, Toshiaki; Tanabe, Kazunari; Masumori, Naoya; Dvorina, Nina; Valujskikh, Anna; Baldwin, William M; Fairchild, Robert L

    2016-06-01

    While the incidence of antibody-mediated kidney graft rejection has increased, the key cellular and molecular participants underlying this graft injury remain unclear. Rejection of kidney allografts in mice lacking the chemokine receptor CCR5 is dependent on production of donor-specific antibody. Here we determine if cells expressing cytotoxic function contributed to antibody-mediated kidney allograft rejection in these recipients. Wild-type C57BL/6, B6.CCR5(-/-), and B6.CD8(-/-)/CCR5(-/-) mice were transplanted with complete MHC-mismatched A/J kidney grafts, and intragraft inflammatory components were followed to rejection. B6.CCR5(-/-) and B6.CD8(-/-)/CCR5(-/-) recipients rejected kidney allografts by day 35, whereas 65% of allografts in wild-type recipients survived past day 80 post-transplant. Rejected allografts in wild-type C57BL/6, B6.CCR5(-/-), and B6.CD8(-/-)/CCR5(-/-) recipients expressed high levels of VCAM-1 and MMP7 mRNA that was associated with high serum titers of donor-specific antibody. High levels of perforin and granzyme B mRNA expression peaked on day 6 post-transplant in allografts in all recipients, but were absent in isografts. Depletion of natural killer cells in B6.CD8(-/-)/CCR5(-/-) recipients reduced this expression to background levels and promoted the long-term survival of 40% of the kidney allografts. Thus, natural killer cells have a role in increased inflammation during antibody-mediated kidney allograft injury and in rejection of the grafts.

  19. Rituximab in Combination With Bortezomib, Plasmapheresis, and High-Dose IVIG to Treat Antibody-Mediated Renal Allograft Rejection

    PubMed Central

    Waiser, Johannes; Duerr, Michael; Schönemann, Constanze; Rudolph, Birgit; Wu, Kaiyin; Halleck, Fabian; Budde, Klemens; Lachmann, Nils

    2016-01-01

    Background Current treatment strategies for antibody-mediated renal allograft rejection (AMR) are not sufficiently effective. In most centers, “standard of care” treatment includes plasmapheresis (PPH) and IVIG preparations. Since several years, modern therapeutics targeting B cells and plasma cells have become available. We investigated, whether combined administration of rituximab and bortezomib in addition to PPH and high-dose IVIG is useful. Methods Between November 2011 and January 2013, we treated 10 consecutive patients with biopsy-proven AMR with rituximab (500 mg), bortezomib (4× 1.3 mg/m2), PPH (6×), and high-dose IVIG (1.5 g/kg) (group A). This group was compared with a group of 11 consecutive patients treated with an identical regimen without rituximab between July 2010 and November 2011 (group B). Results Median follow-up was 41(33-46) months in group A and 55(47-63) months in group B. At 40 months after treatment, graft survival was 60% in group A and 64% in group B, respectively (P = 0.87). Before and after treatment, serum creatinine, estimated glomerular filtration rate, and proteinuria were not different between groups. A significant reduction in donor-specific HLA antibody mean fluorescence intensity was observed in group A (25.2%, P = 0.046) and B (38.3%, P = 0.01) at 3 months posttreatment. In group A, more patients suffered from side effects compared with group B (infections: 70% vs 18%, P = 0.02). Conclusions The addition of rituximab to bortezomib, PPH, and high-dose IVIG did not further improve graft survival. Instead, we observed an increase of side effects. Therefore, combined administration of bortezomib and rituximab in addition to PPH and IVIG should be regarded with caution. PMID:27819032

  20. Urinary C-X-C Motif Chemokine 10 Independently Improves the Noninvasive Diagnosis of Antibody-Mediated Kidney Allograft Rejection.

    PubMed

    Rabant, Marion; Amrouche, Lucile; Lebreton, Xavier; Aulagnon, Florence; Benon, Aurélien; Sauvaget, Virginia; Bonifay, Raja; Morin, Lise; Scemla, Anne; Delville, Marianne; Martinez, Frank; Timsit, Marc Olivier; Duong Van Huyen, Jean-Paul; Legendre, Christophe; Terzi, Fabiola; Anglicheau, Dany

    2015-11-01

    Urinary levels of C-X-C motif chemokine 9 (CXCL9) and CXCL10 can noninvasively diagnose T cell-mediated rejection (TCMR) of renal allografts. However, performance of these molecules as diagnostic/prognostic markers of antibody-mediated rejection (ABMR) is unknown. We investigated urinary CXCL9 and CXCL10 levels in a highly sensitized cohort of 244 renal allograft recipients (67 with preformed donor-specific antibodies [DSAs]) with 281 indication biopsy samples. We assessed the benefit of adding these biomarkers to conventional models for diagnosing/prognosing ABMR. Urinary CXCL9 and CXCL10 levels, normalized to urine creatinine (Cr) levels (CXCL9:Cr and CXCL10:Cr) or not, correlated with the extent of tubulointerstitial (i+t score; all P<0.001) and microvascular (g+ptc score; all P<0.001) inflammation. CXCL10:Cr diagnosed TCMR (area under the curve [AUC]=0.80; 95% confidence interval [95% CI], 0.68 to 0.92; P<0.001) and ABMR (AUC=0.76; 95% CI, 0.69 to 0.82; P<0.001) with high accuracy, even in the absence of tubulointerstitial inflammation (AUC=0.70; 95% CI, 0.61 to 0.79; P<0.001). Although mean fluorescence intensity of the immunodominant DSA diagnosed ABMR (AUC=0.75; 95% CI, 0.68 to 0.82; P<0.001), combining urinary CXCL10:Cr with immunodominant DSA levels improved the diagnosis of ABMR (AUC=0.83; 95% CI, 0.77 to 0.89; P<0.001). At the time of ABMR, urinary CXCL10:Cr ratio was independently associated with an increased risk of graft loss. In conclusion, urinary CXCL10:Cr ratio associates with tubulointerstitial and microvascular inflammation of the renal allograft. Combining the urinary CXCL10:Cr ratio with DSA monitoring significantly improves the noninvasive diagnosis of ABMR and the stratification of patients at high risk for graft loss.

  1. Antibody-Mediated Rejection Due to Preexisting versus De Novo Donor-Specific Antibodies in Kidney Allograft Recipients.

    PubMed

    Aubert, Olivier; Loupy, Alexandre; Hidalgo, Luis; Duong van Huyen, Jean-Paul; Higgins, Sarah; Viglietti, Denis; Jouven, Xavier; Glotz, Denis; Legendre, Christophe; Lefaucheur, Carmen; Halloran, Philip F

    2017-03-02

    Antibody-mediated rejection (ABMR) can occur in patients with preexisting anti-HLA donor-specific antibodies (DSA) or in patients who develop de novo DSA. However, how these processes compare in terms of allograft injury and outcome has not been addressed. From a cohort of 771 kidney biopsy specimens from two North American and five European centers, we performed a systematic assessment of clinical and biologic parameters, histopathology, circulating DSA, and allograft gene expression for all patients with ABMR (n=205). Overall, 103 (50%) patients had preexisting DSA and 102 (50%) had de novo DSA. Compared with patients with preexisting DSA ABMR, patients with de novo DSA ABMR displayed increased proteinuria, more transplant glomerulopathy lesions, and lower glomerulitis, but similar levels of peritubular capillaritis and C4d deposition. De novo DSA ABMR was characterized by increased expression of IFNγ-inducible, natural killer cell, and T cell transcripts, but less expression of AKI transcripts compared with preexisting DSA ABMR. The preexisting DSA ABMR had superior graft survival compared with the de novo DSA ABMR (63% versus 34% at 8 years after rejection, respectively; P<0.001). After adjusting for clinical, histologic, and immunologic characteristics and treatment, we identified de novo DSA ABMR (hazard ratio [HR], 1.82 compared with preexisting DSA ABMR; 95% confidence interval [95% CI], 1.07 to 3.08; P=0.03); low eGFR (<30 ml/min per 1.73 m(2)) at diagnosis (HR, 3.27; 95% CI, 1.48 to 7.23; P<0.001); ≥0.30 g/g urine protein-to-creatinine ratio (HR, 2.44; 95% CI, 1.47 to 4.09; P<0.001); and presence of cg lesions (HR, 2.25; 95% CI, 1.34 to 3.79; P=0.002) as the main independent determinants of allograft loss. Our findings support the transplant of kidneys into highly sensitized patients and should encourage efforts to monitor patients for de novo DSA.

  2. Subclinical antibody-mediated rejection due to anti-human-leukocyte-antigen-DR53 antibody accompanied by plasma cell-rich acute rejection in a patient with cadaveric kidney transplantation.

    PubMed

    Katsuma, Ai; Yamamoto, Izumi; Komatsuzaki, Yo; Niikura, Takahito; Kawabe, Mayuko; Okabayashi, Yusuke; Yamakawa, Takafumi; Katsumata, Haruki; Nakada, Yasuyuki; Kobayashi, Akimitsu; Tanno, Yudo; Miki, Jun; Yamada, Hiroki; Ohkido, Ichiro; Tsuboi, Nobuo; Yamamoto, Hiroyasu; Yokoo, Takashi

    2016-07-01

    A 56-year-old man who had undergone cadaveric kidney transplantation 21 months earlier was admitted to our hospital for a protocol biopsy; he had a serum creatinine level of 1.2 mg/dL and no proteinuria. Histological features showed two distinct entities: (i) inflammatory cell infiltration, in the glomerular and peritubular capillaries and (ii) focal, aggressive tubulointerstitial inflammatory cell infiltration, predominantly plasma cells, with mild tubulitis (Banff 13 classification: i2, t1, g2, ptc2, v0, ci1, ct1, cg0, cv0). Immunohistological studies showed mildly positive C4d immunoreactivity in the peritubular capillaries. The patient had donor specific antibody to human-leucocyte-antigen-DR53. We diagnosed him with subclinical antibody-mediated rejection accompanied by plasma cell-rich acute rejection. Both antibody-mediated rejection due to anti- human-leucocyte-antigen -DR53 antibodies and plasma cell-rich acute rejection are known to be refractory and have a poor prognosis. Thus, we started plasma exchange with intravenous immunoglobulin and rituximab for the former and 3 days of consecutive steroid pulse therapy for the latter. Three months after treatment, a follow-up allograft biopsy showed excellent responses to treatment for both histological features. This case report considers the importance of an early diagnosis and appropriate intervention for subclinical antibody-mediated rejection due to donor specific antibody to human-leucocyte-antigen-DR53 and plasma cell-rich acute rejection.

  3. Markers of Endothelial-to-Mesenchymal Transition: Evidence for Antibody-Endothelium Interaction during Antibody-Mediated Rejection in Kidney Recipients.

    PubMed

    Xu-Dubois, Yi-Chun; Peltier, Julie; Brocheriou, Isabelle; Suberbielle-Boissel, Caroline; Djamali, Arjang; Reese, Shannon; Mooney, Nuala; Keuylian, Zela; Lion, Julien; Ouali, Nacéra; Levy, Pierre P; Jouanneau, Chantal; Rondeau, Eric; Hertig, Alexandre

    2016-01-01

    Antibody-mediated rejection (ABMR) is a leading cause of allograft loss. Treatment efficacy depends on accurate diagnosis at an early stage. However, sensitive and reliable markers of antibody-endothelium interaction during ABMR are not available for routine use. Using immunohistochemistry, we retrospectively studied the diagnostic value of three markers of endothelial-to-mesenchymal transition (EndMT), fascin1, vimentin, and heat shock protein 47, for ABMR in 53 renal transplant biopsy specimens, including 20 ABMR specimens, 24 cell-mediated rejection specimens, and nine normal grafts. We validated our results in an independent set of 74 unselected biopsy specimens. Endothelial cells of the peritubular capillaries in grafts with ABMR expressed fascin1, vimentin, and heat shock protein 47 strongly, whereas those from normal renal grafts did not. The level of EndMT marker expression was significantly associated with current ABMR criteria, including capillaritis, glomerulitis, peritubular capillary C4d deposition, and donor-specific antibodies. These markers allowed us to identify C4d-negative ABMR and to predict late occurrence of disease. EndMT markers were more specific than capillaritis for the diagnosis and prognosis of ABMR and predicted late (up to 4 years after biopsy) renal graft dysfunction and proteinuria. In the independent set of 74 renal graft biopsy specimens, the EndMT markers for the diagnosis of ABMR had a sensitivity of 100% and a specificity of 85%. Fascin1 expression in peritubular capillaries was also induced in a rat model of ABMR. In conclusion, EndMT markers are a sensitive and reliable diagnostic tool for detecting endothelial activation during ABMR and predicting late loss of allograft function.

  4. A refractory case of subclinical antibody-mediated rejection due to anti-HLA-DQ antibody in a kidney transplant patient.

    PubMed

    Fujimoto, Toshinari; Nakada, Yasuyuki; Yamamoto, Izumi; Kobayashi, Akimitsu; Tanno, Yudo; Yamada, Hiroki; Miki, Jun; Ohkido, Ichiro; Tsuboi, Nobuo; Yamamoto, Hiroyasu; Yokoo, Takashi

    2015-07-01

    We herein report a refractory case of subclinical antibody-mediated rejection (AMR) due to anti-HLA-DQ antibody in a kidney transplant patient. A 45-year-old man was admitted for a protocol biopsy; he had a serum creatinine (S-Cr) level of 1.8 mg/dL 3 years following primary kidney transplantation. Histological examination revealed moderate to severe inflammatory cell infiltration in the peritubular capillaries. Thorough laboratory examination showed that the patient had donor-specific antibodies (DSAbs) to DR9 and DQ9. Considering both the histological and laboratory findings, we diagnosed acute antibody-mediated rejection. The patient underwent 3 days of consecutive steroid pulse therapy, intravenous immunoglobulin (IVIG), and plasma exchange. We also administered rituximab (200 mg/body). Six months after the treatment, a second allograft biopsy revealed the progression of interstitial fibrosis and tubular atrophy and persistence of mild peritubular capillaritis. Further analysis showed that the anti-DR9 antibodies had disappeared, but that the mean fluorescence intensity value of the anti-DQ9 antibodies had increased. Therefore, we repeated the plasma exchange and IVIG. Allograft function was stable throughout the course of treatment, and the S-Cr level remained at 1.8 mg/dL. This case report demonstrates the difficulty of treating AMR due to the presence of anti-DQ DSAbs and the necessity for subsequent therapies in refractory cases.

  5. Late antibody-mediated rejection by de novo donor HLA-DP-specific antibody after renal transplantation: a case report.

    PubMed

    Cippà, Pietro E; Gaspert, Ariana; Etter, Christoph; Guenduez, Zehra; Ferrari-Lacraz, Sylvie; Rüsi, Barbara; Fehr, Thomas

    2014-05-01

    The role of donor HLA-DP-specific antibodies after renal transplantation is controversial, and only preformed HLA-DP-specific antibodies have been shown to mediate rejection. Here we present a case of late humoral rejection mediated by de novo donor HLA-DP-specific antibodies in a non-sensitized recipient. This unique case demonstrates the pathogenic role of de novo anti-DP antibodies and suggests that HLA-DP matching might be relevant for renal transplantation.

  6. Banff 2013 meeting report: inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions.

    PubMed

    Haas, M; Sis, B; Racusen, L C; Solez, K; Glotz, D; Colvin, R B; Castro, M C R; David, D S R; David-Neto, E; Bagnasco, S M; Cendales, L C; Cornell, L D; Demetris, A J; Drachenberg, C B; Farver, C F; Farris, A B; Gibson, I W; Kraus, E; Liapis, H; Loupy, A; Nickeleit, V; Randhawa, P; Rodriguez, E R; Rush, D; Smith, R N; Tan, C D; Wallace, W D; Mengel, M

    2014-02-01

    The 12th Banff Conference on Allograft Pathology was held in Comandatuba, Brazil, from August 19-23, 2013, and was preceded by a 2-day Latin American Symposium on Transplant Immunobiology and Immunopathology. The meeting was highlighted by the presentation of the findings of several working groups formed at the 2009 and 2011 Banff meetings to: (1) establish consensus criteria for diagnosing antibody-mediated rejection (ABMR) in the presence and absence of detectable C4d deposition; (2) develop consensus definitions and thresholds for glomerulitis (g score) and chronic glomerulopathy (cg score), associated with improved inter-observer agreement and correlation with clinical, molecular and serological data; (3) determine whether isolated lesions of intimal arteritis ("isolated v") represent acute rejection similar to intimal arteritis in the presence of tubulointerstitial inflammation; (4) compare different methodologies for evaluating interstitial fibrosis and for performing/evaluating implantation biopsies of renal allografts with regard to reproducibility and prediction of subsequent graft function; and (5) define clinically and prognostically significant morphologic criteria for subclassifying polyoma virus nephropathy. The key outcome of the 2013 conference is defining criteria for diagnosis of C4d-negative ABMR and respective modification of the Banff classification. In addition, three new Banff Working Groups were initiated.

  7. Early acute antibody-mediated rejection of a negative flow crossmatch 3rd kidney transplant with exclusive disparity at HLA-DP.

    PubMed

    Mierzejewska, Beata; Schroder, Paul M; Baum, Caitlin E; Blair, Annette; Smith, Connie; Duquesnoy, Rene J; Marrari, Marilyn; Gohara, Amira; Malhotra, Deepak; Kaw, Dinkar; Liwski, Robert; Rees, Michael A; Stepkowski, Stanislaw

    2014-08-01

    Donor-specific alloantibodies (DSA) to HLA-DP may cause antibody-mediated rejection (AMR), especially in re-transplants. We describe the immunization history of a patient who received 3 kidney transplants; the 3rd kidney was completely matched except at DPA1 and DPB1. Prior to the 3rd transplant, single antigen bead analysis (SAB) showed DSA reactivity against DPA1 shared by the 1st and 3rd donors, but B and T flow crossmatch (FXM) results were negative. Within 11 days the 3rd transplant underwent acute C4d+ AMR which coincided with the presence of complement (C1q)-binding IgG1 DSA against donor DPA1 and DPB1. Using HLAMatchmaker and SAB, we provide evidence that eplet (epitope) spreading on DPA1 and eplet sharing on differing DPB1 alleles of the 1st and 3rd transplants was associated with AMR. Since weak DSA to DPA1/DPB1 may induce acute AMR with negative FXM, donor DPA1/DPB1 high resolution typing should be considered in sensitized patients with DP-directed DSA.

  8. Plasma-Derived C1 Esterase Inhibitor for Acute Antibody-Mediated Rejection Following Kidney Transplantation: Results of a Randomized Double-Blind Placebo-Controlled Pilot Study.

    PubMed

    Montgomery, R A; Orandi, B J; Racusen, L; Jackson, A M; Garonzik-Wang, J M; Shah, T; Woodle, E S; Sommerer, C; Fitts, D; Rockich, K; Zhang, P; Uknis, M E

    2016-05-16

    Antibody-mediated rejection (AMR) is typically treated with plasmapheresis (PP) and intravenous immunoglobulin (standard of care; SOC); however, there is an unmet need for more effective therapy. We report a phase 2b, multicenter double-blind randomized placebo-controlled pilot study to evaluate the use of human plasma-derived C1 esterase inhibitor (C1 INH) as add-on therapy to SOC for AMR. Eighteen patients received 20 000 units of C1 INH or placebo (C1 INH n = 9, placebo n = 9) in divided doses every other day for 2 weeks. No discontinuations, graft losses, deaths, or study drug-related serious adverse events occurred. While the study's primary end point, a difference between groups in day 20 pathology or graft survival, was not achieved, the C1 INH group demonstrated a trend toward sustained improvement in renal function. Six-month biopsies performed in 14 subjects (C1 INH = 7, placebo = 7) showed no transplant glomerulopathy (TG) (PTC+cg≥1b) in the C1 INH group, whereas 3 of 7 placebo subjects had TG. Endogenous C1 INH measured before and after PP demonstrated decreased functional C1 INH serum concentration by 43.3% (p < 0.05) for both cohorts (C1 INH and placebo) associated with PP, although exogenous C1 INH-treated patients achieved supraphysiological levels throughout. This new finding suggests that C1 INH replacement may be useful in the treatment of AMR.

  9. Antibody-mediated rejection in heart transplant recipients: potential efficacy of B-cell depletion and antibody removal.

    PubMed

    Bierl, Charlene; Miller, Barry; Prak, Eline Luning; Gasiewski, Allison; Kearns, Jane; Tsai, Donald; Jessup, Mariell; Kamoun, Malek

    2006-01-01

    We present four patients with late AMR following cardiac transplantation, which was associated with de novo post-transplant anti-HLA class II antibody production. All patients had negative anti-HLA class I and class II antibodies prior to transplantation (as assessed by sensitive Flow PRA bead assays) and had a negative retrospective T- and B-cell flow cytometric cross-match. Upon presentation with late graft rejection due to AMR, all patients were treated with rituximab and serial plasmapheresis with IVIg plus triple-drug immunosuppression therapy. Despite initial responses to therapy, relapses occurred in all of the patients and necessitated prolonged or multiple hospital admissions and second transplants in two cases. Post-transplant serum antibody monitoring did not prove to be predictive of treatment success or failure. Serum anti-HLA antibodies should be monitored after heart transplantation. We recommend an assessment of anti-HLA antibodies following a decline in immunosuppressant drug levels or in the presence of heart failure symptoms. Anti-HLA antibody detection should be performed using very sensitive techniques such as microparticle-based assays.

  10. Sex Related Differences in the Risk of Antibody-Mediated Rejection and Subsequent Allograft Vasculopathy Post-Heart Transplantation: A Single-Center Experience

    PubMed Central

    Grupper, Avishay; Nestorovic, Emilija M.; Daly, Richard C.; Milic, Natasa M.; Joyce, Lyle D.; Stulak, John M.; Joyce, David L.; Edwards, Brooks S.; Pereira, Naveen L.; Kushwaha, Sudhir S.

    2016-01-01

    Background Pregnancies may result in antibodies against HLA, a risk factor for antibody-mediated rejection (AMR) and subsequent cardiac allograft vasculopathy (CAV) after heart transplantation (HTx). The aim of this study was to evaluate sex differences in the incidence of AMR events and subsequent risk of CAV among HTx recipients. Methods The study comprised 160 patients (51 [32%] women) who underwent HTx in 2008 to 2014. The cumulative effect of AMR events was calculated by AMR score (sum of myocardial biopsy grading divided by number of biopsies taken during 3 years post-HTx). Results Females had higher levels of anti-HLA I antibodies pre-HTx compared to males which was associated with a history of pregnancies, total number of children and with a higher AMR score at 6 months post-HTx (P < 0.05). Women demonstrated a significant increase in the total incidence of AMR events (27 vs. 7%, P = 0.001) and in AMR scores at 6, 12, 24 and 36 months post-HTx compared to men (P < 0.05). There were no differences in cellular rejection between the groups. A history of AMR events was associated with a significantly increased risk of severe CAV onset (hazard ratio, 7.0; 95% confidence interval, 1.5-31.5; P = 0.012). Conclusions Women are at higher risk for AMR post-HTx which subsequently increases their risk for CAV. Females recipients may benefit from closer surveillance to identify AMR at an earlier stage post-HTx, and targeted immunosuppressive therapy to attenuate the development of CAV. PMID:27795988

  11. Molecular Mechanism of Antibody-Mediated Activation of β-galactosidase

    PubMed Central

    Vinothkumar, Kutti R.; McMullan, Greg; Henderson, Richard

    2014-01-01

    Summary Binding of a single-chain Fv antibody to Escherichia coli β-galactosidase (β-gal) is known to stabilize the enzyme and activate several inactive point mutants, historically called antibody-mediated enzyme formation mutants. To understand the nature of this activation, we have determined by electron cryo-microscopy the structure of the complex between β-gal and the antibody scFv13R4. Our structure localizes the scFv13R4 binding site to the crevice between domains 1 and 3 in each β-gal subunit. The mutations that scFv13R4 counteracts are located between the antibody binding site and the active site of β-gal, at one end of the TIM-barrel that forms domain 3 where the substrate lactose is hydrolyzed. The mode of binding suggests how scFv stabilizes both the active site of β-gal and the tetrameric state. PMID:24613486

  12. Determining donor-specific antibody C1q-binding ability improves the prediction of antibody-mediated rejection in human leucocyte antigen-incompatible kidney transplantation.

    PubMed

    Malheiro, Jorge; Tafulo, Sandra; Dias, Leonídio; Martins, La Salete; Fonseca, Isabel; Beirão, Idalina; Castro-Henriques, António; Cabrita, António

    2017-04-01

    Detrimental impact of preformed donor-specific antibodies (DSAs) against human leucocyte antigens on outcomes after kidney transplantation are well documented, however, the value of their capacity to bind complement for predicting antibody-mediated rejection (AMR) and graft survival still needs to be confirmed. We aimed to study DSA characteristics (strength and C1q binding) that might distinguish harmful DSA from clinically irrelevant ones. We retrospectively studied 60 kidney-transplanted patients with preformed DSA detected by single antigen bead (SAB) assays (IgG and C1q kits), from a cohort of 517 kidney graft recipients (124 with detectable anti-HLA antibodies). Patients were divided into DSA strength (MFI < vs. ≥ 15 000) and C1q-binding ability. AMR frequency was high (30%) and it increased with DSA strength (P = 0.002) and C1q+ DSA (P < 0.001). The performance of DSA C1q-binding ability as a predictor of AMR was better than DSA strength (diagnostic odds ratio 16.3 vs. 6.4, respectively). Furthermore, a multivariable logistic regression showed that C1q+ DSA was a risk factor for AMR (OR = 16.80, P = 0.001), while high MFI DSAs were not. Graft survival was lower in high MFI C1q+ DSA in comparison with patients with C1q- high or low MFI DSA (at 6 years, 38%, 83% and 80%, respectively; P = 0.001). Both DSA strength and C1q-binding ability assessment seem valuable for improving pretransplant risk assessment. Since DSA C1q-binding ability was a better predictor of AMR and correlated with graft survival, C1q-SAB may be a particularly useful tool.

  13. C1q binding is not an independent risk factor for kidney allograft loss after an acute antibody-mediated rejection episode: a retrospective cohort study.

    PubMed

    Moktefi, Anissa; Parisot, Juliette; Desvaux, Dominique; Canoui-Poitrine, Florence; Brocheriou, Isabelle; Peltier, Julie; Audard, Vincent; Kofman, Tomek; Suberbielle, Caroline; Lang, Philippe; Rondeau, Eric; Grimbert, Philippe; Matignon, Marie

    2017-03-01

    After kidney transplantation, C4d is an incomplete marker of acute antibody-mediated rejection (AMR) and C1q-binding donor-specific antibodies (DSA) have been associated with allograft survival. However, the impact on allograft survival of C1q+ DSA after clinical AMR has not been studied yet. We analysed retrospectively in clinical AMR C4d staining and C1q-binding impact on allograft survival. We compared clinical, histological and serological features of C4d- and C4d+ AMR, C1q+ and C1q- DSA AMR and analysed C4d and C1q-binding impact on allograft survival. Among 500 for-cause kidney allograft biopsies, 48 fulfilled AMR criteria. C4d+ AMR [N = 18 (37.5%)] have significantly higher number class I DSA (P = 0.02), higher microvascular score (P = 0.02) and more transplant glomerulopathy (P = 0.04). C1q+ AMR [N = 20 (44%)] presented with significantly more class I and class II DSA (P = 0.005 and 0.04) and C4d+ staining (P = 0.01). Graft losses were significantly higher in the C4d+ group (P = 0.04) but similar in C1q groups. C4d+ but not C1q+ binding was an independent risk factor for graft loss [HR = 2.65; (1.11-6.34); P = 0.028]. In our cohort of clinical AMR, C4d+ staining but not C1q+ binding is an independent risk factor for graft loss. Allograft loss and patient survival were similar in C1q+ and C1q- AMR.

  14. Different regulatory and cytotoxic CD4+ T lymphocyte profiles in renal transplants with antibody-mediated chronic rejection or long-term good graft function.

    PubMed

    Giaretta, Fulvia; Bussolino, Stefania; Beltramo, Silvia; Fop, Fabrizio; Rossetti, Maura; Messina, Maria; Cantaluppi, Vincenzo; Ranghino, Andrea; Basso, Elisa; Camussi, Giovanni; Segoloni, Giuseppe Paolo; Biancone, Luigi

    2013-01-01

    Comparative analysis of the different subsets of CD4(+) T-lymphocytes may provide hints on the immunologic mechanisms operating in the long-term fate of a kidney transplant. We analyzed peripheral regulatory CD4(+) T cells (Tregs) and CD4(+) cytotoxic T lymphocytes (CTLs) in antibody-mediated chronic rejection (AMCR), in middle-term kidney transplants (2-4 years, MTKT) with good graft function and rejection-free history, in long-term kidney transplants (>15 years, LTKT) and in normal healthy subjects (NHS). Transplant groups with good prognosis (MTKT and LTKT) displayed a significant lower amount of CD4(+)CD25(high) T lymphocytes than NHS, with a trend of a higher percentage in AMCR than in MTKT and LTKT. However, CD4(+)CD25(high) Foxp3(+) cells were significantly higher in LTKT and MTKT than AMCR. Characterization of CD4(+)CD25(high) T cells showed a marked increase of intracellular CTLA-4 in the AMCR group in respect to the other transplant groups, while the expression of the surface molecule seemed to follow a reverse trend. In addition, CD27, a costimulatory receptor involved in long-term T cell survival and prevention of immune tolerance, is significantly reduced in CD4(+)CD25(high) and CD4(+)Foxp3(+) T cells in the LTKT in respect to the other transplant groups. CD4(+)CD25(high)CD45RO(+) and CD4(+)Foxp3(+)CD45RO(+) regulatory T cells with memory function were increased in LTKT compared to NHS and for the latter also in AMCR group. Finally, CD4(+)CTLs that were quantified on the basis of granzyme A expression, were more represented in AMCR patients in comparison to the other groups. Strikingly, CD27 in the CD4(+)CTLs was suppressed in LTKT and MTKT and markedly expressed in AMCR group. No significant differences in the expression of CD28 were observed among different groups. In conclusion, different profiles of Tregs and CD4(+)CTL populations correlate with different long-term conditions of kidney-transplanted patients, suggesting their role in the development

  15. Clinical Significance of HLA-DQ Antibodies in the Development of Chronic Antibody-Mediated Rejection and Allograft Failure in Kidney Transplant Recipients.

    PubMed

    Lee, Hyeyoung; Min, Ji Won; Kim, Ji-Il; Moon, In-Sung; Park, Ki-Hyun; Yang, Chul Woo; Chung, Byung Ha; Oh, Eun-Jee

    2016-03-01

    With the development of the single antigen beads assay, the role of donor specific alloantibody (DSA) against human leukocyte antigens in kidney transplantation (KT) has been highlighted. This study aimed to investigate the clinical significance of DQ-DSA detected at renal allograft biopsy. We evaluated 263 KT recipients who underwent allograft biopsy and DSA detection at the same time. Among them, 155 patients who were nonsensitized before transplantation were selected to investigate the role of de-novo DQ-DSA. Both the total and nonsensitized subgroup was categorized into 4 groups each according to DSA results as: DQ only, DQ + non-DQ, non-DQ, and no DSA. In the total patient group, post-KT DSA was positive in 79 (30.0%) patients and DQ-DSA was most prevalent (64.6%). In the nonsensitized subgroup, de-novo DSAs were detected in 45 (29.0%) patients and DQ-DSA was also most prevalent (73.3%). The DQ only group showed a significantly longer post-KT duration compared to the other groups (P < 0.05). The overall incidence of antibody-mediated rejection (AMR) was 17.9%. B-DSA, DR-DSA, and DQ-DSA were associated with AMR (P < 0.05), but in the analysis for chronic AMR, only DQ-DSA showed significance in both the total and the nonsensitized subgroup (P < 0.05). On comparison of Banff scores among groups, those representing humoral immunity were significantly dominant in all DSA positive groups compared to the no DSA group (P < 0.05), and higher scores of markers representing chronic tissue injury were more frequently detected in the groups with DQ-DSA. The worst postbiopsy survival was seen in the DQ + non-DQ group of the total patient group, and patients with de-novo DQ-DSA showed poorer graft survival in the nonsensitized subgroup compared to the no DSA group (P < 0.05). In the multivariate analysis, de-novo DQ-DSA was the only significant risk factor associated with late allograft failure (P < 0.05). Our study is the first to demonstrate

  16. Cell-Free DNA and Active Rejection in Kidney Allografts.

    PubMed

    Bloom, Roy D; Bromberg, Jonathan S; Poggio, Emilio D; Bunnapradist, Suphamai; Langone, Anthony J; Sood, Puneet; Matas, Arthur J; Mehta, Shikha; Mannon, Roslyn B; Sharfuddin, Asif; Fischbach, Bernard; Narayanan, Mohanram; Jordan, Stanley C; Cohen, David; Weir, Matthew R; Hiller, David; Prasad, Preethi; Woodward, Robert N; Grskovic, Marica; Sninsky, John J; Yee, James P; Brennan, Daniel C

    2017-03-09

    Histologic analysis of the allograft biopsy specimen is the standard method used to differentiate rejection from other injury in kidney transplants. Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive test of allograft injury that may enable more frequent, quantitative, and safer assessment of allograft rejection and injury status. To investigate this possibility, we prospectively collected blood specimens at scheduled intervals and at the time of clinically indicated biopsies. In 102 kidney recipients, we measured plasma levels of dd-cfDNA and correlated the levels with allograft rejection status ascertained by histology in 107 biopsy specimens. The dd-cfDNA level discriminated between biopsy specimens showing any rejection (T cell-mediated rejection or antibody-mediated rejection [ABMR]) and controls (no rejection histologically), P<0.001 (receiver operating characteristic area under the curve [AUC], 0.74; 95% confidence interval [95% CI], 0.61 to 0.86). Positive and negative predictive values for active rejection at a cutoff of 1.0% dd-cfDNA were 61% and 84%, respectively. The AUC for discriminating ABMR from samples without ABMR was 0.87 (95% CI, 0.75 to 0.97). Positive and negative predictive values for ABMR at a cutoff of 1.0% dd-cfDNA were 44% and 96%, respectively. Median dd-cfDNA was 2.9% (ABMR), 1.2% (T cell-mediated types ≥IB), 0.2% (T cell-mediated type IA), and 0.3% in controls (P=0.05 for T cell-mediated rejection types ≥IB versus controls). Thus, dd-cfDNA may be used to assess allograft rejection and injury; dd-cfDNA levels <1% reflect the absence of active rejection (T cell-mediated type ≥IB or ABMR) and levels >1% indicate a probability of active rejection.

  17. MiR-142-5p and miR-486-5p as biomarkers for early detection of chronic antibody-mediated rejection in kidney transplantation.

    PubMed

    Iwasaki, Kenta; Yamamoto, Takayuki; Inanaga, Yukiko; Hiramitsu, Takahisa; Miwa, Yuko; Murotani, Kenta; Narumi, Shuji; Watarai, Yoshihiko; Katayama, Akio; Uchida, Kazuharu; Kobayashi, Takaaki

    2017-02-01

    De novo donor-specific HLA antibody (DSA) would not necessarily contribute to chronic antibody-mediated rejection (CAMR) in kidney transplantation. Here, we investigated whether PBMC miRNAs could be predictable biomarkers for CAMR. Microarray profiling of 435 mature miRNAs in pooled samples was conducted. Individual analysis revealed that miR-142-5p was significantly (p < 0.01) underexpressed in patients with DSA. After DSA production, miR-486-5p and its target PTEN/foxO3 mRNA were significantly overexpressed (p < 0.01) and underexpressed (p < 0.01), respectively, in patients with biopsy-proven CAMR, compared with non-CAMR. Our studies suggest that miRNA expression patterns may serve as noninvasive diagnostic biomarkers to evaluate immune response and kidney allograft status.

  18. Seroprevalence of Antibody-Mediated, Complement-Dependent Opsonophagocytic Activity against Neisseria meningitidis Serogroup B in England.

    PubMed

    Humphries, Holly E; Brookes, Charlotte; Allen, Lauren; Kuisma, Eeva; Gorringe, Andrew; Taylor, Stephen

    2015-05-01

    The correlate of protection for the licensure of meningococcal vaccines is serum bactericidal activity. However, evidence indicates that a complex situation and other mechanisms, such as antibody-mediated, complement-dependent opsonophagocytosis (OP), may play a role in protection and should be investigated in order to understand immunity to this disease. In this study, a high-throughput flow cytometric opsonophagocytic assay (OPA) was optimized. The assay measures the presence of killed fluorescently labeled Neisseria meningitidis within human granulocytes (differentiated HL60 cells) by flow cytometry, using IgG-depleted pooled human plasma as an exogenous source of complement. This method was found to be reliable and correlated with the results of an opsonophagocytic killing assay. The OPA was used to measure OP activity in 1,878 serum samples from individuals ranging from 0 to 99 years of age against N. meningitidis strain NZ98/254 (B:4:P1.7-2,4). The levels of OP activity in individual serum samples varied greatly. OP activity showed an initial peak in the 6- to 12-month age group corresponding to a peak in disease incidence. The OP activity dropped in childhood until the late teenage years, although there was still a higher percentage of individuals with OP activity than with protective bactericidal antibody titers. OP activity reached a peak in the 30- to 39-year age group and then declined. This later peak in OP activity did not coincide with the young adults in whom peak serum bactericidal activity and disease incidence occurred. The demonstration of OP activity when disease incidence is low and when protective bactericidal antibody titers are not detected may indicate a role for OP in protection from meningococcal disease in these age groups.

  19. Seroprevalence of Antibody-Mediated, Complement-Dependent Opsonophagocytic Activity against Neisseria meningitidis Serogroup B in England

    PubMed Central

    Brookes, Charlotte; Allen, Lauren; Kuisma, Eeva; Gorringe, Andrew; Taylor, Stephen

    2015-01-01

    The correlate of protection for the licensure of meningococcal vaccines is serum bactericidal activity. However, evidence indicates that a complex situation and other mechanisms, such as antibody-mediated, complement-dependent opsonophagocytosis (OP), may play a role in protection and should be investigated in order to understand immunity to this disease. In this study, a high-throughput flow cytometric opsonophagocytic assay (OPA) was optimized. The assay measures the presence of killed fluorescently labeled Neisseria meningitidis within human granulocytes (differentiated HL60 cells) by flow cytometry, using IgG-depleted pooled human plasma as an exogenous source of complement. This method was found to be reliable and correlated with the results of an opsonophagocytic killing assay. The OPA was used to measure OP activity in 1,878 serum samples from individuals ranging from 0 to 99 years of age against N. meningitidis strain NZ98/254 (B:4:P1.7-2,4). The levels of OP activity in individual serum samples varied greatly. OP activity showed an initial peak in the 6- to 12-month age group corresponding to a peak in disease incidence. The OP activity dropped in childhood until the late teenage years, although there was still a higher percentage of individuals with OP activity than with protective bactericidal antibody titers. OP activity reached a peak in the 30- to 39-year age group and then declined. This later peak in OP activity did not coincide with the young adults in whom peak serum bactericidal activity and disease incidence occurred. The demonstration of OP activity when disease incidence is low and when protective bactericidal antibody titers are not detected may indicate a role for OP in protection from meningococcal disease in these age groups. PMID:25739917

  20. ANTIBODY-MEDIATED ACTIVATION OF A DEFECTIVE β-D-GALACTOSIDASE

    PubMed Central

    Celada, Franco; Ellis, John; Bodlund, Kerstin; Rotman, Boris

    1971-01-01

    Two closely related protein antigens were used to study immunogenic competition. Namely, normal β-D-galactosidase of Escherichia coli (Z) and a genetically defective β-D-galactosidase (AMEF) which seems to differ from the normal in one amino acid substitution. A unique characteristic of this pair of antigens is that, although they are indistinguishable in precipitation and absorption tests with antibodies, the enzymatic activity of AMEF is specifically increased several-hundredfold in the presence of antibodies directed against Z. The following results show that Z and AMEF also differ in their immunogenic ability: (a) antibodies directed against Z activated AMEF; antibodies directed against AMEF did not activate, but competed specifically with activating antibodies. (b) Animals immunized with AMEF failed to produce activating antibodies when they were subsequently challenged with Z, although the presence of some cells primed to produce activating antibodies could be demonstrated by adoptive transfer. (c) Animals preimmunized with Z were stimulated in their production of activating antibodies by AMEF challenge, although not as efficiently as with Z. A model explaining these observations by competition for the immunogenic site among antigen-sensitive cells carrying cross-reacting receptors is presented. PMID:15776573

  1. Antibody-mediated sialidase activity in blood serum of patients with multiple myeloma.

    PubMed

    Bilyy, Rostyslav; Tomin, Andriy; Mahorivska, Iryna; Shalay, Olga; Lohinskyy, Volodymyr; Stoika, Rostyslav; Kit, Yuriy

    2011-01-01

    Cell surface sialylation is known to be tightly connected with tumorigenicity, invasiveness, metastatic potential, clearance of aged cells, while the sialylation of IgG molecules determines their anti-inflammatory properties. Four sialidases - hydrolytic enzymes responsible for cleavage of sialic residues - were described in different cellular compartments. However, sialidases activity in body fluids, and specifically in blood serum, remains poorly studied. Here, we characterize first known IgG antibodies possessing sialidase-like activity in blood serum of multiple myeloma (MM) patients. Ig fractions were precipitated with ammonium sulfate (50% of saturation) from blood serum of 12 healthy donors and 14 MM patients, and screened for the presence of sialidase activity by using 4-MUNA (2'-(4-methylumbelliferyl)-α-D-N-acetylneuraminic acid) as substrate. High level of sialidase activity was detected in the MM patients, but not in healthy donors. Subsequent antibody purification by protein-G affinity chromatography and HPLC size exclusion chromatography at acidic conditions demonstrated that sialidase activity was attributable to IgG molecules. Sialidase activity was also specific for (Fab)(2) fragment of IgG and blocked by sialidase inhibitor DANA. Sialidase activity of IgG molecule was also confirmed by in gel assay for cleavage of sialidase substrate. Kinetic parameters of the catalysis reaction were described by Michaelis-Menten equation with K(m)  = 44.4-108 µM and k(cat) = 2.7-23.1 min(-1). The action of IgG possessing sialidase-like activity towards human red blood cells resulted in a subsequent increase in their agglutination by the peanut agglutinin, that confirms their desialylation by the studied IgG. This is the first demonstration of the intrinsic sialidase activity of IgG isolated from blood serum of MM patients.

  2. Antibody-Mediated Elimination of the Obligate Intracellular Bacterial Pathogen Ehrlichia chaffeensis during Active Infection

    PubMed Central

    Winslow, Gary M.; Yager, Eric; Shilo, Konstantin; Volk, Erin; Reilly, Andrew; Chu, Frederick K.

    2000-01-01

    It is generally accepted that cellular, but not humoral immunity, plays an important role in host defense against intracellular bacteria. However, studies of some of these pathogens have provided evidence that antibodies can provide immunity if present during the initiation of infection. Here, we examined immunity against infection by Ehrlichia chaffeensis, an obligate intracellular bacterium that causes human monocytic ehrlichiosis. Studies with mice have demonstrated that immunocompetent strains are resistant to persistent infection but that SCID mice become persistently and fatally infected. Transfer of immune serum or antibodies obtained from immunocompetent C57BL/6 mice to C57BL/6 scid mice provided significant although transient protection from infection. Bacterial clearance was observed when administration occurred at the time of inoculation or well after infection was established. The effect was dose dependent, occurred within 2 days, and persisted for as long as 2 weeks. Weekly serum administration prolonged the survival of susceptible mice. Although cellular immunity is required for complete bacterial clearance, the data show that antibodies can play a significant role in the elimination of this obligate intracellular bacterium during active infection and thus challenge the paradigm that humoral responses are unimportant for immunity to such organisms. PMID:10722619

  3. Extended active disturbance rejection controller

    NASA Technical Reports Server (NTRS)

    Gao, Zhiqiang (Inventor); Tian, Gang (Inventor)

    2012-01-01

    Multiple designs, systems, methods and processes for controlling a system or plant using an extended active disturbance rejection control (ADRC) based controller are presented. The extended ADRC controller accepts sensor information from the plant. The sensor information is used in conjunction with an extended state observer in combination with a predictor that estimates and predicts the current state of the plant and a co-joined estimate of the system disturbances and system dynamics. The extended state observer estimates and predictions are used in conjunction with a control law that generates an input to the system based in part on the extended state observer estimates and predictions as well as a desired trajectory for the plant to follow.

  4. Extended Active Disturbance Rejection Controller

    NASA Technical Reports Server (NTRS)

    Gao, Zhiqiang (Inventor); Tian, Gang (Inventor)

    2014-01-01

    Multiple designs, systems, methods and processes for controlling a system or plant using an extended active disturbance rejection control (ADRC) based controller are presented. The extended ADRC controller accepts sensor information from the plant. The sensor information is used in conjunction with an extended state observer in combination with a predictor that estimates and predicts the current state of the plant and a co-joined estimate of the system disturbances and system dynamics. The extended state observer estimates and predictions are used in conjunction with a control law that generates an input to the system based in part on the extended state observer estimates and predictions as well as a desired trajectory for the plant to follow.

  5. Extended Active Disturbance Rejection Controller

    NASA Technical Reports Server (NTRS)

    Gao, Zhiqiang (Inventor); Tian, Gang (Inventor)

    2016-01-01

    Multiple designs, systems, methods and processes for controlling a system or plant using an extended active disturbance rejection control (ADRC) based controller are presented. The extended ADRC controller accepts sensor information from the plant. The sensor information is used in conjunction with an extended state observer in combination with a predictor that estimates and predicts the current state of the plant and a co-joined estimate of the system disturbances and system dynamics. The extended state observer estimates and predictions are used in conjunction with a control law that generates an input to the system based in part on the extended state observer estimates and predictions as well as a desired trajectory for the plant to follow.

  6. Fractional active disturbance rejection control.

    PubMed

    Li, Dazi; Ding, Pan; Gao, Zhiqiang

    2016-05-01

    A fractional active disturbance rejection control (FADRC) scheme is proposed to improve the performance of commensurate linear fractional order systems (FOS) and the robust analysis shows that the controller is also applicable to incommensurate linear FOS control. In FADRC, the traditional extended states observer (ESO) is generalized to a fractional order extended states observer (FESO) by using the fractional calculus, and the tracking differentiator plus nonlinear state error feedback are replaced by a fractional proportional-derivative controller. To simplify controller tuning, the linear bandwidth-parameterization method has been adopted. The impacts of the observer bandwidth ωo and controller bandwidth ωc on system performance are then analyzed. Finally, the FADRC stability and frequency-domain characteristics for linear single-input single-output FOS are analyzed. Simulation results by FADRC and ADRC on typical FOS are compared to demonstrate the superiority and effectiveness of the proposed scheme.

  7. Mechanisms involved in antibody- and complement-mediated allograft rejection

    PubMed Central

    2010-01-01

    Antibody-mediated rejection has become critical clinically because this form of rejection is usually unresponsive to conventional anti-rejection therapy, and therefore, it has been recognized as a major cause of allograft loss. Our group developed experimental animal models of vascularized organ transplantation to study pathogenesis of antibody- and complement-mediated endothelial cell injury leading to graft rejection. In this review, we discuss mechanisms of antibody-mediated graft rejection resulting from activation of complement by C1q- and MBL (mannose-binding lectin)-dependent pathways and interactions with a variety of effector cells, including macrophages and monocytes through Fcγ receptors and complement receptors. PMID:20135240

  8. Decreased Fc-Receptor expression on innate immune cells is associated with impaired antibody mediated cellular phagocytic activity in chronically HIV-1 infected individuals

    PubMed Central

    Dugast, Anne-Sophie; Tonelli, Andrew; Berger, Christoph T.; Ackerman, Margaret E.; Sciaranghella, Gaia; Liu, Qingquan; Sips, Magdalena; Toth, Ildiko; Piechocka-Trocha, Alicja; Ghebremichael, Musie; Alter, Galit

    2011-01-01

    In addition to neutralization, antibodies mediate other antiviral activities including antibody-dependent cellular-phagocytosis (ADCP), antibody dependent cellular-cytotoxicity (ADCC), as well as complement deposition. While it is established that progressive HIV infection is associated with reduced ADCC and ADCP, the underlying mechanism for this loss of function is unknown. Here we report considerable changes in FcR expression over the course of HIV infection on both mDCs and monocytes, including elevated FcγRI expression in acute HIV infection and reduced expression of FcγRII and FcγRIIIa in chronic HIV infection. Furthermore, selective blockade of FcγRII alone was associated with a loss in ADCP activity, suggesting that FcγRII plays a central role in modulating ADCP. Overall, HIV infection is associated with a number of changes in FcR expression on phagocytic cells that are associated with changes in their ability to respond to antibody-opsonized targets, potentially contributing to a failure in viral clearance in progressive HIV-1 infection. PMID:21565376

  9. Decreased Fc receptor expression on innate immune cells is associated with impaired antibody-mediated cellular phagocytic activity in chronically HIV-1 infected individuals.

    PubMed

    Dugast, Anne-Sophie; Tonelli, Andrew; Berger, Christoph T; Ackerman, Margaret E; Sciaranghella, Gaia; Liu, Qingquan; Sips, Magdalena; Toth, Ildiko; Piechocka-Trocha, Alicja; Ghebremichael, Musie; Alter, Galit

    2011-07-05

    In addition to neutralization, antibodies mediate other antiviral activities including antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC), as well as complement deposition. While it is established that progressive HIV infection is associated with reduced ADCC and ADCP, the underlying mechanism for this loss of function is unknown. Here we report considerable changes in FcR expression over the course of HIV infection on both mDCs and monocytes, including elevated FcγRI expression in acute HIV infection and reduced expression of FcγRII and FcγRIIIa in chronic HIV infection. Furthermore, selective blockade of FcγRII alone was associated with a loss in ADCP activity, suggesting that FcγRII plays a central role in modulating ADCP. Overall, HIV infection is associated with a number of changes in FcR expression on phagocytic cells that are associated with changes in their ability to respond to antibody-opsonized targets, potentially contributing to a failure in viral clearance in progressive HIV-1 infection.

  10. Antibody-mediated activation of a defective beta-D-galactosidase: dimeric form of the activatable mutant enzyme.

    PubMed

    Conway de Macario, E; Ellis, J; Guzman, R; Rotman, B

    1978-02-01

    Sedimentation analyses of AMEF, an activatable mutant beta-D-galactosidase (beta-D-galactoside galactohydrolase, EC 3.2.1.23), and the products of its reaction with Fab fragments of activating antibody show that this enzyme exists mainly as 10S dimers. Activation of AMEF by purified antibody resulted in formation of 16S tetramers. A unifying hypothesis postulating a dimer--tetramer equilibrium accounts for this observation as the counterpart of inactivation, which was shown to involve the breakdown of tetramers into inactive subunits [Roth, R. A. & Rotman, B. (1975) Biochem. Biophys. Res. Commun. 67, 1382--1390]. Conditions are described under which AMEF loses the specific antigenic determinant(s) responsible for binding activating antibody, allowing its subsequent use as an absorption to obtain immunologically purified activating antibody,

  11. Antibody-mediated activation of a defective beta-D-galactosidase: dimeric form of the activatable mutant enzyme.

    PubMed Central

    de Macario, E C; Ellis, J; Guzman, R; Rotman, B

    1978-01-01

    Sedimentation analyses of AMEF, an activatable mutant beta-D-galactosidase (beta-D-galactoside galactohydrolase, EC 3.2.1.23), and the products of its reaction with Fab fragments of activating antibody show that this enzyme exists mainly as 10S dimers. Activation of AMEF by purified antibody resulted in formation of 16S tetramers. A unifying hypothesis postulating a dimer--tetramer equilibrium accounts for this observation as the counterpart of inactivation, which was shown to involve the breakdown of tetramers into inactive subunits [Roth, R. A. & Rotman, B. (1975) Biochem. Biophys. Res. Commun. 67, 1382--1390]. Conditions are described under which AMEF loses the specific antigenic determinant(s) responsible for binding activating antibody, allowing its subsequent use as an absorption to obtain immunologically purified activating antibody, PMID:416439

  12. Antibody-mediated resistance against plant pathogens.

    PubMed

    Safarnejad, Mohammad Reza; Jouzani, Gholamreza Salehi; Tabatabaei, Meisam; Tabatabaie, Meisam; Twyman, Richard M; Schillberg, Stefan

    2011-01-01

    Plant diseases have a significant impact on the yield and quality of crops. Many strategies have been developed to combat plant diseases, including the transfer of resistance genes to crops by conventional breeding. However, resistance genes can only be introgressed from sexually-compatible species, so breeders need alternative measures to introduce resistance traits from more distant sources. In this context, genetic engineering provides an opportunity to exploit diverse and novel forms of resistance, e.g. the use of recombinant antibodies targeting plant pathogens. Native antibodies, as a part of the vertebrate adaptive immune system, can bind to foreign antigens and eliminate them from the body. The ectopic expression of antibodies in plants can also interfere with pathogen activity to confer disease resistance. With sufficient knowledge of the pathogen life cycle, it is possible to counter any disease by designing expression constructs so that pathogen-specific antibodies accumulate at high levels in appropriate sub-cellular compartments. Although first developed to tackle plant viruses and still used predominantly for this purpose, antibodies have been targeted against a diverse range of pathogens as well as proteins involved in plant-pathogen interactions. Here we comprehensively review the development and implementation of antibody-mediated disease resistance in plants.

  13. Bortezomib for refractory antibody-mediated cardiac allograft rejection.

    PubMed

    Eckman, Peter M; Thorsgard, Marit; Maurer, David; Kim, Youngki; Alloway, Rita R; Woodle, E Steve

    2009-01-01

    This experience demonstrates that a bortezomib-based regimen provided effective therapy for late, refractory AMR in an adult heart transplant recipient and was well tolerated. This remarkably positive experience despite the refractory nature of the AMR episode argues strongly for continued evaluation of bortezomib use in this patient population.

  14. Polymorphisms in the lectin pathway of complement activation influence the incidence of acute rejection and graft outcome after kidney transplantation.

    PubMed

    Golshayan, Déla; Wójtowicz, Agnieszka; Bibert, Stéphanie; Pyndiah, Nitisha; Manuel, Oriol; Binet, Isabelle; Buhler, Leo H; Huynh-Do, Uyen; Mueller, Thomas; Steiger, Jürg; Pascual, Manuel; Meylan, Pascal; Bochud, Pierre-Yves

    2016-04-01

    There are conflicting data on the role of the lectin pathway of complement activation and its recognition molecules in acute rejection and outcome after transplantation. To help resolve this we analyzed polymorphisms and serum levels of lectin pathway components in 710 consecutive kidney transplant recipients enrolled in the nationwide Swiss Transplant Cohort Study, together with all biopsy-proven rejection episodes and 1-year graft and patient survival. Functional mannose-binding lectin (MBL) levels were determined in serum samples, and previously described MBL2, ficolin 2, and MBL-associated serine protease 2 polymorphisms were genotyped. Low MBL serum levels and deficient MBL2 diplotypes were associated with a higher incidence of acute cellular rejection during the first year, in particular in recipients of deceased-donor kidneys. This association remained significant (hazard ratio 1.75, 95% confidence interval 1.18-2.60) in a Cox regression model after adjustment for relevant covariates. In contrast, there was no significant association with rates of antibody-mediated rejection, patient death, early graft dysfunction or loss. Thus, results in a prospective multicenter contemporary cohort suggest that MBL2 polymorphisms result in low MBL serum levels and are associated with acute cellular rejection after kidney transplantation. Since MBL deficiency is a relatively frequent trait in the normal population, our findings may lead to individual risk stratification and customized immunosuppression.

  15. Active disturbance rejection control for fractional-order system.

    PubMed

    Li, Mingda; Li, Donghai; Wang, Jing; Zhao, Chunzhe

    2013-05-01

    Fractional-order proportional-integral (PI) and proportional-integral-derivative (PID) controllers are the most commonly used controllers in fractional-order systems. However, this paper proposes a simple integer-order control scheme for fractional-order system based on active disturbance rejection method. By treating the fractional-order dynamics as a common disturbance and actively rejecting it, active disturbance rejection control (ADRC) can achieve the desired response. External disturbance, sensor noise, and parameter disturbance are also estimated using extended state observer. The ADRC stability of rational-order model is analyzed. Simulation results on three typical fractional-order systems are provided to demonstrate the effectiveness of the proposed method.

  16. Rational clinical trial design for antibody mediated renal allograft injury

    PubMed Central

    Sandal, Shaifali; Zand, Martin S.

    2015-01-01

    Antibody mediated renal allograft rejection is a significant cause of acute and chronic graft loss. Recent work has revealed that AMR is a complex processes, involving B and plasma cells, donor-specific antibodies, complement, vascular endothelial cells, NK cells, Fc receptors, cytokines and chemokines. These insights have led to the development of numerous new therapies, and adaptation of others originally developed for treatment of hemetologic malignancies, autoimmune and complement mediated conditions. Here we review emerging insights into the pathophysiology of AMR as well as current and emerging therapies for both acute and chronic AMR. Finally, we discuss rational clinical trial design in light of antibody and B cell immunobiology, as well as appropriate efficacy metrics to identify robust protocols and therapeutic agents. PMID:25553476

  17. Active disturbance rejection in large flexible space structures

    NASA Technical Reports Server (NTRS)

    Parlos, Alexander G.; Sunkel, John W.

    1990-01-01

    The design of an active control law for the rejection of persistent disturbances, in large space structures is presented. The control system design approach is based on a deterministic model of the disturbances and it optimizes the magnitude of the disturbance that the structure can tolerate without violating certain predetermined constraints. In addition to closed-loop stability, the explicit treatment of state, control, and control rate constraints, such as structural displacement and control actuator effort, guarantees that the final design will exhibit desired performance characteristics. The technique is applied to a simple two-bay truss structure, and its response is compared with that obtained using a linear-quadratic-Gaussian/loop-transfer-recovery (LQG/LTR) compensator. Preliminary results indicate that the proposed control system can reject persistent disturbances of greater magnitude by utilizing most of the available control, while limiting the structural displacements to within desired tolerances.

  18. Modified active disturbance rejection control for time-delay systems.

    PubMed

    Zhao, Shen; Gao, Zhiqiang

    2014-07-01

    Industrial processes are typically nonlinear, time-varying and uncertain, to which active disturbance rejection control (ADRC) has been shown to be an effective solution. The control design becomes even more challenging in the presence of time delay. In this paper, a novel modification of ADRC is proposed so that good disturbance rejection is achieved while maintaining system stability. The proposed design is shown to be more effective than the standard ADRC design for time-delay systems and is also a unified solution for stable, critical stable and unstable systems with time delay. Simulation and test results show the effectiveness and practicality of the proposed design. Linear matrix inequality (LMI) based stability analysis is provided as well.

  19. Dynamic positioning system based on active disturbance rejection technology

    NASA Astrophysics Data System (ADS)

    Lei, Zhengling; Guo, Chen; Fan, Yunsheng

    2015-08-01

    A dynamically positioned vessel, by the International Maritime Organization (IMO) and the certifying class societies (DNV, ABS, LR, etc.), is defined as a vessel that maintains its position and heading (fixed location or pre-determined track) exclusively by means of active thrusters. The development of control technology promotes the upgrading of dynamic positioning (DP) systems. Today there are two different DP systems solutions available on the market: DP system based on PID regulator and that based on model-based control. Both systems have limited disturbance rejection capability due to their design principle. In this paper, a new DP system solution is proposed based on Active Disturbance Rejection Control (ADRC) technology. This technology is composed of Tracking-Differentiator (TD), Extended State Observer (ESO) and Nonlinear Feedback Combination. On one hand, both TD and ESO can act as filters and can be used in place of conventional filters; on the other hand, the total disturbance of the system can be estimated and compensated by ESO, which therefore enhances the system's disturbance rejection capability. This technology's advantages over other methods lie in two aspects: 1) This method itself can not only achieve control objectives but also filter noisy measurements without other specialized filters; 2) This method offers a new useful approach to suppress the ocean disturbance. The simulation results demonstrate the effectiveness of the proposed method.

  20. Antibody-mediated activation of a defective beta-D-galactosidase. II. Immunological relationship between the normal and the defective enzyme.

    PubMed

    Celada, F; Ellis, J; Bodlund, K; Rotman, B

    1971-09-01

    Two closely related protein antigens were used to study immunogenic competition. Namely, normal beta-D-galactosidase of Escherichia coli (Z) and a genetically defective beta-D-galactosidase (AMEF) which seems to differ from the normal in one amino acid substitution. A unique characteristic of this pair of antigens is that, although they are indistinguishable in precipitation and absorption tests with antibodies, the enzymatic activity of AMEF is specifically increased several-hundredfold in the presence of antibodies directed against Z. The following results show that Z and AMEF also differ in their immunogenic ability: (a) antibodies directed against Z activated AMEF; antibodies directed against AMEF did not activate, but competed specifically with activating antibodies. (b) Animals immunized with AMEF failed to produce activating antibodies when they were subsequently challenged with Z, although the presence of some cells primed to produce activating antibodies could be demonstrated by adoptive transfer. (c) Animals preimmunized with Z were stimulated in their production of activating antibodies by AMEF challenge, although not as efficiently as with Z. A model explaining these observations by competition for the immunogenic site among antigen-sensitive cells carrying cross-reacting receptors is presented.

  1. The Fc-region of a new class of intact bispecific antibody mediates activation of accessory cells and NK cells and induces direct phagocytosis of tumour cells

    PubMed Central

    Zeidler, R; Mysliwietz, J; Csánady, M; Walz, A; Ziegler, I; Schmitt, B; Wollenberg, B; Lindhofer, H

    2000-01-01

    Bispecific antibodies (bsAb) are considered as promising tools for the elimination of disseminated tumour cells in a minimal residual disease situation. The bsAb-mediated recruitment of an immune effector cell in close vicinity of a tumour cell is thought to induce an antitumoural immune response. However, classical bispecific molecules activate only a single class of immune effector cell that may not yield optimal immune responses. We therefore constructed an intact bispecific antibody, BiUII (anti-CD3 × anti-EpCAM), that not only recognizes tumour cells and T lymphocytes with its two binding arms, but also binds and activates Fcγ-receptor positive accessory cells through its Fc-region. We have demonstrated recently that activated accessory cells contribute to the bsAb-induced antitumoural activity. We now analyse this stimulation in more detail and demonstrate here the BiUll-induced upregulation of activation markers like CD83 and CD95 on accessory cells and the induction of neopterin and biopterin synthesis. Experiments with pure cell subpopulations revealed binding of BiUll to CD64+ accessory cells and CD16+ NK cells, but not to CD32+ B lymphocytes. We provide further evidence for the importance of the Fc-region in that this bispecific molecule stimulates Fcγ-R-positive accessory cells to eliminate tumour cells in vitro by direct phagocytosis. © 2000 Cancer Research Campaign PMID:10901380

  2. HA Antibody-Mediated FcγRIIIa Activity Is Both Dependent on FcR Engagement and Interactions between HA and Sialic Acids

    PubMed Central

    Cox, Freek; Kwaks, Ted; Brandenburg, Boerries; Koldijk, Martin H.; Klaren, Vincent; Smal, Bastiaan; Korse, Hans J. W. M.; Geelen, Eric; Tettero, Lisanne; Zuijdgeest, David; Stoop, Esther J. M.; Saeland, Eirikur; Vogels, Ronald; Friesen, Robert H. E.; Koudstaal, Wouter; Goudsmit, Jaap

    2016-01-01

    Interactions with receptors for the Fc region of IgG (FcγRs) have been shown to contribute to the in vivo protection against influenza A viruses provided by broadly neutralizing antibodies (bnAbs) that bind to the viral hemagglutinin (HA) stem. In particular, Fc-mediated antibody-dependent cellular cytotoxicity (ADCC) has been shown to contribute to protection by stem-binding bnAbs. Fc-mediated effector functions appear not to contribute to protection provided by strain-specific HA head-binding antibodies. We used a panel of anti-stem and anti-head influenza A and B monoclonal antibodies with identical human IgG1 Fc domains and investigated their ability to mediate ADCC-associated FcγRIIIa activation. Antibodies which do not interfere with sialic acid binding of HA can mediate FcγRIIIa activation. However, the FcγRIIIa activation was inhibited when a mutant HA, unable to bind sialic acids, was used. Antibodies which block sialic acid receptor interactions of HA interfered with FcγRIIIa activation. The inhibition of FcγRIIIa activation by HA head-binding and sialic acid receptor-blocking antibodies was confirmed in plasma samples of H5N1 vaccinated human subjects. Together, these results suggest that in addition to Fc–FcγR binding, interactions between HA and sialic acids on immune cells are required for optimal Fc-mediated effector functions by anti-HA antibodies. PMID:27746785

  3. HIV-specific CD4-induced Antibodies Mediate Broad and Potent Antibody-dependent Cellular Cytotoxicity Activity and are Commonly Detected in Plasma from HIV-infected Humans

    PubMed Central

    Williams, Katherine L.; Cortez, Valerie; Dingens, Adam S.; Gach, Johannes S.; Rainwater, Stephanie; Weis, Julie F.; Chen, Xuemin; Spearman, Paul; Forthal, Donald N.; Overbaugh, Julie

    2015-01-01

    HIV-specific antibodies (Abs) can reduce viral burden by blocking new rounds of infection or by destroying infected cells via activation of effector cells through Fc–FcR interaction. This latter process, referred to as antibody-dependent cellular cytotoxicity (ADCC), has been associated with viral control and improved clinical outcome following both HIV and SIV infections. Here we describe an HIV viral-like particle (VLP)-based sorting strategy that led to identification of HIV-specific memory B cells encoding Abs that mediate ADCC from a subtype A-infected Kenyan woman at 914 days post-infection. Using this strategy, 12 HIV-envelope-specific monoclonal antibodies (mAbs) were isolated and three mediated potent ADCC activity when compared to well-characterized ADCC mAbs. The ADCC-mediating Abs also mediated antibody-dependent cell-mediated virus inhibition (ADCVI), which provides a net measure of Fc receptor-triggered effects against replicating virus. Two of the three ADCC-mediating Abs targeted a CD4-induced (CD4i) epitope also bound by the mAb C11; the third antibody targeted the N-terminus of V3. Both CD4i Abs identified here demonstrated strong cross-clade breadth with activity against 10 of 11 envelopes tested, including those from clades A, B, C, A/D and C/D, whereas the V3-specific antibody showed more limited breadth. Variants of these CD4i, C11-like mAbs engineered to interrupt binding to FcγRs inhibited a measurable percentage of the donor's ADCC activity starting as early as 189 days post-infection. C11-like antibodies also accounted for between 18–78% of ADCC activity in 9 chronically infected individuals from the same cohort study. Further, the two CD4i Abs originated from unique B cells, suggesting that antibodies targeting this epitope can be commonly produced. Taken together, these data provide strong evidence that CD4i, C11-like antibodies develop within the first 6 months of infection and they can arise from unique B-cell lineages in the

  4. Active disturbance rejection control of temperature for ultrastable optical cavities.

    PubMed

    Pizzocaro, Marco; Calonico, Davide; Calosso, Claudio; Clivati, Cecilia; Costanzo, Giovanni A; Levi, Filippo; Mura, Alberto

    2013-02-01

    This paper describes the application of a novel active disturbance rejection control (ADRC) to the stabilization of the temperature of two ultra-stable Fabry-Perot cavities. The cavities are 10 cm long and entirely made of ultralow- expansion glass. The control is based on a linear extended state observer that estimates and compensates the disturbance in the system in real time. The resulting control is inherently robust and easy to tune. A digital implementation of ADRC gives a temperature instability of 200 μK at one day of integration time.

  5. Active rejection of persistent disturbances in flexible space structures

    NASA Technical Reports Server (NTRS)

    Hwang, Cheng-Neng; Jayasuriya, Suhada; Parlos, Alexander G.; Sunkel, John W.

    1990-01-01

    A dynamic compensator for active rejection of persistent disturbances in flexible space structures is designed on the principle of the H(infinity)-optimization of the sensitivity transfer function matrix. A general state space solution is formulated to the multiinput multioutput H(infinity)-optimal control problem, allowing the use of the H(infinity)-optimal synthesis algorithm for the state-space models of space structures that result from model order reduction. Disturbances encountered in flexible space structures, such as shuttle docking, are investigated using the high-mode and the reduced-order models of a cantilevered two-bay truss, demonstrating the applicability of the H(infinity)-optimal approach.

  6. CD147 monoclonal antibody mediated by chitosan nanoparticles loaded with α-hederin enhances antineoplastic activity and cellular uptake in liver cancer cells

    PubMed Central

    Zhu, Rong; Zhang, Chun-ge; Liu, Yang; Yuan, Zhi-qiang; Chen, Wei-liang; Yang, Shu-di; Li, Ji-zhao; Zhu, Wen-jing; Zhou, Xiao-feng; You, Ben-gang; Zhang, Xue-nong

    2015-01-01

    An antibody that specifically interacts with an antigen could be applied to an active targeting delivery system. In this study, CD147 antibody was coupled with α-hed chitosan nanoparticles (α-Hed-CS-NPs). α-Hed-CS-CD147-NPs were round and spherical in shape, with an average particle size of 148.23 ± 1.75 nm. The half-maximum inhibiting concentration (IC50) of α-Hed-CS-CD147-NPs in human liver cancer cell lines HepG2 and SMMC-7721 was lower than that of free α-Hed and α-Hed-CS-NPs. α-Hed-induced cell death was mainly triggered by apoptosis. The increase in intracellular accumulation of α-Hed-CS-CD147-NPs was also related to CD147-mediated internalization through the Caveolae-dependent pathway and lysosomal escape. The higher targeting antitumor efficacy of α-Hed-CS-CD147-NPs than that α-Hed-CS-NPs was attributed to its stronger fluorescence intensity in the tumor site in nude mice. PMID:26639052

  7. CD147 monoclonal antibody mediated by chitosan nanoparticles loaded with α-hederin enhances antineoplastic activity and cellular uptake in liver cancer cells.

    PubMed

    Zhu, Rong; Zhang, Chun-ge; Liu, Yang; Yuan, Zhi-qiang; Chen, Wei-liang; Yang, Shu-di; Li, Ji-zhao; Zhu, Wen-jing; Zhou, Xiao-feng; You, Ben-gang; Zhang, Xue-nong

    2015-12-07

    An antibody that specifically interacts with an antigen could be applied to an active targeting delivery system. In this study, CD147 antibody was coupled with α-hed chitosan nanoparticles (α-Hed-CS-NPs). α-Hed-CS-CD147-NPs were round and spherical in shape, with an average particle size of 148.23 ± 1.75 nm. The half-maximum inhibiting concentration (IC50) of α-Hed-CS-CD147-NPs in human liver cancer cell lines HepG2 and SMMC-7721 was lower than that of free α-Hed and α-Hed-CS-NPs. α-Hed-induced cell death was mainly triggered by apoptosis. The increase in intracellular accumulation of α-Hed-CS-CD147-NPs was also related to CD147-mediated internalization through the Caveolae-dependent pathway and lysosomal escape. The higher targeting antitumor efficacy of α-Hed-CS-CD147-NPs than that α-Hed-CS-NPs was attributed to its stronger fluorescence intensity in the tumor site in nude mice.

  8. Cross-Neutralization Activity of Single-Chain Variable Fragment (scFv) Derived from Anti-V3 Monoclonal Antibodies Mediated by Post-Attachment Binding.

    PubMed

    Maruta, Yasuhiro; Kuwata, Takeo; Tanaka, Kazuki; Alam, Muntasir; Valdez, Kristel Paola Ramirez; Egami, Yoshika; Suwa, Yoshiaki; Morioka, Hiroshi; Matsushita, Shuzo

    2016-09-21

    The V3 loop in the envelope (Env) of HIV-1 is one of the major targets of neutralizing antibodies. However, this antigen is hidden inside the Env trimer in most isolates and is fully exposed only during CD4-gp120 interaction. Thus, primary HIV-1 isolates are relatively resistant to anti-V3 antibodies because IgG is too large to access the V3 loop. To overcome this obstacle, we constructed single-chain variable fragments (scFvs) from anti-V3 monoclonal antibodies 0.5γ, 5G2, and 16G6. Enhanced neutralization by 0.5γ and 5G2 scFvs was observed in strains resistant to their IgG counterparts. Neutralization coverage by 0.5γ scFv reached up to 90% of the tested viruses (tier 2 and 3 classes). The temperature-regulated neutralization assay revealed that extensive cross-neutralization of 0.5γ scFv can be explained by post-attachment neutralization. Neutralization assay involving viruses carrying an inter-subunit disulfide bond (SOS virus) showed that the neutralization-susceptible timeframe after attachment was 60 to 120 min. These results indicate that the scFvs efficiently access the V3 loop and subsequently neutralize HIV-1, even after virus attachment to the target cells. Based on its broad and potent neutralizing activity, further development of anti-V3 scFv for therapeutic and preventive strategies is warranted.

  9. Release of platelet activating factor in rabbits with antibody-mediated injury of the lung: the role of leukocytes and of pulmonary endothelial cells.

    PubMed

    Camussi, G; Pawlowski, I; Bussolino, F; Caldwell, P R; Brentjens, J; Andres, G

    1983-10-01

    This paper describes the release of platelet-activating factor (PAF) into the circulation of rabbits with acute pulmonary injury induced by antibody reacting with pulmonary endothelium. Eight rabbits were injected i.v. with 2 mg/kg of body weight of goat anti-rabbit lung angiotensin-converting enzyme gamma-globulin (GtARbACE). All animals developed acute pneumonitis, characterized by severe endothelial damage, accumulation of polymorphonuclear leukocytes (PMN) and platelets (Plt) in the lumina of alveolar capillaries, and deposits of goat IgG and rabbit C3 along alveolar capillary walls. Six of the rabbits died from acute pulmonary edema. PAF was detected in the plasma of all animals within 5 min after injection of GtARbACE. Five other rabbits were depleted of leukocytes by nitrogen mustard and then injected with 2 mg/kg of body weight of GtARbACE. In three of these rabbits release of PAF was demonstrated, though in amounts smaller than in non-leukocyte-depleted rabbits; all three animals died from pulmonary edema. After injection of 0.03 mg/kg of body weight of GtARbACE in six additional rabbits, three of them leukocyte-depleted, small amounts of PAF were detected in the circulation. None of these six rabbits died of pulmonary edema. PAF release was not observed in ten rabbits injected i.v. with 2 or 0.03 mg/kg of body weight of normal goat gamma-globulin. In separate experiments in vitro, incubation of isolated lung or thoracic aorta with GtARbACE resulted in deposits of goat IgG along endothelia and significant release of PAF. PAF was also released from endothelial cells removed from thoracic aorta by cellulose acetate paper and then incubated with GtARbACE. When segments of thoracic aorta were stripped of endothelium and then incubated with GtARbACE, PAF release could not be shown. The data obtained are consistent with the interpretation that PAF released into the circulation after binding of GtARbACE to the endothelia of lung and aorta originates from

  10. On Rejecting Emotional Lures Created by Phonological Neighborhood Activation

    ERIC Educational Resources Information Center

    Starns, Jeffrey J.; Cook, Gabriel I.; Hicks, Jason L.; Marsh, Richard L.

    2006-01-01

    The authors conducted 2 experiments to assess how phonologically related lures are rejected in a false memory paradigm. Some phonological lures were emotional (i.e., taboo) words, and others were not. The authors manipulated the presence of taboo items on the study list and reduced the ability to use controlled rejection strategies by dividing…

  11. Neuronal Surface Antibody-Mediated Autoimmune Encephalitis

    PubMed Central

    Linnoila, Jenny J.; Rosenfeld, Myrna R.; Dalmau, Josep

    2016-01-01

    In the past few years, many autoimmune encephalitides have been identified, with specific clinical syndromes and associated antibodies against neuronal surface antigens. There is compelling evidence that many of these antibodies are pathogenic and most of these encephalitides are highly responsive to immunotherapies. The clinical spectra of some of these antibody-mediated syndromes, especially those reported in only a few patients, are evolving. Others, such as anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, are well characterized. Diagnosis involves recognizing the specific syndromes and identifying the antibody in a patient’s cerebrospinal fluid (CSF) and/or serum. These syndromes are associated with variable abnormalities in CSF, magnetic resonance imaging, and electroencephalography. Treatment is often multidisciplinary and should be focused upon neutralizing the effects of antibodies and eliminating their source. Overlapping disorders have been noted, with some patients having more than one neurologic autoimmune disease. In other patients, viral infections such as herpes simplex virus encephalitis trigger robust antineuronal autoimmune responses. PMID:25369441

  12. Monocyte procoagulant activity and plasminogen activator. Role in human renal allograft rejection

    SciTech Connect

    Cole, E.H.; Cardella, C.J.; Schulman, J.; Levy, G.A.

    1985-10-01

    Currently the mechanism of renal allograft rejection is not well understood. This study was designed to determine whether induction of monocyte procoagulant activity (MCPA) is important in the pathogenesis of renal allograft rejection. The MPCA assay was performed utilizing a one stage clotting assay both in normal and in factor-VII-deficient plasma. There was no increase in spontaneous MPCA in 20 patients with endstage renal failure and in 10 patients following abdominal or orthopedic operation, as compared with 20 normal controls. MPCA was assessed daily in 18 patients who had received renal allografts. Rejection episodes (RE) were predicted on the basis of persistent elevation in MPCA as compared with pretransplant levels. Rejection was diagnosed clinically and treated on the basis of standard criteria. Treated RE were compared with those predicted by elevated MPCA, and 3 patients were assessed as having no RE by MPCA and by standard criteria. In 8 RE, MPCA correlated temporally with RE (same day) when compared with standard criteria. In 12 RE, MPCA was predictive of rejection preceding standard criteria by at least 24 hr. There were 7 false-positive predictions on the basis of MPCA; however, there was only 1 false negative. MPCA was shown to be a prothrombinase by its dependence only on prothrombin and fibrinogen for full activity. MPCA may be important in the pathogenesis of allograft rejection, and additionally it may be a useful adjunct in the clinical management of this disease.

  13. Predictive active disturbance rejection control for processes with time delay.

    PubMed

    Zheng, Qinling; Gao, Zhiqiang

    2014-07-01

    Active disturbance rejection control (ADRC) has been shown to be an effective tool in dealing with real world problems of dynamic uncertainties, disturbances, nonlinearities, etc. This paper addresses its existing limitations with plants that have a large transport delay. In particular, to overcome the delay, the extended state observer (ESO) in ADRC is modified to form a predictive ADRC, leading to significant improvements in the transient response and stability characteristics, as shown in extensive simulation studies and hardware-in-the-loop tests, as well as in the frequency response analysis. In this research, it is assumed that the amount of delay is approximately known, as is the approximated model of the plant. Even with such uncharacteristic assumptions for ADRC, the proposed method still exhibits significant improvements in both performance and robustness over the existing methods such as the dead-time compensator based on disturbance observer and the Filtered Smith Predictor, in the context of some well-known problems of chemical reactor and boiler control problems.

  14. Social exclusion in middle childhood: rejection events, slow-wave neural activity, and ostracism distress.

    PubMed

    Crowley, Michael J; Wu, Jia; Molfese, Peter J; Mayes, Linda C

    2010-01-01

    This study examined neural activity with event-related potentials (ERPs) in middle childhood during a computer-simulated ball-toss game, Cyberball. After experiencing fair play initially, children were ultimately excluded by the other players. We focused specifically on “not my turn” events within fair play and rejection events within social exclusion. Dense-array ERPs revealed that rejection events are perceived rapidly. Condition differences (“not my turn” vs. rejection) were evident in a posterior ERP peaking at 420 ms consistent, with a larger P3 effect for rejection events indicating that in middle childhood rejection events are differentiated in <500 ms. Condition differences were evident for slow-wave activity (500-900 ms) in the medial frontal cortical region and the posterior occipital-parietal region, with rejection events more negative frontally and more positive posteriorly. Distress from the rejection experience was associated with a more negative frontal slow wave and a larger late positive slow wave, but only for rejection events. Source modeling with Geosouce software suggested that slow-wave neural activity in cortical regions previously identified in functional imaging studies of ostracism, including subgenual cortex, ventral anterior cingulate cortex, and insula, was greater for rejection events vs. “not my turn” events.

  15. Generalized proportional integral control for periodic signals under active disturbance rejection approach.

    PubMed

    Cortés-Romero, John; Ramos, Germán A; Coral-Enriquez, Horacio

    2014-11-01

    Conventional repetitive control has proven to be an effective strategy to reject/track periodic signals with constant frequency; however, it shows poor performance in varying frequency applications. This paper proposes an active disturbance rejection methodology applied to a large class of uncertain flat systems for the tracking and rejection of periodic signals, in which the possibilities of the generalized proportional integral (GPI) observer-based control to address repetitive control problems are studied. In the proposed scheme, model uncertainties and external disturbances are lumped together in a general additive disturbance input that is estimated and rejected on-line. An illustrative case study of mechatronic nature is considered. Experimental results show that the proposed GPI observer-based control successfully rejects periodic disturbances even under varying speed conditions.

  16. Gamma Interferon Is Required for Optimal Antibody-Mediated Immunity against Genital Chlamydia Infection

    PubMed Central

    Naglak, Elizabeth K.; Morrison, Sandra G.

    2016-01-01

    Defining the mechanisms of immunity conferred by the combination of antibody and CD4+ T cells is fundamental to designing an efficacious chlamydial vaccine. Using the Chlamydia muridarum genital infection model of mice, which replicates many features of human C. trachomatis infection and avoids the characteristic low virulence of C. trachomatis in the mouse, we previously demonstrated a significant role for antibody in immunity to chlamydial infection. We found that antibody alone was not protective. Instead, protection appeared to be conferred through an undefined antibody-cell interaction. Using gene knockout mice and in vivo cellular depletion methods, our data suggest that antibody-mediated protection is dependent on the activation of an effector cell population in genital tract tissues by CD4+ T cells. Furthermore, the CD4+ T cell-secreted cytokine gamma interferon (IFN-γ) was found to be a key component of the protective antibody response. The protective function of IFN-γ was not related to the immunoglobulin class or to the magnitude of the Chlamydia-specific antibody response or to recruitment of an effector cell population to genital tract tissue. Rather, IFN-γ appears to be necessary for activation of the effector cell population that functions in antibody-mediated chlamydial immunity. Our results confirm the central role of antibody in immunity to chlamydia reinfection and demonstrate a key function for IFN-γ in antibody-mediated protection. PMID:27600502

  17. Decreased chronic cellular and antibody-mediated injury in the kidney following simultaneous liver-kidney transplantation.

    PubMed

    Taner, Timucin; Heimbach, Julie K; Rosen, Charles B; Nyberg, Scott L; Park, Walter D; Stegall, Mark D

    2016-04-01

    In simultaneous liver-kidney transplantation (SLK), the liver can protect the kidney from hyperacute rejection and may also decrease acute cellular rejection rates. Whether the liver protects against chronic injury is unknown. To answer this we studied renal allograft surveillance biopsies in 68 consecutive SLK recipients (14 with donor-specific alloantibodies at transplantation [DSA+], 54 with low or no DSA, [DSA-]). These were compared with biopsies of a matched cohort of kidney transplant alone (KTA) recipients (28 DSA+, 108 DSA-). Overall 5-year patient and graft survival was not different: 93.8% and 91.2% in SLK, and 91.9% and 77.1% in KTA. In DSA+ recipients, KTA had a significantly higher incidence of acute antibody-mediated rejection (46.4% vs. 7.1%) and chronic transplant glomerulopathy (53.6% vs. 0%). In DSA- recipients at 5 years, KTA had a significantly higher cumulative incidence of T cell-mediated rejection (clinical plus subclinical, 30.6% vs. 7.4%). By 5 years, DSA+ KTA had a 44% decline in mean GFR while DSA+SLK had stable GFR. In DSA- KTA, the incidence of a combined endpoint of renal allograft loss or over a 50% decline in GFR was significantly higher (20.4% vs. 7.4%). Simultaneously transplanted liver allograft was the most predictive factor for a significantly lower incidence of cellular (odds ratio 0.13, 95% confidence interval 0.06-0.27) and antibody-mediated injury (odds ratio 0.11, confidence interval 0.03-0.32), as well as graft functional decline (odds ratio 0.22, confidence interval 0.06-0.59). Thus, SLK is associated with reduced chronic cellular and antibody-mediated alloimmune injury in the kidney allograft.

  18. Active disturbance rejection control in steering by wire haptic systems.

    PubMed

    Rodriguez-Angeles, A; Garcia-Antonio, J A

    2014-07-01

    This paper introduces a steering by wired haptic system based on disturbance rejection control techniques. High gain Generalized Proportional Integral (GPI) observers are considered for the estimation of tire and steering wheel dynamic disturbances. These disturbances are on line canceled to ensure tracking between the commanded steering wheel angle and the tire orientation angle. The estimated disturbances at the steering rack are feedback to the steering wheel to provide a haptic interface with the driver. The overall system behaves as a bilateral master-slave system. Very few sensors and minimum knowledge of the dynamic model are required. Experimental results are presented on a prototype platform that consists on: (1) half of the steering rack of a beetle VW vehicle, (2) a steering wheel.

  19. A novel active disturbance rejection based tracking design for laser system with quadrant photodetector

    NASA Astrophysics Data System (ADS)

    Manojlović, Stojadin M.; Barbarić, Žarko P.; Mitrović, Srđan T.

    2015-06-01

    A new tracking design for laser systems with different arrangements of a quadrant photodetector, based on the principle of active disturbance rejection control is suggested. The detailed models of quadrant photodetector with standard add-subtract, difference-over-sum and diagonal-difference-over-sum algorithms for displacement signals are included in the control loop. Target moving, non-linearity of a photodetector, parameter perturbations and exterior disturbances are treated as a total disturbance. Active disturbance rejection controllers with linear extended state observers for total disturbance estimation and rejection are designed. Proposed methods are analysed in frequency domain to quantify their stability characteristics and disturbance rejection performances. It is shown through simulations, that tracking errors are effectively compensated, providing the laser spot positioning in the area near the centre of quadrant photodetector where the mentioned algorithms have the highest sensitivity, which provides tracking of the manoeuvring targets with high accuracy.

  20. Antibody-mediated immunity against tuberculosis: implications for vaccine development.

    PubMed

    Achkar, Jacqueline M; Casadevall, Arturo

    2013-03-13

    There is an urgent need for new and better vaccines against tuberculosis (TB). Current vaccine design strategies are generally focused on the enhancement of cell-mediated immunity. Antibody-based approaches are not being considered, mostly due to the paradigm that humoral immunity plays little role in the protection against intracellular pathogens. Here, we reappraise and update the increasing evidence for antibody-mediated immunity against Mycobacterium tuberculosis, discuss the complexity of antibody responses to mycobacteria, and address mechanism of protection. Based on these findings and discussions, we challenge the common belief that immunity against M. tuberculosis relies solely on cellular defense mechanisms, and posit that induction of antibody-mediated immunity should be included in TB vaccine development strategies.

  1. Pathogenesis and mechanisms of antibody-mediated hemolysis

    PubMed Central

    Flegel, Willy A

    2015-01-01

    Background The clinical consequences of antibodies to red blood cells (RBC) have been studied for a century. Most clinically relevant antibodies can be detected by sensitive in vitro assays. Several mechanisms of antibody-mediated hemolysis are well understood. Such hemolysis following transfusion is reliably avoided in a donor/recipient pair, if one individual is negative for the cognate antigen to which the other has the antibody. Study design and results Mechanisms of antibody-mediated hemolysis were reviewed based on a presentation at the Strategies to Address Hemolytic Complications of Immune Globulin Infusions Workshop addressing intravenous immunoglobulin (IVIG) and ABO antibodies. The presented topics included the rates of intravascular and extravascular hemolysis; IgM and IgG isoagglutinins; auto- and alloantibodies; antibody specificity; A, B, A,B and A1 antigens; A1 versus A2 phenotypes; monocytes/macrophages, other immune cells and complement; monocyte monolayer assay (MMA); antibody-dependent cell-mediated cytotoxicity (ADCC); and transfusion reactions due to ABO and other antibodies. Conclusion Several clinically relevant questions remained unresolved, and diagnostic tools were lacking to routinely and reliably predict the clinical consequences of RBC antibodies. Most hemolytic transfusion reactions associated with IVIG were due to ABO antibodies. Reducing the titers of such antibodies in IVIG may lower the frequency of this kind of adverse event. The only way to stop these events is to have no anti-A or anti-B antibodies in the IVIG products. PMID:26174897

  2. A shed NKG2D ligand that promotes natural killer cell activation and tumor rejection

    PubMed Central

    Deng, Weiwen; Gowen, Benjamin G.; Zhang, Li; Wang, Lin; Lau, Stephanie; Iannello, Alexandre; Xu, Jianfeng; Rovis, Tihana L.; Xiong, Na; Raulet, David H.

    2016-01-01

    Immune cells, including natural killer (NK) cells, recognize transformed cells and eliminate them in a process termed immunosurveillance. It is thought that tumor cells evade immunosurveillance by shedding membrane ligands that bind to the NKG2D activating receptor on NK cells and/or T cells, and desensitize these cells. In contrast, we show that in mice, shedding of MULT1, a high affinity NKG2D ligand, causes NK cell activation and tumor rejection. Recombinant soluble MULT1 stimulated tumor rejection in mice. Soluble MULT1 functions, at least in part, by competitively reversing a global desensitization of NK cells imposed by engagement of membrane NKG2D ligands on tumor-associated cells, such as myeloid cells. The results overturn conventional wisdom that soluble ligands are inhibitory, and suggest a new approach for cancer immunotherapy. PMID:25745066

  3. Active disturbance rejection control for drag tracking in mars entry guidance

    NASA Astrophysics Data System (ADS)

    Xia, Yuanqing; Chen, Rongfang; Pu, Fan; Dai, Li

    2014-03-01

    Future Mars missions will require precision landing capability, which motivates the need for entry closed-loop guidance schemes. A new tracking law - active disturbance rejection control (ADRC) - is presented in this paper. The ability of the ADRC tracking law to handle the atmospheric models and the vehicle’s aerodynamic errors is investigated. Monte Carlo simulations with dispersions in entry state variables, drag and lift coefficients, and atmospheric density show effectiveness of the proposed algorithm.

  4. Design of active disturbance rejection controller for the hydraulic APC system of the rolling mill

    NASA Astrophysics Data System (ADS)

    Zhang, Ruicheng; Chen, Zhikun

    2011-10-01

    Considering uncertain external disturbance, the model of automatic position control system is established. Then, according to the information of input and output, using extended states observer (ESO), a newer observer is proposed to observe and compensate this integrated disturbance, and a controller is designed based on active disturbance rejection control (ADRC). This controller has very strong robustness not only to external disturbance, but also to unpredictable plant parameter variations.

  5. Rejected applications

    PubMed Central

    2014-01-01

    Objective: To review membership application materials (especially rejected applications) to the American Academy of Neurology (AAN) during its formative years (1947–1953). Methods: Detailed study of materials in the AAN Historical Collection. Results: The author identified 73 rejected applications. Rejected applicants (71 male, 2 female) lived in 25 states. The largest number was for the Associate membership category (49). These were individuals “in related fields who have made and are making contributions to the field of neurology.” By contrast, few applicants to Active membership or Fellowship status were rejected. The largest numbers of rejectees were neuropsychiatrists (19), neurosurgeons (16), and psychiatrists (14). Conclusion: The AAN, established in the late 1940s, was a small and politically vulnerable organization. A defining feature of the fledgling society was its inclusiveness; its membership was less restrictive than that of the older American Neurological Association. At the same time, the society needed to preserve its core as a neurologic society rather than one of psychiatry or neurosurgery. Hence, the balance between inclusiveness and exclusive identity was a difficult one to maintain. The Associate membership category, more than any other, was at the heart of this issue of self-definition. Associate members were largely practitioners of psychiatry or neurosurgery. Their membership was a source of consternation and was to be carefully been held in check during these critical formative years. PMID:24944256

  6. Design of active disturbance rejection controller for space optical communication coarse tracking system

    NASA Astrophysics Data System (ADS)

    Gu, Jian; Ai, Yong

    2015-10-01

    In order to improve the dynamic tracking performance of coarse tracking system in space optical communication, a new control method based on active disturbance rejection controller (ADRC) is proposed. Firstly, based on the structure analysis of coarse tracking system, the simplified system model was obtained, and then the extended state observer was designed to calculate state variables and spot disturbance from the input and output signals. Finally, the ADRC controller of coarse tracking system is realized with the combination of nonlinear PID controller. The simulation experimental results show that compared with the PID method, this method can significantly reduce the step response overshoot and settling time. When the target angular velocity is120mrad/s, tracking error with ADRC method is 30μrad, which decreases 85% compared with the PID method. Meanwhile the disturbance rejection bandwidth is increased by 3 times with ADRC. This method can effectively improve the dynamic tracking performance of coarse tracking and disturbance rejection degree, with no need of hardware upgrade, and is of certain reference value to the wide range and high dynamic precision photoelectric tracking system.

  7. Hyaluronan Contributes to Bronchiolitis Obliterans Syndrome and Stimulates Lung Allograft Rejection through Activation of Innate Immunity

    PubMed Central

    Wang, Xingan; Sugimoto, Seichiro; Kennedy, Vanessa E.; Zhang, Helen L.; Pavlisko, Elizabeth N.; Kelly, Fran L.; Huang, Howard; Kreisel, Daniel; Palmer, Scott M.

    2014-01-01

    Rationale: Although innate immunity is increasingly recognized to contribute to lung allograft rejection, the significance of endogenous innate ligands, such as hyaluronan (HA) fragments, in clinical or experimental lung transplantation is uncertain. Objectives: To determine if HA is associated with clinical bronchiolitis obliterans syndrome (BOS) in lung transplant recipients, and evaluate the effect of low- or high-molecular-weight HA on experimental lung allograft rejection, including dependence on innate signaling pathways or effector cells. Methods: HA concentrations were measured in bronchoalveolar lavage and plasma samples from lung recipients with or without established BOS. BOS and normal lung tissues were assessed for HA localization and expression of HA synthases. Murine orthotopic lung recipients with established tolerance were treated with low- or high-molecular-weight HA under varied experimental conditions, including Toll-like receptor (TLR) 2/4 and myeloid differentiation protein 88 deficiency and neutrophil depletion. Measurements and Main Results: HA localized within areas of intraluminal small airways fibrosis in BOS lung tissue. Moreover, transcripts for HA synthase enzymes were significantly elevated in BOS versus normal lung tissues and both lavage fluid and plasma HA concentrations were increased in recipients with BOS. Treatment with low-molecular-weight HA abrogated tolerance in murine orthotopic lung recipients in a TLR2/4- and myeloid differentiation protein 88–dependent fashion and drove expansion of alloantigen-specific T lymphocytes. Additionally, TLR-dependent signals stimulated neutrophilia that promoted rejection. In contrast, high-molecular-weight HA attenuated basal allograft inflammation. Conclusions: These data suggest that accumulation of HA could contribute to BOS by directly activating innate immune signaling pathways that promote allograft rejection and neutrophilia. PMID:24471427

  8. Antibody-Mediated Protection Against SHIV Challenge Includes Systemic Clearance of Distal Virus

    PubMed Central

    Liu, Jinyan; Ghneim, Khader; Sok, Devin; Bosche, William J.; Li, Yuan; Chipriano, Elizabeth; Berkemeier, Brian; Oswald, Kelli; Borducchi, Erica; Cabral, Crystal; Peter, Lauren; Brinkman, Amanda; Shetty, Mayuri; Jimenez, Jessica; Mondesir, Jade; Lee, Benjamin; Giglio, Patricia; Chandrashekar, Abishek; Abbink, Peter; Colantonio, Arnaud; Gittens, Courtney; Baker, Chantelle; Wagner, Wendeline; Lewis, Mark G.; Li, Wenjun; Sekaly, Rafick-Pierre; Lifson, Jeffrey D.; Burton, Dennis R.; Barouch, Dan H.

    2017-01-01

    HIV-1-specific broadly neutralizing antibodies (bNAbs) can protect rhesus monkeys against simian-human immunodeficiency virus (SHIV) challenge. However, the site of antibody interception of virus and the mechanism of antibody-mediated protection remain unclear. We administered a fully protective dose of the bNAb PGT121 to rhesus monkeys and challenged them intravaginally with SHIV-SF162P3. In PGT121 treated animals, we detected low levels of viral RNA and viral DNA in distal tissues for several days following challenge. Viral RNA positive tissues showed transcriptomic changes indicative of innate immune activation, and cells from these tissues initiated infection following adoptive transfer into naïve hosts. These data demonstrate that bNAb mediated protection against a mucosal virus challenge can involve clearance of infectious virus in distal tissues. PMID:27540005

  9. JC polyomavirus mutants escape antibody-mediated neutralization.

    PubMed

    Ray, Upasana; Cinque, Paola; Gerevini, Simonetta; Longo, Valeria; Lazzarin, Adriano; Schippling, Sven; Martin, Roland; Buck, Christopher B; Pastrana, Diana V

    2015-09-23

    JC polyomavirus (JCV) persistently infects the urinary tract of most adults. Under conditions of immune impairment, JCV causes an opportunistic brain disease, progressive multifocal leukoencephalopathy (PML). JCV strains found in the cerebrospinal fluid of PML patients contain distinctive mutations in surface loops of the major capsid protein, VP1. We hypothesized that VP1 mutations might allow the virus to evade antibody-mediated neutralization. Consistent with this hypothesis, neutralization serology revealed that plasma samples from PML patients neutralized wild-type JCV strains but failed to neutralize patient-cognate PML-mutant JCV strains. This contrasted with serological results for healthy individuals, most of whom robustly cross-neutralized all tested JCV variants. Mice administered a JCV virus-like particle (VLP) vaccine initially showed neutralizing "blind spots" (akin to those observed in PML patients) that closed after booster immunization. A PML patient administered an experimental JCV VLP vaccine likewise showed markedly increased neutralizing titer against her cognate PML-mutant JCV. The results indicate that deficient humoral immunity is a common aspect of PML pathogenesis and that vaccination may overcome this humoral deficiency. Thus, vaccination with JCV VLPs might prevent the development of PML.

  10. Molecular Communication Modeling of Antibody-Mediated Drug Delivery Systems.

    PubMed

    Chahibi, Youssef; Akyildiz, Ian F; Balasubramaniam, Sasitharan; Koucheryavy, Yevgeni

    2015-07-01

    Antibody-mediated Drug Delivery Systems (ADDS) are emerging as one of the most encouraging therapeutic solutions for treating several diseases such as human cancers. ADDS use small molecules (antibodies) that propagate in the body and bind selectively to their corresponding receptors (antigens) expressed at the surface of the diseased cells. In this paper, the Molecular Communication (MC) paradigm, where information is conveyed through the concentration of molecules, is advocated for the engineering of ADDS and modeling their complex behavior, to provide a realistic model without the over-complication of system biology models, and the limitations of experimental approaches. The peculiarities of antibodies, including their anisotropic transport and complex electrochemical structure, are taken into account to develop an analytical model of the ADDS transport and antigen-binding kinetics. The end-to-end response of ADDS, from the drug injection to the drug absorption, is mathematically derived based on the geometry of the antibody molecule, the electrochemical structure of the antibody-antigen complex, and the physiology of the patient. The accuracy of the MC model is validated by finite-element (COMSOL) simulations. The implications of the complex interplay between the transport and kinetics parameters on the performance of ADDS are effectively captured by the proposed MC model. The MC model of ADDS will enable the discovery and optimization of drugs in a versatile, cost-efficient, and reliable manner.

  11. Limit cycle analysis of active disturbance rejection control system with two nonlinearities.

    PubMed

    Wu, Dan; Chen, Ken

    2014-07-01

    Introduction of nonlinearities to active disturbance rejection control algorithm might have high control efficiency in some situations, but makes the systems with complex nonlinearity. Limit cycle is a typical phenomenon that can be observed in the nonlinear systems, usually causing failure or danger of the systems. This paper approaches the problem of the existence of limit cycles of a second-order fast tool servo system using active disturbance rejection control algorithm with two fal nonlinearities. A frequency domain approach is presented by using describing function technique and transfer function representation to characterize the nonlinear system. The derivations of the describing functions for fal nonlinearities and treatment of two nonlinearities connected in series are given to facilitate the limit cycles analysis. The effects of the parameters of both the nonlinearity and the controller on the limit cycles are presented, indicating that the limit cycles caused by the nonlinearities can be easily suppressed if the parameters are chosen carefully. Simulations in the time domain are performed to assess the prediction accuracy based on the describing function.

  12. Analysis of leukocyte activation during acute rejection of pulmonary allografts in noninfected and cytomegalovirus-infected rats.

    PubMed

    Steinmüller, C; Steinhoff, G; Bauer, D; You, X M; Denzin, H; Franke-Ullmann, G; Hausen, B; Bruggemann, C; Wagner, T O; Lohmann-Matthes, M L; Emmendörffer, A

    1997-01-01

    After human lung transplantation acute rejection and cytomegalovirus (CMV) infections may occur, probably contributing to the development of chronic rejection. We established a model of subacute allograft rejection in rats to analyze leukocyte activation and effects of a CMV infection. Histoincompatible lung transplants (BN/LEW) without immunosuppression (group A) and lungs of initially immunosuppressed animals (group B) were analyzed. The production of inflammatory mediators (interleukin-6, tumor necrosis factor alpha, nitric oxides) and the expression of MHC class II antigens by alveolar and lung tissue macrophages were significantly enhanced during the alloresponse. In recipients without immunosuppression (group A) allograft necrosis was detected by day 6, whereas group B allografts were fully rejected by day 25. In allografts of immunosuppressed, CMV-infected animals (group C) the CMV infection was clearly aggravated and the number of activated lung tissue macrophages was increased when compared with noninfected allografts or isografts. The subacute model provides the advantage of allowing us to study mechanisms of acute rejection without the effects of reperfusion injury. Furthermore these findings underline the role of inflammatory mediators produced by macrophages during rejection.

  13. Improved clipped periodic optimal control for semi-active harmonic disturbance rejection

    NASA Astrophysics Data System (ADS)

    Couillard, Maxime; Micheau, Philippe; Masson, Patrice

    2008-12-01

    This paper presents a new approach for harmonic disturbance rejection using semi-active vibration control. The approach is illustrated through application to the problem of maximizing the energy dissipated by a semi-active damper under harmonic excitation. In order to establish a baseline for the evaluation of the performance of the semi-active damper, the effectiveness of the optimal passive and active cases are first presented. The study then examines the ability of the clipped optimal control (or clipping control) approach to improve the energy dissipation capacity of the semi-active damper over the optimal passive damper. An approximate solution to the nonlinear dynamic problem, obtained using the method of averaging, and a time integration based numerical method indicate that this approach improves the energy dissipated by the semi-active damper over the optimal passive damper. The approach presented in this paper intends to further "improve", or "fine tune", the control parameters given by the clipped optimal control approach. This is done using an approximated solution of the problem and an appropriate optimization algorithm. Results clearly indicate that this new approach provides significant improvement on energy dissipation over the clipped optimal control approach for the semi-active damper.

  14. CMOS common-mode rejection filter with floating active transformer operation

    NASA Astrophysics Data System (ADS)

    Uchida, Daisuke; Ikebe, Masayuki; Motohisa, Junichi; Sano, Eiichi; Kondou, Akira

    2014-01-01

    We propose an inductorless common-mode rejection filter with a gyrator-C network for common-mode-noise reduction. By adopting a gyrator-C network and ladder structure, high-order and small filter circuits with active transformer operation were fabricated. The filter was designed and fabricated in a Taiwan Semiconductor Manufacturing Company (TSMC) 0.18 µm CMOS process. This filter exhibited a CMRR of 80 dB, output noise voltage of 103 nV/Hz1/2, third-order input intercept point of 8.8 dBm at 1 MHz operation, and cutoff frequency of under 6 MHz. The total power consumption was 14.8 mW with a 2.5 V supply, and the chip area was 0.7 × 0.4 mm2.

  15. Active disturbance rejection control based human gait tracking for lower extremity rehabilitation exoskeleton.

    PubMed

    Long, Yi; Du, Zhijiang; Cong, Lin; Wang, Weidong; Zhang, Zhiming; Dong, Wei

    2017-03-01

    This paper presents an active disturbance rejection control (ADRC) based strategy, which is applied to track the human gait trajectory for a lower limb rehabilitation exoskeleton. The desired human gait trajectory is derived from the Clinical Gait Analysis (CGA). In ADRC, the total external disturbance can be estimated by the extended state observer (ESO) and canceled by the designed control law. The observer bandwidth and the controller bandwidth are determined by the practical principles. We simulated the proposed methodology in MATLAB. The numerical simulation shows the tracking error comparison and the estimated errors of the extended state observer. Two experimental tests were carried out to prove the performance of the algorithm presented in this paper. The experiment results show that the proposed ADRC behaves a better performance than the regular proportional integral derivative (PID) controller. With the proposed ADRC, the rehabilitation system is capable of tracking the target gait more accurately.

  16. Linear active disturbance rejection control of underactuated systems: the case of the Furuta pendulum.

    PubMed

    Ramírez-Neria, M; Sira-Ramírez, H; Garrido-Moctezuma, R; Luviano-Juárez, A

    2014-07-01

    An Active Disturbance Rejection Control (ADRC) scheme is proposed for a trajectory tracking problem defined on a nonfeedback linearizable Furuta Pendulum example. A desired rest to rest angular position reference trajectory is to be tracked by the horizontal arm while the unactuated vertical pendulum arm stays around its unstable vertical position without falling down during the entire maneuver and long after it concludes. A linear observer-based linear controller of the ADRC type is designed on the basis of the flat tangent linearization of the system around an arbitrary equilibrium. The advantageous combination of flatness and the ADRC method makes it possible to on-line estimate and cancels the undesirable effects of the higher order nonlinearities disregarded by the linearization. These effects are triggered by fast horizontal arm tracking maneuvers driving the pendulum substantially away from the initial equilibrium point. Convincing experimental results, including a comparative test with a sliding mode controller, are presented.

  17. Induction Motor Drive System Based on Linear Active Disturbance Rejection Controller

    NASA Astrophysics Data System (ADS)

    Liu, Liying; Zhang, Yongli; Yao, Qingmei

    It is difficult to establish an exact mathematical model for the induction motor and the robustness is poor of the vector control system using PI regulator. This paper adopts the linear active disturbance rejection controller (LADRC) to control inductor motor. LADRC doesn't need the exact mathematical model of motor and it can not only estimate but also compensate the general disturbance that includes the coupling items in model of motor and parameters perturbations by linear extended state observer (LESO), so the rotor flux and torque fully decouple. As a result, the performance is improved. To prove the above control scheme, the proposed control system has been simulated in MATLAB/SIMULINK, and the comparison was made with PID. Simulation results show that LADRC' has better performance and robustness than PID.

  18. Flatness-based active disturbance rejection control for linear systems with unknown time-varying coefficients

    NASA Astrophysics Data System (ADS)

    Huang, Congzhi; Sira-Ramírez, Hebertt

    2015-12-01

    A flatness-based active disturbance rejection control approach is proposed to deal with the linear systems with unknown time-varying coefficients and external disturbances. By selecting appropriate nominal values for the parameters of the system, all the deviation between the nominal and actual dynamics of the controlled process, as well as all the external disturbances can be viewed as a total disturbance. Based on the accurately estimated total disturbance with the aid of the proposed extended state observer, a linear proportional derivative feedback control law taking into account the derivatives of the desired output is designed to eliminate the effect of the total disturbance on the system performance. Finally, the load frequency control problem of a single-area power system with non-reheated unit is employed as an illustrative example to demonstrate the effectiveness of the proposed approach.

  19. Frequency domain stability analysis of nonlinear active disturbance rejection control system.

    PubMed

    Li, Jie; Qi, Xiaohui; Xia, Yuanqing; Pu, Fan; Chang, Kai

    2015-05-01

    This paper applies three methods (i.e., root locus analysis, describing function method and extended circle criterion) to approach the frequency domain stability analysis of the fast tool servo system using nonlinear active disturbance rejection control (ADRC) algorithm. Root locus qualitative analysis shows that limit cycle is generated because the gain of the nonlinear function used in ADRC varies with its input. The parameters in the nonlinear function are adjustable to suppress limit cycle. In the process of root locus analysis, the nonlinear function is transformed based on the concept of equivalent gain. Then, frequency domain description of the nonlinear function via describing function is presented and limit cycle quantitative analysis including estimating prediction error is presented, which virtually and theoretically demonstrates that the describing function method cannot guarantee enough precision in this case. Furthermore, absolute stability analysis based on extended circle criterion is investigated as a complement.

  20. Performance analysis of active disturbance rejection tracking control for a class of uncertain LTI systems.

    PubMed

    Xue, Wenchao; Huang, Yi

    2015-09-01

    The paper considers the tracking problem for a class of uncertain linear time invariant (LTI) systems with both uncertain parameters and external disturbances. The active disturbance rejection tracking controller is designed and the resulting closed-loop system's characteristics are comprehensively studied. In the time-domain, it is proven that the output of closed-loop system can approach its ideal trajectory in the transient process against different kinds of uncertainties by tuning the bandwidth of extended state observer (ESO). In the frequency-domain, different kinds of parameters' influences on the phase margin and the crossover frequency of the resulting control system are illuminated. Finally, the effectiveness and robustness of the controller are verified through the actuator position control system with uncertain parameters and load disturbances in the simulations.

  1. On active disturbance rejection based control design for superconducting RF cavities

    NASA Astrophysics Data System (ADS)

    Vincent, John; Morris, Dan; Usher, Nathan; Gao, Zhiqiang; Zhao, Shen; Nicoletti, Achille; Zheng, Qinling

    2011-07-01

    Superconducting RF (SRF) cavities are key components of modern linear particle accelerators. The National Superconducting Cyclotron Laboratory (NSCL) is building a 3 MeV/u re-accelerator (ReA3) using SRF cavities. Lightly loaded SRF cavities have very small bandwidths (high Q) making them very sensitive to mechanical perturbations whether external or self-induced. Additionally, some cavity types exhibit mechanical responses to perturbations that lead to high-order non-stationary transfer functions resulting in very complex control problems. A control system that can adapt to the changing perturbing conditions and transfer functions of these systems would be ideal. This paper describes the application of a control technique known as "Active Disturbance Rejection Control" (ARDC) to this problem.

  2. Active Heat Rejection System on Mars Exploration Rover - Design Changes from Mars Pathfinder

    NASA Astrophysics Data System (ADS)

    Ganapathi, Gani B.; Birur, Gajanana C.; Tsuyuki, Glenn T.; McGrath, Paul L.; Patzold, Jack D.

    2003-01-01

    The active Heat Rejection System designed for Mars Pathfinder was modified for the Mars Exploration Rover (Mars '03) mission and will be used to remove excess heat from the Rover electronics during the cruise part of the mission. The Integrated Pump Assembly design from MPF remained essentially intact; changes were primarily made to reduce weight. However, the cooling loop was significantly redesigned to service totally different requirements for the MER rovers. In addition, the vent design was readdressed to alleviate potentially excessive nutation as was induced on the MPF spacecraft in the process of dumping the CFC-11 overboard prior to Entry/Descent/Landing. The current vent design was based on a better understanding of the flow characteristics during the blowdown process. This paper addresses some of the key design changes. This paper also addresses lessons learned from the performance testing, and potential changes to improve the HRS performance (e.g. temperature oscillations).

  3. Active disturbance rejection controller of fine tracking system for free space optical communication

    NASA Astrophysics Data System (ADS)

    Cui, Ning; Liu, Yang; Chen, Xinglin; Wang, Yan

    2013-08-01

    Free space optical communication is one of the best approaches in future communications. Laser beam's acquisition, pointing and tracking are crucial technologies of free space optical communication. Fine tracking system is important component of APT (acquisition, pointing and tracking) system. It cooperates with the coarse pointing system in executing the APT mission. Satellite platform vibration and disturbance, which reduce received optical power, increase bit error rate and affect seriously the natural performance of laser communication. For the characteristic of satellite platform, an active disturbance rejection controller was designed to reduce the vibration and disturbance. There are three major contributions in the paper. Firstly, the effects of vibration on the inter satellite optical communications were analyzed, and the reasons and characters of vibration of the satellite platform were summarized. The amplitude-frequency response of a filter was designed according to the power spectral density of platform vibration of SILEX (Semiconductor Inter-satellite Laser Experiment), and then the signals of platform vibration were generated by filtering white Gaussian noise using the filter. Secondly, the fast steering mirror is a key component of the fine tracking system for optical communication. The mechanical design and model analysis was made to the tip/tilt mirror driven by the piezoelectric actuator and transmitted by the flexure hinge. The transfer function of the fast steering mirror, camera, D/A data acquisition card was established, and the theory model of transfer function of this system was further obtained. Finally, an active disturbance rejection control method is developed, multiple parallel extended state observers were designed for estimation of unknown dynamics and external disturbance, and the estimated states were used for nonlinear feedback control and compensation to improve system performance. The simulation results show that the designed

  4. Role of Fc fragments in antibody-mediated recovery from ocular and subcutaneous herpes simplex virus infections.

    PubMed Central

    Oakes, J E; Lausch, R N

    1981-01-01

    The contributions of the Fc fragment of virus-specific antibody in the resistance of mice to peripheral herpes simplex virus infection were investigated. Rabbit anti-herpes simplex virus-specific F(ab')2 fragments prepared by pepsin digestion of immune immunoglobulin G (IgG) were found to be inactive in complement-mediated cytolysis while retaining their capacity to neutralize virus infectivity in vitro. When F(ab')2 fragments were passively transferred either before or simultaneously with virus inoculation, they were as efficient as intact IgG was in protecting animals from virus challenge. However, if passive transfer was delayed until 8 h after herpes simplex virus infection, only IgG antibody was protective. The loss of protective activity could not be attributed to a rapid disappearance of F(ab')2 fragments, because comparable levels of F(ab')2 fragments and IgG antibody were maintained in the blood of recipients during the time that antibody mediated its protective effects. The inability of F(ab')2 subunits to activate complement was also not a factor, because complement-deficient A/J mice and complement-sufficient SJL/J mice recovered from herpes simplex virus infection after the passive transfer of IgG. We concluded that the Fc component of the antibody molecule is needed to resolve intracellular infection and that the mechanism by which antibody mediates recovery remains undefined but does not appear to involve virus neutralization or complement activation. PMID:6266961

  5. Antibody-Mediated Internalization of Infectious HIV-1 Virions Differs among Antibody Isotypes and Subclasses

    PubMed Central

    McRaven, Michael D; Sawant, Sheetal; Gurley, Thaddeus C; Xu, Thomas T.; Dennison, S. Moses; Liao, Hua-Xin; Chenine, Agnès-Laurence; Alam, S. Munir; Haynes, Barton F.; Tomaras, Georgia D.

    2016-01-01

    Emerging data support a role for antibody Fc-mediated antiviral activity in vaccine efficacy and in the control of HIV-1 replication by broadly neutralizing antibodies. Antibody-mediated virus internalization is an Fc-mediated function that may act at the portal of entry whereby effector cells may be triggered by pre-existing antibodies to prevent HIV-1 acquisition. Understanding the capacity of HIV-1 antibodies in mediating internalization of HIV-1 virions by primary monocytes is critical to understanding their full antiviral potency. Antibody isotypes/subclasses differ in functional profile, with consequences for their antiviral activity. For instance, in the RV144 vaccine trial that achieved partial efficacy, Env IgA correlated with increased risk of HIV-1 infection (i.e. decreased vaccine efficacy), whereas V1-V2 IgG3 correlated with decreased risk of HIV-1 infection (i.e. increased vaccine efficacy). Thus, understanding the different functional attributes of HIV-1 specific IgG1, IgG3 and IgA antibodies will help define the mechanisms of immune protection. Here, we utilized an in vitro flow cytometric method utilizing primary monocytes as phagocytes and infectious HIV-1 virions as targets to determine the capacity of Env IgA (IgA1, IgA2), IgG1 and IgG3 antibodies to mediate HIV-1 infectious virion internalization. Importantly, both broadly neutralizing antibodies (i.e. PG9, 2G12, CH31, VRC01 IgG) and non-broadly neutralizing antibodies (i.e. 7B2 mAb, mucosal HIV-1+ IgG) mediated internalization of HIV-1 virions. Furthermore, we found that Env IgG3 of multiple specificities (i.e. CD4bs, V1-V2 and gp41) mediated increased infectious virion internalization over Env IgG1 of the same specificity, while Env IgA mediated decreased infectious virion internalization compared to IgG1. These data demonstrate that antibody-mediated internalization of HIV-1 virions depends on antibody specificity and isotype. Evaluation of the phagocytic potency of vaccine

  6. Antibody-Mediated Internalization of Infectious HIV-1 Virions Differs among Antibody Isotypes and Subclasses.

    PubMed

    Tay, Matthew Zirui; Liu, Pinghuang; Williams, LaTonya D; McRaven, Michael D; Sawant, Sheetal; Gurley, Thaddeus C; Xu, Thomas T; Dennison, S Moses; Liao, Hua-Xin; Chenine, Agnès-Laurence; Alam, S Munir; Moody, M Anthony; Hope, Thomas J; Haynes, Barton F; Tomaras, Georgia D

    2016-08-01

    Emerging data support a role for antibody Fc-mediated antiviral activity in vaccine efficacy and in the control of HIV-1 replication by broadly neutralizing antibodies. Antibody-mediated virus internalization is an Fc-mediated function that may act at the portal of entry whereby effector cells may be triggered by pre-existing antibodies to prevent HIV-1 acquisition. Understanding the capacity of HIV-1 antibodies in mediating internalization of HIV-1 virions by primary monocytes is critical to understanding their full antiviral potency. Antibody isotypes/subclasses differ in functional profile, with consequences for their antiviral activity. For instance, in the RV144 vaccine trial that achieved partial efficacy, Env IgA correlated with increased risk of HIV-1 infection (i.e. decreased vaccine efficacy), whereas V1-V2 IgG3 correlated with decreased risk of HIV-1 infection (i.e. increased vaccine efficacy). Thus, understanding the different functional attributes of HIV-1 specific IgG1, IgG3 and IgA antibodies will help define the mechanisms of immune protection. Here, we utilized an in vitro flow cytometric method utilizing primary monocytes as phagocytes and infectious HIV-1 virions as targets to determine the capacity of Env IgA (IgA1, IgA2), IgG1 and IgG3 antibodies to mediate HIV-1 infectious virion internalization. Importantly, both broadly neutralizing antibodies (i.e. PG9, 2G12, CH31, VRC01 IgG) and non-broadly neutralizing antibodies (i.e. 7B2 mAb, mucosal HIV-1+ IgG) mediated internalization of HIV-1 virions. Furthermore, we found that Env IgG3 of multiple specificities (i.e. CD4bs, V1-V2 and gp41) mediated increased infectious virion internalization over Env IgG1 of the same specificity, while Env IgA mediated decreased infectious virion internalization compared to IgG1. These data demonstrate that antibody-mediated internalization of HIV-1 virions depends on antibody specificity and isotype. Evaluation of the phagocytic potency of vaccine

  7. Active tracking of rejected dried blood samples in a large program in Nigeria

    PubMed Central

    Inalegwu, Auchi; Phillips, Sunny; Datir, Rawlings; Chime, Christopher; Ozumba, Petronilla; Peters, Samuel; Ogbanufe, Obinna; Mensah, Charles; Abimiku, Alash’Le; Dakum, Patrick; Ndembi, Nicaise

    2016-01-01

    AIM: To study the impact of rejection at different levels of health care by retrospectively reviewing records of dried blood spot samples received at the molecular laboratory for human immunodeficiency virus (HIV) early infant diagnosis (EID) between January 2008 and December 2012. METHODS: The specimen rejection rate, reasons for rejection and the impact of rejection at different levels of health care was examined. The extracted data were cleaned and checked for consistency and then de-duplicated using the unique patient and clinic identifiers. The cleaned data were ciphered and exported to SPSS version 19 (SPSS 2010 IBM Corp, New York, United States) for statistical analyses. RESULTS: Sample rejection rate of 2.4% (n = 786/32552) and repeat rate of 8.8% (n = 69/786) were established. The mean age of infants presenting for first HIV molecular test among accepted valid samples was 17.83 wk (95%CI: 17.65-18.01) vs 20.30 wk (95%CI: 16.53-24.06) for repeated samples. HIV infection rate was 9.8% vs 15.9% for accepted and repeated samples. Compared to tertiary healthcare clinics, secondary and primary clinics had two-fold and three-fold higher likelihood of sample rejection, respectively (P < 0.05). We observed a significant increase in sample rejection rate with increasing number of EID clinics (r = 0.893, P = 0.041). The major reasons for rejection were improper sample collection (26.3%), improper labeling (16.4%) and insufficient blood (14.8%). CONCLUSION: Programs should monitor pre-analytical variables and incorporate continuous quality improvement interventions to reduce errors associated with sample rejection and improve patient retention. PMID:27175352

  8. Thiopurine methyltransferase activity and its relationship to the occurrence of rejection episodes in paediatric renal transplant recipients treated with azathioprine

    PubMed Central

    Dervieux, T; Médard, Y; Baudouin, V; Maisin, A; Zhang, D; Broly, F; Loirat, C; Jacqz-Aigrain, E

    1999-01-01

    Aims Azathioprine is a prodrug commonly used in combination therapy to prevent allograft rejection after renal transplantation. After conversion to 6-mercaptopurine, the drug is metabolized into 6-thioguanine nucleotides (6-TGN) and catabolized by thiopurine methyltransferase (TPMT), an enzyme under monogenic control. The aim of this study was to evaluate the inter- and intraindividual variability of red blood cell thiopurine methyltransferase and 6-TGN concentrations and their relationship to the clinical effects of azathioprine in paediatric patients. Methods In the present study, the interand intraindividual variations in red blood cell TPMT activity and 6-TGN concentrations and their relationship to the actions of azathioprine were evaluated during the first year after renal transplantation in 22 paediatric patients. Results 6-TGN concentration reached steady-state values after 6 months and correlated negatively with TPMT activity (P=0.004). Initial TPMT activity (median: 20.8 nmol h−1 ml−1, range 7.8–34.6) and 6-TGN concentration at steady-state (median: 80 pmol 8×108–1 cells, range not detected to 366) were not related to the occurrence of rejection episodes during the period of the study. In contrast, TPMT activity and the percentage difference in TPMT activity from the day of transplantation determined at month 1 were higher in the patients with rejection episodes by comparison with those that did not reject during the first 3 months or the first year following transplantation (P<0.005). Conclusions We report a relationship between TPMT activity and occurrence of rejection in paediatric kidney transplant patients undergoing azathioprine therapy. These data suggest a link between high red blood cell TPMT activity and poor clinical outcome probably caused by rapid azathioprine catabolism. PMID:10594482

  9. Both associative activation and thematic extraction count, but thematic false memories are more easily rejected.

    PubMed

    Carneiro, Paula; Garcia-Marques, Leonel; Fernandez, Angel; Albuquerque, Pedro

    2014-01-01

    The main aim of this study was to analyse the roles played by associative activation and thematic extraction in the explanation of false memories using the Deese, Roediger, McDermott (DRM) paradigm. Associative lists with two different types of critical items (CIs) were used: one, the associative CI, corresponded to the word most strongly primed by the associates in the list and another, the thematic CI, was the word that best described the theme of the list. Following three different types of encoding instructions (standard, warning or strategic), false recognition for these two types of CIs was analysed in either self-paced or speeded response recognition tests. The results showed considerable levels of false memories for both types of CIs. Even without the quality of being "good themes", associative CIs produced high levels of false recognition, which suggests that associative activation plays a prominent role in false memory formation. More interestingly, thematic CIs were more prone to be edited out, reinforcing the argument that thematic identifiability has a major role in the rejection of false memories.

  10. Interleukin-6, A Cytokine Critical to Mediation of Inflammation, Autoimmunity and Allograft Rejection: Therapeutic Implications of IL-6 Receptor Blockade.

    PubMed

    Jordan, Stanley C; Choi, Jua; Kim, Irene; Wu, Gordon; Toyoda, Mieko; Shin, Bonga; Vo, Ashley

    2017-01-01

    The success of kidney transplants is limited by the lack of robust improvements in long-term survival. It is now recognized that alloimmune responses are responsible for the majority of allograft failures. Development of novel therapies to decrease allosensitization is critical. The lack of new drug development in kidney transplantation necessitated repurposing drugs initially developed in oncology and autoimmunity. Among these is tocilizumab (anti-IL-6 receptor [IL-6R]) which holds promise for modulating multiple immune pathways responsible for allograft injury and loss. Interleukin-6 is a cytokine critical to proinflammatory and immune regulatory cascades. Emerging data have identified important roles for IL-6 in innate immune responses and adaptive immunity. Excessive IL-6 production is associated with activation of T-helper 17 cell and inhibition of regulatory T cell with attendant inflammation. Plasmablast production of IL-6 is critical for initiation of T follicular helper cells and production of high-affinity IgG. Tocilizumab is the first-in-class drug developed to treat diseases mediated by IL-6. Data are emerging from animal and human studies indicating a critical role for IL-6 in mediation of cell-mediated rejection, antibody-mediated rejection, and chronic allograft vasculopathy. This suggests that anti-IL-6/IL-6R blockade could be effective in modifying T- and B-cell responses to allografts. Initial data from our group suggest anti-IL-6R therapy is of value in desensitization and prevention and treatment of antibody-mediated rejection. In addition, human trials have shown benefits in treatment of graft versus host disease in matched or mismatched stem cell transplants. Here, we explore the biology of IL-6/IL-6R interactions and the evidence for an important role of IL-6 in mediating allograft rejection.

  11. Antidotes, antibody-mediated immunity and the future of pharmaceutical product development.

    PubMed

    Caoili, Salvador Eugenio C

    2013-02-01

    If new scientific knowledge is to be more efficiently generated and applied toward the advancement of health, human safety must be more effectively addressed in the conduct of research. Given the present difficulties of accurately predicting biological outcomes of novel interventions in vivo, the imperative of human safety suggests the development of novel pharmaceutical products in tandem with their prospective antidotes in anticipation of possible adverse events, to render the risks of initial clinical trials more acceptable from a regulatory standpoint. Antibody-mediated immunity provides a generally applicable mechanistic basis for developing antidotes to both biologicals and small-molecule drugs (such that antibodies may serve as antidotes to pharmaceutical agents as a class including other antibodies) and also for the control and prevention of both infectious and noninfectious diseases via passive or active immunization. Accordingly, the development of prophylactic or therapeutic passive-immunization strategies using antipeptide antibodies is a plausible prelude to the development of corresponding active-immunization strategies using peptide-based vaccines. In line with this scheme, global proliferation of antibody- and vaccine-production technologies, especially those that obviate dependence on the cold chain for storage and transport of finished products, could provide geographically distributed breakout capability against emerging and future health challenges.

  12. Renal allograft rejection: possible involvement of lymphokine-activated killer cells.

    PubMed Central

    Kirby, J A; Forsythe, J L; Proud, G; Taylor, R M

    1989-01-01

    Human renal allograft tissue was recovered at transplant nephrectomy from three patients with irreversible loss of graft function. This tissue was disaggregated and separated into two fractions on the basis of particle size. Fraction 1 contained glomeruli and developed a mixed outgrowth containing adherent epithelial and mesangial cells after a limited period of culture. Fraction 2 contained fragments of renal tubules and produced monolayers of tubular epithelial cells during culture. A population of lymphoid cells was observed to grow from the primary disaggregate into medium supplemented with recombinant human interleukin-2 (IL-2). After culture for 5 days these lymphoid cells were predominantly CD3-positive and carried both class II major histocompatibility antigens (MHC) and the CD25 IL-2 receptor. Culture of peripheral blood-derived mononuclear cells with IL-2 caused the generation of lymphokine-activated killer (LAK) cells; these cells were able to lyse both glomerular and tubular cells grown from nephrectomy tissue without showing MHC antigen restriction. The lymphoid cells grown from renal allograft tissue showed a similar lytic potential for both renal cells prepared from the same nephrectomy specimen and from third party renal tissue. It is possible that any LAK cells formed within a renal allograft by the action of IL-2 may contribute to the tissue destruction observed during graft rejection. Images Figure 2 PMID:2661417

  13. Active disturbance rejection control for output force creep characteristics of ionic polymer metal composites

    NASA Astrophysics Data System (ADS)

    Xiong, Yan; Chen, Yang; Sun, Zhiyong; Hao, Lina; Dong, Jie

    2014-07-01

    Ionic polymer metal composites (IPMCs) are a type of electroactive polymer (EAP) that can be used as both sensors and actuators. An IPMC has enormous potential application in the field of biomimetic robotics, medical devices, and so on. However, an IPMC actuator has a great number of disadvantages, such as creep and time-variation, making it vulnerable to external disturbances. In addition, the complex actuation mechanism makes it difficult to model and the demand of the control algorithm is laborious to implement. In this paper, we obtain a creep model of the IPMC by means of model identification based on the method of creep operator linear superposition. Although the mathematical model is not approximate to the IPMC accurate model, it is accurate enough to be used in MATLAB to prove the control algorithm. A controller based on the active disturbance rejection control (ADRC) method is designed to solve the drawbacks previously given. Because the ADRC controller is separate from the mathematical model of the controlled plant, the control algorithm has the ability to complete disturbance estimation and compensation. Some factors, such as all external disturbances, uncertainty factors, the inaccuracy of the identification model and different kinds of IPMCs, have little effect on controlling the output block force of the IPMC. Furthermore, we use the particle swarm optimization algorithm to adjust ADRC parameters so that the IPMC actuator can approach the desired block force with unknown external disturbances. Simulations and experimental examples validate the effectiveness of the ADRC controller.

  14. Active disturbance rejection based trajectory linearization control for hypersonic reentry vehicle with bounded uncertainties.

    PubMed

    Shao, Xingling; Wang, Honglun

    2015-01-01

    This paper investigates a novel compound control scheme combined with the advantages of trajectory linearization control (TLC) and alternative active disturbance rejection control (ADRC) for hypersonic reentry vehicle (HRV) attitude tracking system with bounded uncertainties. Firstly, in order to overcome actuator saturation problem, nonlinear tracking differentiator (TD) is applied in the attitude loop to achieve fewer control consumption. Then, linear extended state observers (LESO) are constructed to estimate the uncertainties acting on the LTV system in the attitude and angular rate loop. In addition, feedback linearization (FL) based controllers are designed using estimates of uncertainties generated by LESO in each loop, which enable the tracking error for closed-loop system in the presence of large uncertainties to converge to the residual set of the origin asymptotically. Finally, the compound controllers are derived by integrating with the nominal controller for open-loop nonlinear system and FL based controller. Also, comparisons and simulation results are presented to illustrate the effectiveness of the control strategy.

  15. Predictive current control of permanent magnet synchronous motor based on linear active disturbance rejection control

    NASA Astrophysics Data System (ADS)

    Li, Kunpeng

    2017-01-01

    The compatibility problem between rapidity and overshooting in the traditional predictive current control structure is inevitable and difficult to solve by reason of using PI controller. A novel predictive current control (PCC) algorithm for permanent magnet synchronous motor (PMSM) based on linear active disturbance rejection control (LADRC) is presented in this paper. In order to displace PI controller, the LADRC strategy which consisted of linear state error feedback (LSEF) control algorithm and linear extended state observer (LESO), is designed based on the mathematic model of PMSM. The purpose of LSEF is to make sure fast response to load mutation and system uncertainties, and LESO is designed to estimate the uncertain disturbances. The principal structures of the proposed system are speed outer loop based on LADRC and current inner loop based on predictive current control. Especially, the instruction value of qaxis current in inner loop is derived from the control quantity which is designed in speed outer loop. The simulation is carried out in Matlab/Simulink software, and the results illustrate that the dynamic and static performances of proposed system are satisfied. Moreover the robust against model parameters mismatch is enhanced obviously.

  16. Combined feedforward and model-assisted active disturbance rejection control for non-minimum phase system.

    PubMed

    Sun, Li; Li, Donghai; Gao, Zhiqiang; Yang, Zhao; Zhao, Shen

    2016-09-01

    Control of the non-minimum phase (NMP) system is challenging, especially in the presence of modelling uncertainties and external disturbances. To this end, this paper presents a combined feedforward and model-assisted Active Disturbance Rejection Control (MADRC) strategy. Based on the nominal model, the feedforward controller is used to produce a tracking performance that has minimum settling time subject to a prescribed undershoot constraint. On the other hand, the unknown disturbances and uncertain dynamics beyond the nominal model are compensated by MADRC. Since the conventional Extended State Observer (ESO) is not suitable for the NMP system, a model-assisted ESO (MESO) is proposed based on the nominal observable canonical form. The convergence of MESO is proved in time domain. The stability, steady-state characteristics and robustness of the closed-loop system are analyzed in frequency domain. The proposed strategy has only one tuning parameter, i.e., the bandwidth of MESO, which can be readily determined with a prescribed robustness level. Some comparative examples are given to show the efficacy of the proposed method. This paper depicts a promising prospect of the model-assisted ADRC in dealing with complex systems.

  17. On active disturbance rejection in temperature regulation of the proton exchange membrane fuel cells

    NASA Astrophysics Data System (ADS)

    Li, Dazi; Li, Chong; Gao, Zhiqiang; Jin, Qibing

    2015-06-01

    Operating a Proton Exchange Membrane fuel cell (PEMFC) system to maintain the stack temperature stable is one of the key issues in PEMFC's normal electrochemical reaction process. Its temperature characteristic is easily affected by inlet gas humidity, external disturbances, and electrical load changes and so on. Because of the complexity and nonlinearity of the reaction process, it is hard to build a model totally consistent with the real characteristic of the process. If model uncertainty, external disturbances, parameters changes can be regarded as "total disturbance", which is then estimated and compensated, the accurate model is no longer required and the control design can be greatly simplified to meet the practical needs. Based on this idea, an active disturbance rejection control (ADRC) with a switching law is proposed for the problem of precise temperature regulation in PEMFC. Results of the work show that the proposed control system allows the PEMFC to operate successfully at the temperature of 343 K point in the presence of two different disturbances.

  18. SARS CoV subunit vaccine: antibody-mediated neutralisation and enhancement.

    PubMed

    Jaume, M; Yip, M S; Kam, Y W; Cheung, C Y; Kien, F; Roberts, A; Li, P H; Dutry, I; Escriou, N; Daeron, M; Bruzzone, R; Subbarao, K; Peiris, J S M; Nal, B; Altmeyer, R

    2012-02-01

    1. A SARS vaccine was produced based on recombinant native full-length Spike-protein trimers (triSpike) and efficient establishment of a vaccination procedure in rodents. 2. Antibody-mediated enhancement of SARS-CoV infection with anti-SARS-CoV Spike immune-serum was observed in vitro. 3. Antibody-mediated infection of SARS-CoV triggers entry into human haematopoietic cells via an FcγR-dependent and ACE2-, pH-, cysteine-protease-independent pathways. 4. The antibody-mediated enhancement phenomenon is not a mandatory component of the humoral immune response elicited by SARS vaccines, as pure neutralising antibody only could be obtained. 5. Occurrence of immune-mediated enhancement of SARS-CoV infection raises safety concerns regarding the use of SARS-CoV vaccine in humans and enables new ways to investigate SARS pathogenesis (tropism and immune response deregulation).

  19. Design and Testing of an Active Heat Rejection Radiator with Digital Turn-Down Capability

    NASA Technical Reports Server (NTRS)

    Sunada, Eric; Birur, Gajanana C.; Ganapathi, Gani B.; Miller, Jennifer; Berisford, Daniel; Stephan, Ryan

    2010-01-01

    NASA's proposed lunar lander, Altair, will be exposed to vastly different external environment temperatures. The challenges to the active thermal control system (ATCS) are compounded by unfavorable transients in the internal waste heat dissipation profile: the lowest heat load occurs in the coldest environment while peak loads coincide with the warmest environment. The current baseline for this fluid is a 50/50 inhibited propylene glycol/water mixture with a freeze temperature around -35 C. While the overall size of the radiator's heat rejection area is dictated by the worst case hot scenario, a turn-down feature is necessary to tolerate the worst case cold scenario. A radiator with digital turn-down capability is being designed as a robust means to maintain cabin environment and equipment temperatures while minimizing mass and power consumption. It utilizes active valving to isolate and render ineffective any number of parallel flow tubes which span across the ATCS radiator. Several options were assessed in a trade-study to accommodate flow tube isolation and how to deal with the stagnant fluid that would otherwise remain in the tube. Bread-board environmental tests were conducted for options to drain the fluid from a turned-down leg as well an option to allow a leg to freeze/thaw. Each drain option involved a positive displacement gear pump with different methods of providing a pressure head to feed it. Test results showed that a start-up heater used to generate vapor at the tube inlet held the most promise for tube evacuation. Based on these test results and conclusions drawn from the trade-study, a full-scale radiator design is being worked for the Altair mission profile.

  20. The 20S proteasome core, active within apoptotic exosome-like vesicles, induces autoantibody production and accelerates rejection.

    PubMed

    Dieudé, Mélanie; Bell, Christina; Turgeon, Julie; Beillevaire, Deborah; Pomerleau, Luc; Yang, Bing; Hamelin, Katia; Qi, Shijie; Pallet, Nicolas; Béland, Chanel; Dhahri, Wahiba; Cailhier, Jean-François; Rousseau, Matthieu; Duchez, Anne-Claire; Lévesque, Tania; Lau, Arthur; Rondeau, Christiane; Gingras, Diane; Muruve, Danie; Rivard, Alain; Cardinal, Héloise; Perreault, Claude; Desjardins, Michel; Boilard, Éric; Thibault, Pierre; Hébert, Marie-Josée

    2015-12-16

    Autoantibodies to components of apoptotic cells, such as anti-perlecan antibodies, contribute to rejection in organ transplant recipients. However, mechanisms of immunization to apoptotic components remain largely uncharacterized. We used large-scale proteomics, with validation by electron microscopy and biochemical methods, to compare the protein profiles of apoptotic bodies and apoptotic exosome-like vesicles, smaller extracellular vesicles released by endothelial cells downstream of caspase-3 activation. We identified apoptotic exosome-like vesicles as a central trigger for production of anti-perlecan antibodies and acceleration of rejection. Unlike apoptotic bodies, apoptotic exosome-like vesicles triggered the production of anti-perlecan antibodies in naïve mice and enhanced anti-perlecan antibody production and allograft inflammation in mice transplanted with an MHC (major histocompatibility complex)-incompatible aortic graft. The 20S proteasome core was active within apoptotic exosome-like vesicles and controlled their immunogenic activity. Finally, we showed that proteasome activity in circulating exosome-like vesicles increased after vascular injury in mice. These findings open new avenues for predicting and controlling maladaptive humoral responses to apoptotic cell components that enhance the risk of rejection after transplantation.

  1. It still hurts: altered endogenous opioid activity in the brain during social rejection and acceptance in major depressive disorder.

    PubMed

    Hsu, D T; Sanford, B J; Meyers, K K; Love, T M; Hazlett, K E; Walker, S J; Mickey, B J; Koeppe, R A; Langenecker, S A; Zubieta, J-K

    2015-02-01

    The μ-opioid receptor (MOR) system, well known for dampening physical pain, is also hypothesized to dampen 'social pain.' We used positron emission tomography scanning with the selective MOR radioligand [(11)C]carfentanil to test the hypothesis that MOR system activation (reflecting endogenous opioid release) in response to social rejection and acceptance is altered in medication-free patients diagnosed with current major depressive disorder (MDD, n=17) compared with healthy controls (HCs, n=18). During rejection, MDD patients showed reduced endogenous opioid release in brain regions regulating stress, mood and motivation, and slower emotional recovery compared with HCs. During acceptance, only HCs showed increased social motivation, which was positively correlated with endogenous opioid release in the nucleus accumbens, a reward structure. Altered endogenous opioid activity in MDD may hinder emotional recovery from negative social interactions and decrease pleasure derived from positive interactions. Both effects may reinforce depression, trigger relapse and contribute to poor treatment outcomes.

  2. The Banff 2015 Kidney Meeting Report: Current Challenges in Rejection Classification and Prospects for Adopting Molecular Pathology.

    PubMed

    Loupy, A; Haas, M; Solez, K; Racusen, L; Glotz, D; Seron, D; Nankivell, B J; Colvin, R B; Afrouzian, M; Akalin, E; Alachkar, N; Bagnasco, S; Becker, J U; Cornell, L; Drachenberg, C; Dragun, D; de Kort, H; Gibson, I W; Kraus, E S; Lefaucheur, C; Legendre, C; Liapis, H; Muthukumar, T; Nickeleit, V; Orandi, B; Park, W; Rabant, M; Randhawa, P; Reed, E F; Roufosse, C; Seshan, S V; Sis, B; Singh, H K; Schinstock, C; Tambur, A; Zeevi, A; Mengel, M

    2017-01-01

    The XIII Banff meeting, held in conjunction the Canadian Society of Transplantation in Vancouver, Canada, reviewed the clinical impact of updates of C4d-negative antibody-mediated rejection (ABMR) from the 2013 meeting, reports from active Banff Working Groups, the relationships of donor-specific antibody tests (anti-HLA and non-HLA) with transplant histopathology, and questions of molecular transplant diagnostics. The use of transcriptome gene sets, their resultant diagnostic classifiers, or common key genes to supplement the diagnosis and classification of rejection requires further consensus agreement and validation in biopsies. Newly introduced concepts include the i-IFTA score, comprising inflammation within areas of fibrosis and atrophy and acceptance of transplant arteriolopathy within the descriptions of chronic active T cell-mediated rejection (TCMR) or chronic ABMR. The pattern of mixed TCMR and ABMR was increasingly recognized. This report also includes improved definitions of TCMR and ABMR in pancreas transplants with specification of vascular lesions and prospects for defining a vascularized composite allograft rejection classification. The goal of the Banff process is ongoing integration of advances in histologic, serologic, and molecular diagnostic techniques to produce a consensus-based reporting system that offers precise composite scores, accurate routine diagnostics, and applicability to next-generation clinical trials.

  3. The active disturbance rejection control approach to stabilisation of coupled heat and ODE system subject to boundary control matched disturbance

    NASA Astrophysics Data System (ADS)

    Guo, Bao-Zhu; Liu, Jun-Jun; AL-Fhaid, A. S.; Younas, Arshad Mahmood M.; Asiri, Asim

    2015-08-01

    We consider stabilisation for a linear ordinary differential equation system with input dynamics governed by a heat equation, subject to boundary control matched disturbance. The active disturbance rejection control approach is applied to estimate, in real time, the disturbance with both constant high gain and time-varying high gain. The disturbance is cancelled in the feedback loop. The closed-loop systems with constant high gain and time-varying high gain are shown, respectively, to be practically stable and asymptotically stable.

  4. A Novel Cardioprotective Agent in Cardiac Transplantation: Metformin Activation of AMP-Activated Protein Kinase Decreases Acute Ischemia-Reperfusion Injury and Chronic Rejection

    PubMed Central

    Chin, Jocelyn T.; Troke, Joshua J.; Kimura, Naoyuki; Itoh, Satoshi; Wang, Xi; Palmer, Owen P.; Robbins, Robert C.; Fischbein, Michael P.

    2011-01-01

    The main cause of mortality after the first year from cardiac transplantation is cardiac allograft vasculopathy (CAV), which leads to chronic rejection of the heart. To improve long-term outcomes in cardiac transplantation, treatments to prevent or diminish CAV are actively being researched. Ischemia-reperfusion (I-R) injury has been shown to be the strongest alloantigen-independent factor in the development of CAV. Here, we investigate the use of metformin in murine cardiac transplantation models as a novel cardioprotective agent to limit acute I-R injury and subsequent chronic rejection. We show that metformin treatment activates AMP-activated kinase (AMPK) in vitro and in vivo. In the acute transplantation model, metformin activation of AMPK resulted in significantly decreased apoptosis in cardiac allografts on postoperative day (POD) 1 and 8. In the chronic transplantation model, metformin pretreatment of allografts led to significantly improved graft function and significantly decreased CAV, as measured on POD 52. Taken together, our results in the acute and chronic rejection studies suggest a potential cardioprotective mechanism for metformin; we demonstrate a correlation between metformin-induced decrease in acute I-R injury and metformin-related decrease in chronic rejection. Thus, one of the ways by which metformin and AMPK activation may protect the transplanted heart from chronic rejection is by decreasing initial I-R injury inherent in donor organ preservation and implantation. Our findings suggest novel therapeutic strategies for minimizing chronic cardiac rejection via the use of metformin- and AMPK-mediated pathways to suppress acute I-R injury. PMID:22180679

  5. A novel cardioprotective agent in cardiac transplantation: metformin activation of AMP-activated protein kinase decreases acute ischemia-reperfusion injury and chronic rejection.

    PubMed

    Chin, Jocelyn T; Troke, Joshua J; Kimura, Naoyuki; Itoh, Satoshi; Wang, Xi; Palmer, Owen P; Robbins, Robert C; Fischbein, Michael P

    2011-12-01

    The main cause of mortality after the first year from cardiac transplantation is cardiac allograft vasculopathy (CAV), which leads to chronic rejection of the heart. To improve long-term outcomes in cardiac transplantation, treatments to prevent or diminish CAV are actively being researched. Ischemia-reperfusion (I-R) injury has been shown to be the strongest alloantigen-independent factor in the development of CAV. Here, we investigate the use of metformin in murine cardiac transplantation models as a novel cardioprotective agent to limit acute I-R injury and subsequent chronic rejection. We show that metformin treatment activates AMP-activated kinase (AMPK) in vitro and in vivo. In the acute transplantation model, metformin activation of AMPK resulted in significantly decreased apoptosis in cardiac allografts on postoperative day (POD) 1 and 8. In the chronic transplantation model, metformin pretreatment of allografts led to significantly improved graft function and significantly decreased CAV, as measured on POD 52. Taken together, our results in the acute and chronic rejection studies suggest a potential cardioprotective mechanism for metformin; we demonstrate a correlation between metformin-induced decrease in acute I-R injury and metformin-related decrease in chronic rejection. Thus, one of the ways by which metformin and AMPK activation may protect the transplanted heart from chronic rejection is by decreasing initial I-R injury inherent in donor organ preservation and implantation. Our findings suggest novel therapeutic strategies for minimizing chronic cardiac rejection via the use of metformin- and AMPK-mediated pathways to suppress acute I-R injury.

  6. Input Shaping enhanced Active Disturbance Rejection Control for a twin rotor multi-input multi-output system (TRMS).

    PubMed

    Yang, Xiaoyan; Cui, Jianwei; Lao, Dazhong; Li, Donghai; Chen, Junhui

    2016-05-01

    In this paper, a composite control based on Active Disturbance Rejection Control (ADRC) and Input Shaping is presented for TRMS with two degrees of freedom (DOF). The control tasks consist of accurately tracking desired trajectories and obtaining disturbance rejection in both horizontal and vertical planes. Due to un-measurable states as well as uncertainties stemming from modeling uncertainty and unknown disturbance torques, ADRC is employed, and feed-forward Input Shaping is used to improve the dynamical response. In the proposed approach, because the coupling effects are maintained in controller derivation, there is no requirement to decouple the TRMS into horizontal and vertical subsystems, which is usually performed in the literature. Finally, the proposed method is implemented on the TRMS platform, and the results are compared with those of PID and ADRC in a similar structure. The experimental results demonstrate the effectiveness of the proposed method. The operation of the controller allows for an excellent set-point tracking behavior and disturbance rejection with system nonlinearity and complex coupling conditions.

  7. Intravenous Immunoglobulin Prevents Murine Antibody-Mediated Acute Lung Injury at the Level of Neutrophil Reactive Oxygen Species (ROS) Production

    PubMed Central

    Semple, John W.; Kim, Michael; Hou, Jing; McVey, Mark; Lee, Young Jin; Tabuchi, Arata; Kuebler, Wolfgang M.; Chai, Zhong-Wei; Lazarus, Alan H.

    2012-01-01

    Transfusion-related acute lung injury (TRALI) is a leading cause of transfusion-associated mortality that can occur with any type of transfusion and is thought to be primarily due to donor antibodies activating pulmonary neutrophils in recipients. Recently, a large prospective case controlled clinical study of cardiac surgery patients demonstrated that despite implementation of male donors, a high incidence of TRALI still occurred and suggested a need for additional interventions in susceptible patient populations. To examine if intravenous immunoglobulin (IVIg) may be effective, a murine model of antibody-mediated acute lung injury that approximates human TRALI was examined. When BALB/c mice were injected with the anti-major histocompatibility complex class I antibody 34-1-2s, mild shock (reduced rectal temperature) and respiratory distress (dyspnea) were observed and pre-treatment of the mice with 2 g/kg IVIg completely prevented these symptoms. To determine IVIg's usefulness to affect severe lung damage, SCID mice, previously shown to be hypersensitive to 34-1-2s were used. SCID mice treated with 34-1-2s underwent severe shock, lung damage (increased wet/dry ratios) and 40% mortality within 2 hours. Treatment with 2 g/kg IVIg 18 hours before 34-1-2s administration completely protected the mice from all adverse events. Treatment with IVIg after symptoms began also reduced lung damage and mortality. While the prophylactic IVIg administration did not affect 34-1-2s-induced pulmonary neutrophil accumulation, bone marrow-derived neutrophils from the IVIg-treated mice displayed no spontaneous ROS production nor could they be stimulated in vitro with fMLP or 34-1-2s. These results suggest that IVIg prevents murine antibody-mediated acute lung injury at the level of neutrophil ROS production and thus, alleviating tissue damage. PMID:22363629

  8. Antibody mediated transduction of therapeutic proteins into living cells.

    PubMed

    Hansen, James E; Weisbart, Richard H; Nishimura, Robert N

    2005-09-16

    Protein therapy refers to the direct delivery of therapeutic proteins to cells and tissues with the goal of ameliorating or modifying a disease process. Current techniques for delivering proteins across cell membranes include taking advantage of receptor-mediated endocytosis or using protein transduction domains that penetrate directly into cells. The most commonly used protein transduction domains are small cell-penetrating peptides derived from such proteins as the HIV-1 Tat protein. A novel protein transduction domain developed as the single chain fragment (Fv) of a murine anti-DNA autoantibody, mAb 3E10, has recently been developed and used to deliver biologically active proteins to living cells in vitro. This review will provide a brief overview of the development of the Fv fragment and provide a summary of recent studies using Fv to deliver therapeutic peptides and proteins (such as a C-terminal p53 peptide, C-terminal p53 antibody fragment, full-length p53, and micro-dystrophin) to cells.

  9. What is antibody-mediated pure red cell aplasia (PRCA)?

    PubMed

    Casadevall, Nicole

    2005-05-01

    Antibody (Ab)-mediated pure red cell aplasia (PRCA) is an immunological pathology associated with the production of neutralizing Abs that inhibit the erythropoietic activity of endogenous erythropoietin (EPO) and recombinant erythropoiesis-stimulating agents (ESAs). Although this disorder occurs very rarely, the number of reported cases has increased dramatically in recent years, predominantly in patients with chronic kidney disease (CKD)-associated anaemia receiving subcutaneous (s.c.) injections of one particular formulation of recombinant epoetin-alpha. This disorder is differentiated from classic forms of PRCA that are caused by chemical toxaemia (i.e. erythroblastopenia induced by chemical compounds), lymphoproliferative neoplasms, thymoma, human parvovirus B19 and certain autoimmune disorders. Patients with Ab-mediated PRCA develop resistance to EPO and severe anaemia that follows a period of successful erythropoietic response, and exhibit characteristic decreases in blood haemoglobin (Hb) level and in the number of circulating reticulocytes. However, it is not yet possible to predict which patients will develop PRCA or when in the course of their treatments PRCA may develop. Laboratory confirmation of Ab-mediated PRCA requires bone marrow examination demonstrating few or no erythroid precursors and the presence of serum anti-EPO Abs using a validated assay. These neutralizing anti-EPO Abs recognize the protein core of the EPO molecule; carbohydrate groups on EPO can affect the binding of Abs but are themselves not immunological determinants. Animal models are being developed to increase further our understanding of the immunological mechanisms underlying the onset and progression of Ab-mediated PRCA.

  10. It still hurts: altered opioid activity in the brain during social rejection and acceptance in major depressive disorder

    PubMed Central

    Hsu, David T; Sanford, Benjamin J; Meyers, Kortni K; Love, Tiffany M; Hazlett, Kathleen E; Walker, Sara J; Mickey, Brian J; Koeppe, Robert A; Langenecker, Scott A; Zubieta, Jon-Kar

    2015-01-01

    The μ-opioid receptor (MOR) system, well known for dampening physical pain, is also hypothesized to dampen “social pain.” We used positron emission tomography scanning with the selective MOR radioligand [11C]carfentanil to test the hypothesis that MOR system activation in response to social rejection and acceptance is altered in medication-free patients diagnosed with current major depressive disorder (MDD, n = 17) compared to healthy controls (HCs, n = 18). During rejection, MDD patients showed reduced MOR activation (e.g., reduced endogenous opioid release) in brain regions regulating stress, mood, and motivation, and slower emotional recovery compared to HCs. During acceptance, only HCs showed increased social motivation, which was positively correlated with MOR activation in the nucleus accumbens, a reward structure. Abnormal MOR function in MDD may hinder emotional recovery from negative social interactions and decrease pleasure derived from positive interactions. Both effects may reinforce depression, trigger relapse, and contribute to poor treatment outcomes. PMID:25600108

  11. Active Metal Brazing and Adhesive Bonding of Titanium to C/C Composites for Heat Rejection System

    NASA Technical Reports Server (NTRS)

    Singh, M.; Shpargel, Tarah; Cerny, Jennifer

    2006-01-01

    Robust assembly and integration technologies are critically needed for the manufacturing of heat rejection system (HRS) components for current and future space exploration missions. Active metal brazing and adhesive bonding technologies are being assessed for the bonding of titanium to high conductivity Carbon-Carbon composite sub components in various shapes and sizes. Currently a number of different silver and copper based active metal brazes and adhesive compositions are being evaluated. The joint microstructures were examined using optical microscopy, and scanning electron microscopy (SEM) coupled with energy dispersive spectrometry (EDS). Several mechanical tests have been employed to ascertain the effectiveness of different brazing and adhesive approaches in tension and in shear that are both simple and representative of the actual system and relatively straightforward in analysis. The results of these mechanical tests along with the fractographic analysis will be discussed. In addition, advantages, technical issues and concerns in using different bonding approaches will also be presented.

  12. Reduced-order model based active disturbance rejection control of hydraulic servo system with singular value perturbation theory.

    PubMed

    Wang, Chengwen; Quan, Long; Zhang, Shijie; Meng, Hongjun; Lan, Yuan

    2017-03-01

    Hydraulic servomechanism is the typical mechanical/hydraulic double-dynamics coupling system with the high stiffness control and mismatched uncertainties input problems, which hinder direct applications of many advanced control approaches in the hydraulic servo fields. In this paper, by introducing the singular value perturbation theory, the original double-dynamics coupling model of the hydraulic servomechanism was reduced to a integral chain system. So that, the popular ADRC (active disturbance rejection control) technology could be directly applied to the reduced system. In addition, the high stiffness control and mismatched uncertainties input problems are avoided. The validity of the simplified model is analyzed and proven theoretically. The standard linear ADRC algorithm is then developed based on the obtained reduced-order model. Extensive comparative co-simulations and experiments are carried out to illustrate the effectiveness of the proposed method.

  13. Active vibration control of Flexible Joint Manipulator using Input Shaping and Adaptive Parameter Auto Disturbance Rejection Controller

    NASA Astrophysics Data System (ADS)

    Li, W. P.; Luo, B.; Huang, H.

    2016-02-01

    This paper presents a vibration control strategy for a two-link Flexible Joint Manipulator (FJM) with a Hexapod Active Manipulator (HAM). A dynamic model of the multi-body, rigid-flexible system composed of an FJM, a HAM and a spacecraft was built. A hybrid controller was proposed by combining the Input Shaping (IS) technique with an Adaptive-Parameter Auto Disturbance Rejection Controller (APADRC). The controller was used to suppress the vibration caused by external disturbances and input motions. Parameters of the APADRC were adaptively adjusted to ensure the characteristic of the closed loop system to be a given reference system, even if the configuration of the manipulator significantly changes during motion. Because precise parameters of the flexible manipulator are not required in the IS system, the operation of the controller was sufficiently robust to accommodate uncertainties in system parameters. Simulations results verified the effectiveness of the HAM scheme and controller in the vibration suppression of FJM during operation.

  14. Asymmetric frontal brain activity and parental rejection predict altruistic behavior: moderation of oxytocin effects.

    PubMed

    Huffmeijer, Renske; Alink, Lenneke R A; Tops, Mattie; Bakermans-Kranenburg, Marian J; van IJzendoorn, Marinus H

    2012-06-01

    Asymmetric frontal brain activity has been widely implicated in reactions to emotional stimuli and is thought to reflect individual differences in approach-withdrawal motivation. Here, we investigate whether asymmetric frontal activity, as a measure of approach-withdrawal motivation, also predicts charitable donations after a charity's (emotion-eliciting) promotional video showing a child in need is viewed, in a sample of 47 young adult women. In addition, we explore possibilities for mediation and moderation, by asymmetric frontal activity, of the effects of intranasally administered oxytocin and parental love withdrawal on charitable donations. Greater relative left frontal activity was related to larger donations. In addition, we found evidence of moderation: Low levels of parental love withdrawal predicted larger donations in the oxytocin condition for participants showing greater relative right frontal activity. We suggest that when approach motivation is high (reflected in greater relative left frontal activity), individuals are generally inclined to take action upon seeing someone in need and, thus, to donate money to actively help out. Only when approach motivation is low (reflected in less relative left/greater relative right activity) do empathic concerns affected by oxytocin and experiences of love withdrawal play an important part in deciding about donations.

  15. A Critical Analysis of Rejection in Vascularized Composite Allotransplantation: Clinical, Cellular and Molecular Aspects, Current Challenges, and Novel Concepts

    PubMed Central

    Sarhane, Karim A.; Tuffaha, Sami H.; Broyles, Justin M.; Ibrahim, Amir E.; Khalifian, Saami; Baltodano, Pablo; Santiago, Gabriel F.; Alrakan, Mohammed; Ibrahim, Zuhaib

    2013-01-01

    Advances in microsurgical techniques and immunomodulatory protocols have contributed to the expansion of vascularized composite allotransplantation (VCA) with very encouraging immunological, functional, and cosmetic results. Rejection remains however a major hurdle that portends serious threats to recipients. Rejection features in VCA have been described in a number of studies, and an international consensus on the classification of rejection was established. Unfortunately, current available diagnostic methods carry many shortcomings that, in certain cases, pose a great diagnostic challenge to physicians especially in borderline rejection cases. In this review, we revisit the features of acute skin rejection in hand and face transplantation at the clinical, cellular, and molecular levels. The multiple challenges in diagnosing rejection and in defining chronic and antibody-mediated rejection in VCA are then presented, and we finish by analyzing current research directions and novel concepts aiming at improving available diagnostic measures. PMID:24324470

  16. Modeling the effect of charge density in the active layers of reverse osmosis and nanofiltration membranes on the rejection of arsenic(III) and potassium iodide.

    PubMed

    Coronell, Orlando; Mi, Baoxia; Mariñas, Benito J; Cahill, David G

    2013-01-02

    We used an extended solution-diffusion model that incorporates Donnan electrostatic exclusion of ions and unhindered advection due to imperfections, and measurements of charge density in the polyamide active layers of reverse osmosis (RO) and nanofiltration (NF) membranes, to predict the rejection of a strong electrolyte (i.e., potassium iodide) and a weak acid (i.e., arsenious acid) as a function of the pH of the feed aqueous solution. Predictions of solute rejection were in agreement with experimental data indicating that (i) the extended solution-diffusion model taking into account Donnan exclusion and unhindered advection due to imperfections satisfactorily describes the effect of pH on solute rejection by RO/NF membranes and (ii) measurement of charge density in active layers provides a valuable characterization of RO/NF membranes. Our results and analysis also indicate that independent ions, and not ion pairs, dominate the permeation of salts.

  17. Antibody-mediated FOXP3 protein therapy induces apoptosis in cancer cells in vitro and inhibits metastasis in vivo.

    PubMed

    Heinze, Emil; Baldwin, Scott; Chan, Grace; Hansen, James; Song, Jason; Clements, Douglas; Aragon, Robert; Nishimura, Robert; Reeves, Mark; Weisbart, Richard

    2009-07-01

    In addition to its immune suppressive function in T-regulatory cells, the nuclear transcription factor, FOXP3, has been identified as a tumor suppressor. To evaluate the clinical efficacy of monoclonal antibody (mAb) 3E10 Fv antibody-mediated FOXP3 protein therapy of cancer, the Fv-FOXP3 fusion protein produced in Pichia pastoris was tested on breast, ovarian, and colon cancer cells in vitro, and with colon cancer cells in vivo in a mouse model of colon cancer metastasis to liver. Treatment with Fv-FOXP3 resulted in dose-dependent cell death of cancer cells in vitro. Apoptosis was established as a mechanism of cell death by demonstrating increased production of the p17 activated fragment of caspase-3 by cancer cells in response to Fv-FOXP3 and inhibition of cell killing by the caspase inhibitor, Z-VAD-FMK. Fv-FOXP3 treatment resulted in clinically significant reduction in tumor burden in a syngeneic model of colon cancer metastasis to liver in Balb/c mice. These results represent the first demonstration of effective full-length FOXP3 protein therapy and emphasize the clinical potential of mAb 3E10 as an intracellular and intranuclear delivery vehicle of FOXP3 for prevention and treatment of cancer metastasis.

  18. Antibody-Mediated Phosphatidylserine Blockade Enhances the Antitumor Responses to CTLA-4 and PD-1 Antibodies in Melanoma.

    PubMed

    Freimark, Bruce D; Gong, Jian; Ye, Dan; Gray, Michael J; Nguyen, Van; Yin, Shen; Hatch, Michaela M S; Hughes, Christopher C W; Schroit, Alan J; Hutchins, Jeff T; Brekken, Rolf A; Huang, Xianming

    2016-06-01

    In tumor-bearing animals, the membrane phospholipid phosphatidylserine (PS) suppresses immune responses, suggesting that PS signaling could counteract the antitumor effect of antibody-driven immune checkpoint blockade. Here, we show that treating melanoma-bearing mice with a PS-targeting antibody enhances the antitumor activity of downstream checkpoint inhibition. Combining PS-targeting antibodies with CTLA-4 or PD-1 blockade resulted in significantly greater inhibition of tumor growth than did single-agent therapy. Moreover, combination therapy enhanced CD4(+) and CD8(+) tumor-infiltrating lymphocyte numbers; elevated the fraction of cells expressing the proinflammatory cytokines IL2, IFNγ, and TNFα; and increased the ratio of CD8 T cells to myeloid-derived suppressor cells and regulatory T cells in tumors. Similar changes in immune cell profiles were observed in splenocytes. Taken together, these data show that antibody-mediated PS blockade enhances the antitumor efficacy of immune checkpoint inhibition. Cancer Immunol Res; 4(6); 531-40. ©2016 AACR.

  19. An Fcγ receptor-dependent mechanism drives antibody-mediated target-receptor signaling in cancer cells.

    PubMed

    Wilson, Nicholas S; Yang, Becky; Yang, Annie; Loeser, Stefanie; Marsters, Scot; Lawrence, David; Li, Yun; Pitti, Robert; Totpal, Klara; Yee, Sharon; Ross, Sarajane; Vernes, Jean-Michel; Lu, Yanmei; Adams, Cam; Offringa, Rienk; Kelley, Bob; Hymowitz, Sarah; Daniel, Dylan; Meng, Gloria; Ashkenazi, Avi

    2011-01-18

    Antibodies to cell-surface antigens trigger activatory Fcγ receptor (FcγR)-mediated retrograde signals in leukocytes to control immune effector functions. Here, we uncover an FcγR mechanism that drives antibody-dependent forward signaling in target cells. Agonistic antibodies to death receptor 5 (DR5) induce cancer-cell apoptosis and are in clinical trials; however, their mechanism of action in vivo is not fully defined. Interaction of the DR5-agonistic antibody drozitumab with leukocyte FcγRs promoted DR5-mediated tumor-cell apoptosis. Whereas the anti-CD20 antibody rituximab required activatory FcγRs for tumoricidal function, drozitumab was effective in the context of either activatory or inhibitory FcγRs. A CD40-agonistic antibody required similar FcγR interactions to stimulate nuclear factor-κB activity in B cells. Thus, FcγRs can drive antibody-mediated receptor signaling in target cells.

  20. MP-4 Contributes to Snake Venom Neutralization by Mucuna pruriens Seeds through an Indirect Antibody-mediated Mechanism.

    PubMed

    Kumar, Ashish; Gupta, Chitra; Nair, Deepak T; Salunke, Dinakar M

    2016-05-20

    Mortality due to snakebite is a serious public health problem, and available therapeutics are known to induce debilitating side effects. Traditional medicine suggests that seeds of Mucuna pruriens can provide protection against the effects of snakebite. Our aim is to identify the protein(s) that may be important for snake venom neutralization and elucidate its mechanism of action. To this end, we have identified and purified a protein from M. pruriens, which we have named MP-4. The full-length polypeptide sequence of MP-4 was obtained through N-terminal sequencing of peptide fragments. Sequence analysis suggested that the protein may belong to the Kunitz-type protease inhibitor family and therefore may potentially neutralize the proteases present in snake venom. Using various structural and biochemical tools coupled with in vivo assays, we are able to show that MP-4 does not afford direct protection against snake venom because it is actually a poor inhibitor of serine proteases. Further experiments showed that antibodies generated against MP-4 cross-react with the whole venom and provide protection to mice against Echis carinatus snake venom. This study shows that the MP-4 contributes significantly to the snake venom neutralization activity of M. pruriens seeds through an indirect antibody-mediated mechanism.

  1. Serum Therapy for Tuberculosis Revisited: Reappraisal of the Role of Antibody-Mediated Immunity against Mycobacterium tuberculosis

    PubMed Central

    Glatman-Freedman, Aharona; Casadevall, Arturo

    1998-01-01

    Fifty years after the introduction of the first effective antimicrobial agents against Mycobacterium tuberculosis, this pathogen continues to be a tremendous public health problem. The rise in the number of resistant strains and the difficulties involved in the therapy of tuberculosis in immunocompromised AIDS patients have renewed the interest in the development of effective vaccines. To evaluate whether a potential vaccine against tuberculosis could prevent infection by eliciting a protective antibody response, we reviewed the history of antibody-mediated immunity against tuberculosis. Review of the literature of the past 100 years demonstrates that there is sufficient evidence to conclude that antibody-mediated immunity can modify the course of infection in certain situations. Based on our findings and on what is known in other systems, we propose that the role of antibody-mediated immunity to M. tuberculosis be reexamined, using advanced technology. PMID:9665981

  2. Parallel-path biquad active-RC oscillator with enhanced harmonic rejection

    NASA Astrophysics Data System (ADS)

    Vosper, J. V.; Heima, M.; Cryan, R. A.

    1995-04-01

    A biquad active-RC oscillator is described and a linear analysis given which shows that harmonics injected within the feedback loop are multiplied by a factor which is inversely proportional to the effective open-loop Q-factor Q(sub 0). Experimental results show that distortion is low at high Q(sub 0) values even when saturated operation of the main gain-producing opamp is allowed.

  3. MHC-derived allopeptide activates TCR-biased CD8+ Tregs and suppresses organ rejection

    PubMed Central

    Picarda, Elodie; Bézie, Séverine; Venturi, Vanessa; Echasserieau, Klara; Mérieau, Emmanuel; Delhumeau, Aurélie; Renaudin, Karine; Brouard, Sophie; Bernardeau, Karine; Anegon, Ignacio; Guillonneau, Carole

    2014-01-01

    In a rat heart allograft model, preventing T cell costimulation with CD40Ig leads to indefinite allograft survival, which is mediated by the induction of CD8+CD45RClo regulatory T cells (CD8+CD40Ig Tregs) interacting with plasmacytoid dendritic cells (pDCs). The role of TCR-MHC-peptide interaction in regulating Treg activity remains a topic of debate. Here, we identified a donor MHC class II–derived peptide (Du51) that is recognized by TCR-biased CD8+CD40Ig Tregs and activating CD8+CD40Ig Tregs in both its phenotype and suppression of antidonor alloreactive T cell responses. We generated a labeled tetramer (MHC-I RT1.Aa/Du51) to localize and quantify Du51-specific T cells within rat cardiac allografts and spleen. RT1.Aa/Du51-specific CD8+CD40Ig Tregs were the most suppressive subset of the total Treg population, were essential for in vivo tolerance induction, and expressed a biased, restricted Vβ11-TCR repertoire in the spleen and the graft. Finally, we demonstrated that treatment of transplant recipients with the Du51 peptide resulted in indefinite prolongation of allograft survival. These results show that CD8+CD40Ig Tregs recognize a dominant donor antigen, resulting in TCR repertoire alterations in the graft and periphery. Furthermore, this allopeptide has strong therapeutic activity and highlights the importance of TCR-peptide-MHC interaction for Treg generation and function. PMID:24789907

  4. Influence of IgG Subclass on Human Antimannan Antibody-Mediated Resistance to Hematogenously Disseminated Candidiasis in Mice.

    PubMed

    Nishiya, Casey T; Boxx, Gayle M; Robison, Kerry; Itatani, Carol; Kozel, Thomas R; Zhang, Mason X

    2015-11-16

    Candida albicans is a yeast-like pathogen and can cause life-threatening systemic candidiasis. Its cell surface is enriched with mannan that is resistant to complement activation. Previously, we developed the recombinant human IgG1 antimannan antibody M1g1. M1g1 was found to promote complement activation and phagocytosis and protect mice from systemic candidiasis. Here, we evaluate the influence of IgG subclass on antimannan antibody-mediated protection. Three IgG subclass variants of M1g1 were constructed: M1g2, M1g3, and M1g4. The IgG subclass identity for each variant was confirmed with DNA sequence and subclass-specific antibodies. These variants contain identical M1 Fabs and exhibited similar binding affinities for C. albicans yeast and purified mannan. Yeast cells and hyphae recovered from the kidney of antibody-treated mice with systemic candidiasis showed uniform binding of each variant, indicating constitutive expression of the M1 epitope and antibody opsonization in the kidney. All variants promoted deposition of both murine and human C3 onto the yeast cell surface, with M1g4 showing delayed activation, as determined by flow cytometry and immunofluorescence microscopy. M1g4-mediated complement activation was found to be associated with its M1 Fab that activates the alternative pathway in an Fc-independent manner. Treatment with each subclass variant extended the survival of mice with systemic candidiasis (P < 0.001). However, treatment with M1g1, M1g3, or M1g4, but not with M1g2, also reduced the kidney fungal burden (P < 0.001). Thus, the role of human antimannan antibody in host resistance to systemic candidiasis is influenced by its IgG subclass.

  5. Early eradication of persistent Salmonella infection primes antibody-mediated protective immunity to recurrent infection.

    PubMed

    Johanns, Tanner M; Law, Calvin Y; Kalekar, Lokeshchandra A; O'Donnell, Hope; Ertelt, James M; Rowe, Jared H; Way, Sing Sing

    2011-04-01

    Typhoid fever is a systemic, persistent infection caused by host-specific strains of Salmonella. Although the use of antibiotics has reduced the complications associated with primary infection, recurrent infection remains an important cause of ongoing human morbidity and mortality. Herein, we investigated the impacts of antibiotic eradication of primary infection on protection against secondary recurrent infection. Using a murine model of persistent Salmonella infection, we demonstrate protection against recurrent infection is sustained despite early eradication of primary infection. In this model, protection is not mediated by CD4(+) or CD8(+) T cells because depletion of these cells either alone or in combination prior to rechallenge does not abrogate protection. Instead, infection followed by antibiotic-mediated clearance primes robust levels of Salmonella-specific antibody that can adoptively transfer protection to naïve mice. Thus, eradication of persistent Salmonella infection primes antibody-mediated protective immunity to recurrent infection.

  6. Novel mutations in Marburg virus glycoprotein associated with viral evasion from antibody mediated immune pressure.

    PubMed

    Kajihara, Masahiro; Nakayama, Eri; Marzi, Andrea; Igarashi, Manabu; Feldmann, Heinz; Takada, Ayato

    2013-04-01

    Marburg virus (MARV) and Ebola virus, members of the family Filoviridae, cause lethal haemorrhagic fever in humans and non-human primates. Although the outbreaks are concentrated mainly in Central Africa, these viruses are potential agents of imported infectious diseases and bioterrorism in non-African countries. Recent studies demonstrated that non-human primates passively immunized with virus-specific antibodies were successfully protected against fatal filovirus infection, highlighting the important role of antibodies in protective immunity for this disease. However, the mechanisms underlying potential evasion from antibody mediated immune pressure are not well understood. To analyse possible mutations involved in immune evasion in the MARV envelope glycoprotein (GP) which is the major target of protective antibodies, we selected escape mutants of recombinant vesicular stomatitis virus (rVSV) expressing MARV GP (rVSVΔG/MARVGP) by using two GP-specific mAbs, AGP127-8 and MGP72-17, which have been previously shown to inhibit MARV budding. Interestingly, several rVSVΔG/MARVGP variants escaping from the mAb pressure-acquired amino acid substitutions in the furin-cleavage site rather than in the mAb-specific epitopes, suggesting that these epitopes are recessed, not exposed on the uncleaved GP molecule, and therefore inaccessible to the mAbs. More surprisingly, some variants escaping mAb MGP72-17 lacked a large proportion of the mucin-like region of GP, indicating that these mutants efficiently escaped the selective pressure by deleting the mucin-like region including the mAb-specific epitope. Our data demonstrate that MARV GP possesses the potential to evade antibody mediated immune pressure due to extraordinary structural flexibility and variability.

  7. Back-stepping active disturbance rejection control design for integrated missile guidance and control system via reduced-order ESO.

    PubMed

    Xingling, Shao; Honglun, Wang

    2015-07-01

    This paper proposes a novel composite integrated guidance and control (IGC) law for missile intercepting against unknown maneuvering target with multiple uncertainties and control constraint. First, by using back-stepping technique, the proposed IGC law design is separated into guidance loop and control loop. The unknown target maneuvers and variations of aerodynamics parameters in guidance and control loop are viewed as uncertainties, which are estimated and compensated by designed model-assisted reduced-order extended state observer (ESO). Second, based on the principle of active disturbance rejection control (ADRC), enhanced feedback linearization (FL) based control law is implemented for the IGC model using the estimates generated by reduced-order ESO. In addition, performance analysis and comparisons between ESO and reduced-order ESO are examined. Nonlinear tracking differentiator is employed to construct the derivative of virtual control command in the control loop. Third, the closed-loop stability for the considered system is established. Finally, the effectiveness of the proposed IGC law in enhanced interception performance such as smooth interception course, improved robustness against multiple uncertainties as well as reduced control consumption during initial phase are demonstrated through simulations.

  8. Nonlinear fractional order proportion-integral-derivative active disturbance rejection control method design for hypersonic vehicle attitude control

    NASA Astrophysics Data System (ADS)

    Song, Jia; Wang, Lun; Cai, Guobiao; Qi, Xiaoqiang

    2015-06-01

    Near space hypersonic vehicle model is nonlinear, multivariable and couples in the reentry process, which are challenging for the controller design. In this paper, a nonlinear fractional order proportion integral derivative (NFOPIλDμ) active disturbance rejection control (ADRC) strategy based on a natural selection particle swarm (NSPSO) algorithm is proposed for the hypersonic vehicle flight control. The NFOPIλDμ ADRC method consists of a tracking-differentiator (TD), an NFOPIλDμ controller and an extended state observer (ESO). The NFOPIλDμ controller designed by combining an FOPIλDμ method and a nonlinear states error feedback control law (NLSEF) is to overcome concussion caused by the NLSEF and conversely compensate the insufficiency for relatively simple and rough signal processing caused by the FOPIλDμ method. The TD is applied to coordinate the contradiction between rapidity and overshoot. By attributing all uncertain factors to unknown disturbances, the ESO can achieve dynamic feedback compensation for these disturbances and thus reduce their effects. Simulation results show that the NFOPIλDμ ADRC method can make the hypersonic vehicle six-degree-of-freedom nonlinear model track desired nominal signals accurately and fast, has good stability, dynamic properties and strong robustness against external environmental disturbances.

  9. Colostral antibody-mediated and cell-mediated immunity contributes to innate and antigen-specific immunity in piglets

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Immunoglobulins and immune cells are critical components of colostral immunity; however, their transfer to and function in the neonate, especially maternal lymphocytes, is unclear. Cell-mediated and antibody-mediated immunity in sow blood and colostrum and piglet blood before (PS) and after (AS) suc...

  10. Regression of melanoma metastases after immunotherapy is associated with activation of antigen presentation and interferon-mediated rejection genes

    PubMed Central

    Carretero, Rafael; Wang, Ena; Rodriguez, Ana I.; Reinboth, Jennifer; Ascierto, Maria L.; Engle, Alyson M.; Liu, Hui; Camacho, Francisco M.; Marincola, Francesco M.; Garrido, Federico; Cabrera, Teresa

    2012-01-01

    We present the results of a comparative gene expression analysis of 15 metastases (10 regressing and 5 progressing) obtained from 2 melanoma patients with mixed response following different forms of immunotherapy. Whole genome transcriptional analysis clearly indicate that regression of melanoma metastases is due to an acute immune rejection mediated by the upregulation of genes involved in antigen presentation and interferon mediated response (STAT-1/IRF-1) in all the regressing metastases from both patients. In contrast, progressing metastases showed low transcription levels of genes involved in these pathways. Histological analysis showed T cells and HLA-DR positive infiltrating cells in the regressing but not in the progressing metastases. Quantitative expression analysis of HLA-A, B and C genes on microdisected tumoral regions indicate higher HLA expression in regressing than in progressing metastases. The molecular signature obtained in melanoma rejection appeared to be similar to that observed in other forms of immune-mediated tissue-specific rejection such as allograft, pathogen clearance, graft versus host or autoimmune disease, supporting the immunological constant of rejection. We favor the idea that the major factor determining the success or failure of immunotherapy is the nature of HLA Class I alterations in tumor cells and not the type of immunotherapy used. If the molecular alteration is reversible by the immunotherapy, the HLA expression will be upregulated and the lesion will be recognized and rejected. In contrast, if the defect is structural the MHC Class I expression will remain unchanged and the lesion will progress. PMID:21964766

  11. Target deletion of complement component 9 attenuates antibody-mediated hemolysis and lipopolysaccharide (LPS)-induced acute shock in mice

    PubMed Central

    Fu, Xiaoyan; Ju, Jiyu; Lin, Zhijuan; Xiao, Weiling; Li, Xiaofang; Zhuang, Baoxiang; Zhang, Tingting; Ma, Xiaojun; Li, Xiangyu; Ma, Chao; Su, Weiliang; Wang, Yuqi; Qin, Xuebin; Liang, Shujuan

    2016-01-01

    Terminal complement membrane attack complex (MAC) formation is induced initially by C5b, followed by the sequential condensation of the C6, C7, C8. Polymerization of C9 to the C5b-8 complex forms the C5b-9 (or MAC). The C5b-9 forms lytic or non lytic pores in the cell membrane destroys membrane integrity. The biological functionalities of MAC has been previously investigated by using either the mice deficient in C5 and C6, or MAC’s regulator CD59. However, there is no available C9 deficient mice (mC9−/−) for directly dissecting the role of C5b-9 in the pathogenesis of human diseases. Further, since C5b-7 and C5b-8 complexes form non lytic pore, it may also plays biological functionality. To better understand the role of terminal complement cascades, here we report a successful generation of mC9−/−. We demonstrated that lack of C9 attenuates anti-erythrocyte antibody-mediated hemolysis or LPS-induced acute shock. Further, the rescuing effect on the acute shock correlates with the less release of IL-1β in mC9−/−, which is associated with suppression of MAC-mediated inflammasome activation in mC9−/−. Taken together, these results not only confirm the critical role of C5b-9 in complement-mediated hemolysis and but also highlight the critical role of C5b-9 in inflammasome activation. PMID:27444648

  12. Incidence of erythropoietin antibody-mediated pure red cell aplasia: the Prospective Immunogenicity Surveillance Registry (PRIMS)

    PubMed Central

    Macdougall, Iain C.; Casadevall, Nicole; Locatelli, Francesco; Combe, Christian; London, Gerard M.; Di Paolo, Salvatore; Kribben, Andreas; Fliser, Danilo; Messner, Hans; McNeil, John; Stevens, Paul; Santoro, Antonio; De Francisco, Angel L.M.; Percheson, Paul; Potamianou, Anna; Foucher, Arnaud; Fife, Daniel; Mérit, Véronique; Vercammen, Els

    2015-01-01

    Background Subcutaneous administration of Eprex® (epoetin alfa) in patients with chronic kidney disease (CKD) was contraindicated in the European Union between 2002 and 2006 after increased reports of anti-erythropoietin antibody-mediated pure red cell aplasia (PRCA). The Prospective Immunogenicity Surveillance Registry (PRIMS) was conducted to estimate the incidence of antibody-mediated PRCA with subcutaneous administration of a new coated-stopper syringe presentation of Eprex® and to compare this with the PRCA incidence with subcutaneous NeoRecormon® (epoetin beta) and Aranesp® (darbepoetin alfa). Methods PRIMS was a multicentre, multinational, non-interventional, parallel-group, immunogenicity surveillance registry. Adults with CKD receiving or about to initiate subcutaneous Eprex®, NeoRecormon® or Aranesp® for anaemia were enrolled and followed for up to 3 years. Unexplained loss or lack of effect (LOE), including suspected PRCA, was reported, with antibody testing for confirmation of PRCA. Results Of the 15 333 patients enrolled, 5948 received Eprex® (8377 patient-years) and 9356 received NeoRecormon®/Aranesp® (14 286 patient-years). No treatment data were available for 29 patients. Among 23 patients with LOE, five cases of PRCA were confirmed (Eprex®, n = 3; NeoRecormon®, n = 1; Aranesp®, n = 1). Based on exposed time, PRCA incidence was 35.8/100 000 patient-years (95% CI 7.4–104.7) for Eprex® versus 14.0/100 000 patient-years (95% CI 1.7–50.6) for NeoRecormon®/Aranesp®. The incidence of PRCA with Eprex® was not significantly different versus comparator ESAs (rate ratio: 2.56; 95% CI 0.43–15.31). An analysis based on observed time produced similar findings. Conclusion This large, prospective registry demonstrates that PRCA is rare with subcutaneous administration of either the new coated-stopper syringe presentation of Eprex®, or NeoRecormon® or Aranesp®. PMID:25239637

  13. Structural insight into antibody-mediated antagonism of the Glucagon-like peptide-1 Receptor

    PubMed Central

    Hennen, Stephanie; Kodra, János T.; Soroka, Vladyslav; Krogh, Berit O.; Wu, Xiaoai; Kaastrup, Peter; Ørskov, Cathrine; Rønn, Sif G.; Schluckebier, Gerd; Barbateskovic, Silvia; Gandhi, Prafull S.; Reedtz-Runge, Steffen

    2016-01-01

    The Glucagon-like peptide-1 receptor (GLP-1R) is a member of the class B G protein-coupled receptor (GPCR) family and a well-established target for the treatment of type 2 diabetes. The N-terminal extracellular domain (ECD) of GLP-1R is important for GLP-1 binding and the crystal structure of the GLP-1/ECD complex was reported previously. The first structure of a class B GPCR transmembrane (TM) domain was solved recently, but the full length receptor structure is still not well understood. Here we describe the molecular details of antibody-mediated antagonism of the GLP-1R using both in vitro pharmacology and x-ray crystallography. We showed that the antibody Fab fragment (Fab 3F52) blocked the GLP-1 binding site of the ECD directly and thereby acts as a competitive antagonist of native GLP-1. Interestingly, Fab 3F52 also blocked a short peptide agonist believed to engage primarily the transmembrane and extracellular loop region of GLP-1R, whereas functionality of an allosteric small-molecule agonist was not inhibited. This study has implications for the structural understanding of the GLP-1R and related class B GPCRs, which is important for the development of new and improved therapeutics targeting these receptors. PMID:27196125

  14. Antibody-mediated Impairment and Homeostatic Plasticity of Autonomic Ganglionic Synaptic Transmission

    PubMed Central

    Wang, Zhengbei; Low, Phillip A.; Vernino, Steven

    2010-01-01

    Antibodies against ganglionic acetylcholine receptors (AChR) are implicated as the cause of autoimmune autonomic ganglionopathy (AAG). To characterize ganglionic neurotransmission in an animal model of AAG, evoked and spontaneous excitatory post-synaptic potentials (EPSP) were recorded from neurons in isolated mouse superior cervical ganglia (SCG). In vitro exposure of ganglia to IgG from AAG patients progressively inhibited synaptic transmission. After passive transfer of antibody to mice, evoked EPSP amplitude decreased, and some neurons showed no synaptic responses. EPSP amplitude recovered by day seven despite persistence of ganglionic AChR antibody in the mouse serum. There was a more persistent (at least 14 day) reduction in miniature EPSP amplitude consistent with antibody-mediated reduction in post-synaptic AChR. Although the quantal size was reduced, a progressive increase in the frequency of spontaneous synaptic events occurred, suggesting a compensatory increase in presynaptic efficacy. The quantal size returned to baseline by 21 days while the frequency remained increased for at least four weeks. Ganglionic AChR antibodies cause an impairment of autonomic ganglionic synaptic transmission. Homeostatic plasticity in autonomic neurotransmission could help explain the spontaneous clinical recovery seen in some AAG patients and may also play an important role in regulating normal autonomic reflexes. PMID:20044994

  15. Structural insight into antibody-mediated antagonism of the Glucagon-like peptide-1 Receptor.

    PubMed

    Hennen, Stephanie; Kodra, János T; Soroka, Vladyslav; Krogh, Berit O; Wu, Xiaoai; Kaastrup, Peter; Ørskov, Cathrine; Rønn, Sif G; Schluckebier, Gerd; Barbateskovic, Silvia; Gandhi, Prafull S; Reedtz-Runge, Steffen

    2016-05-19

    The Glucagon-like peptide-1 receptor (GLP-1R) is a member of the class B G protein-coupled receptor (GPCR) family and a well-established target for the treatment of type 2 diabetes. The N-terminal extracellular domain (ECD) of GLP-1R is important for GLP-1 binding and the crystal structure of the GLP-1/ECD complex was reported previously. The first structure of a class B GPCR transmembrane (TM) domain was solved recently, but the full length receptor structure is still not well understood. Here we describe the molecular details of antibody-mediated antagonism of the GLP-1R using both in vitro pharmacology and x-ray crystallography. We showed that the antibody Fab fragment (Fab 3F52) blocked the GLP-1 binding site of the ECD directly and thereby acts as a competitive antagonist of native GLP-1. Interestingly, Fab 3F52 also blocked a short peptide agonist believed to engage primarily the transmembrane and extracellular loop region of GLP-1R, whereas functionality of an allosteric small-molecule agonist was not inhibited. This study has implications for the structural understanding of the GLP-1R and related class B GPCRs, which is important for the development of new and improved therapeutics targeting these receptors.

  16. Immunization with heat-killed Francisella tularensis LVS elicits protective antibody-mediated immunity.

    PubMed

    Lavine, Christy L; Clinton, Shawn R; Angelova-Fischer, Irena; Marion, Tony N; Bina, Xiaowen R; Bina, James E; Whitt, Michael A; Miller, Mark A

    2007-11-01

    Francisella tularensis (FT) has been classified by the CDC as a category A pathogen because of its high virulence and the high mortality rate associated with infection via the aerosol route. Because there is no licensed vaccine available for FT, development of prophylactic and therapeutic regimens for the prevention/treatment of infection is a high priority. In this report, heat-killed FT live vaccine strain (HKLVS) was employed as a vaccine immunogen, either alone or in combination with an adjuvant, and was found to elicit protective immunity against high-dose FT live vaccine strain (FTLVS) challenge. FT-specific antibodies produced in response to immunization with HKLVS alone were subsequently found to completely protect naive mice against high-dose FT challenge in both infection-interference and passive immunization experiments. Additional passive immunization trials employing serum collected from mice immunized with a heat-killed preparation of an O-antigen-deficient transposon mutant of FTLVS (HKLVS-OAg(neg)) yielded similar results. These findings demonstrated that FT-specific antibodies alone can confer immunity against high-dose FTLVS challenge, and they reveal that antibody-mediated protection is not dependent upon production of LPS-specific antibodies.

  17. Effector Mechanisms of Rejection

    PubMed Central

    Moreau, Aurélie; Varey, Emilie; Anegon, Ignacio; Cuturi, Maria-Cristina

    2013-01-01

    Organ transplantation appears today to be the best alternative to replace the loss of vital organs induced by various diseases. Transplants can, however, also be rejected by the recipient. In this review, we provide an overview of the mechanisms and the cells/molecules involved in acute and chronic rejections. T cells and B cells mainly control the antigen-specific rejection and act either as effector, regulatory, or memory cells. On the other hand, nonspecific cells such as endothelial cells, NK cells, macrophages, or polymorphonuclear cells are also crucial actors of transplant rejection. Last, beyond cells, the high contribution of antibodies, chemokines, and complement molecules in graft rejection is discussed in this article. The understanding of the different components involved in graft rejection is essential as some of them are used in the clinic as biomarkers to detect and quantify the level of rejection. PMID:24186491

  18. Acute Rejection Phenotypes in the Current Era of Immunosuppression: A Single-Center Analysis

    PubMed Central

    Wehmeier, Caroline; Amico, Patrizia; Hirt-Minkowski, Patricia; Georgalis, Argyrios; Höenger, Gideon; Menter, Thomas; Mihatsch, Michael; Burkhalter, Felix; Steiger, Juerg; Dickenmann, Michael; Hopfer, Helmut; Schaub, Stefan

    2017-01-01

    Background Besides ‘definitive rejection’, the Banff classification includes categories for ‘suspicious for rejection’ phenotypes. The aim of this study was to determine the frequency and phenotypes of rejection episodes in 316 consecutive renal transplants from 2009 to 2014 grouped into patients without/with pretransplant HLA-DSA (ptDSAneg, n = 251; ptDSApos, n = 65). Methods All adequate indication (n = 125) and surveillance biopsies (n = 538) performed within the first year posttransplant were classified according to the current Banff criteria. Results ‘Suspicious for rejection’ phenotypes were 3 times more common than ‘definitive rejection’ phenotypes in biopsies from ptDSAneg patients (35% vs 11%) and equally common in biopsies from ptDSApos patients (25% vs 27%). In both groups, ‘suspicious for rejection’ phenotypes were more frequent in surveillance than in indication biopsies (28% vs 16% in ptDSAneg patients, and 37% vs 29% in ptDSApos patients). ‘Borderline changes: ‘Suspicious' for acute T-cell mediated rejection’ (91%) were the dominant ‘suspicious for rejection’ phenotype in ptDSAneg patients, whereas ‘borderline changes’ (58%) and ‘suspicious for acute/active antibody-mediated rejection’ (42%) were equally frequent in biopsies from ptDSApos patients. Inclusion of ‘suspicious for rejection’ phenotypes increased the 1-year incidence of clinical (ptDSAneg patients: 18% vs 8%, P = 0.0005; ptDSApos patients: 24% vs 18%, P = 0.31) and (sub)clinical rejection (ptDSAneg patients: 59% vs 22%, P < 0.0001; ptDSApos patients: 68% vs 40%, P = 0.004). Conclusions ‘Suspicious for rejection’ phenotypes are very common in the current era and outnumber the frequency of ‘definitive rejection’ within the first year posttransplant. PMID:28361120

  19. A reappraisal of humoral immunity based on mechanisms of antibody-mediated protection against intracellular pathogens.

    PubMed

    Casadevall, Arturo; Pirofski, Liise-anne

    2006-01-01

    Sometime in the mid to late twentieth century the study of antibody-mediated immunity (AMI) entered the doldrums, as many immunologists believed that the function of AMI was well understood, and was no longer deserving of intensive investigation. However, beginning in the 1990s studies using monoclonal antibodies (mAbs) revealed new functions for antibodies, including direct antimicrobial effects and their ability to modify host inflammatory and cellular responses. Furthermore, the demonstration that mAbs to several intracellular bacterial and fungal pathogens were protective issued a serious challenge to the paradigm that host defense against such microbes was strictly governed by cell-mediated immunity (CMI). Hence, a new view of AMI is emerging. This view is based on the concept that a major function of antibody (Ab) is to amplify or subdue the inflammatory response to a microbe. In this regard, the "damage-response framework" of microbial pathogenesis provides a new conceptual viewpoint for understanding mechanisms of AMI. According to this view, the ability of an Ab to affect the outcome of a host-microbe interaction is a function of its capacity to modify the damage ensuing from such an interaction. In fact, it is increasingly apparent that the efficacy of an Ab cannot be defined either by immunoglobulin or epitope characteristics alone, but rather by a complex function of Ab variables, such as specificity, isotype, and amount, host variables, such as genetic background and immune status, and microbial variables, such as inoculum, mechanisms of avoiding host immune surveillance and pathogenic strategy. Consequently, far from being understood, recent findings in AMI imply a system with unfathomable complexity and the field is poised for a long overdue renaissance.

  20. Antibody-mediated p53 protein therapy prevents liver metastasis in vivo.

    PubMed

    Hansen, James E; Fischer, Laurice K; Chan, Grace; Chang, Sophia S; Baldwin, Scott W; Aragon, Robert J; Carter, Jacqueline J; Lilly, Michael; Nishimura, Robert N; Weisbart, Richard H; Reeves, Mark E

    2007-02-15

    To evaluate the clinical efficacy of monoclonal antibody (mAb) 3E10 Fv antibody-mediated p53 protein therapy, an Fv-p53 fusion protein produced in Pichia pastoris was tested on CT26.CL25 colon cancer cells in vitro and in vivo in a mouse model of colon cancer metastasis to the liver. In vitro experiments showed killing of CT26.CL25 cells by Fv-p53 but not Fv or p53 alone, and immunohistochemical staining confirmed that Fv was required for transport of p53 into cells. Prevention of liver metastasis in vivo was tested by splenic injection of 100 nmol/L Fv-p53 10 min and 1 week after injection of CT26.CL25 cancer cells into the portal vein of BALB/c mice. Mice were sacrificed 1 week after the second injection of Fv-p53 and assigned a quantitative metastasis score. Control mice had an average metastasis score of 3.3 +/- 1.3, whereas mice treated with Fv-p53 had an average metastasis score of 0.8 +/- 0.4 (P = 0.004). These results indicate that Fv-p53 treatment had a profound effect on liver metastasis and represent the first demonstration of effective full-length p53 protein therapy in vivo. mAb 3E10 Fv has significant clinical potential as a mediator of intracellular and intranuclear delivery of p53 for prevention and treatment of cancer metastasis.

  1. Escaping from Rejection

    PubMed Central

    Lynch, Raymond J.; Platt, Jeffrey L.

    2009-01-01

    Summary Those engaged in clinical transplantation and transplantation immunology have always taken as a central objective the elucidation of means to prevent graft rejection by the recipient immune system. Conceptually, such mechanisms stem from the concept of Paul Ehrlich that all organisms can selectively avoid autotoxicity; i.e. they exhibit horror autotoxicus. Some mechanisms of horror autotoxicus now understood. T lymphocytes and B lymphocytes recognize foreign antigens but not some auto-antigens. Clonal deletion generates lacunae in what is otherwise a virtually limitless potential to recognize antigens. We call this mechanism structural tolerance. Where imperfections in structural tolerance allow self-recognition, the full activation of lymphocytes and generation of effector activity depends on delivery of accessory signals generated by infection and/or injury. The absence of accessory signals prevents or even suppresses immunological responses. We call this dichotomy of responsiveness conditional tolerance. When, despite structural and conditional tolerance, effector activity perturbs autologous cells, metabolism changes in ways that protect against injury. We use the term accommodation to refer to this acquired protection against injury. Structural and conditional tolerance and accommodation overlap in such a way that potentially toxic products can be generated to control microorganisms and neutralize toxins without overly damaging adjacent cells. The central challenge in transplantation, then, should be the orchestration of structural and conditional tolerance and accommodation in such a way that toxic products can still be generated for defense while preserving graft function and survival. Since the earliest days of transplantation, immunobiologists have sought means by which to prevent recognition and rejection of foreign tissue. The goal of these strategies is the retention of recipient immune function while selectively avoiding graft injury. While

  2. Utilization of cholera toxin B as a mucosal adjuvant elicits antibody-mediated protection against S. pneumoniae infection in mice

    PubMed Central

    Wiedinger, Kari; Pinho, Daniel; Bitsaktsis, Constantine

    2017-01-01

    adoptive transfer passively protected animals against subsequent challenge while IFN-γ neutralization had no impact on the outcome of immunization, suggesting a primary role for antibody-mediated protection in the context of this immunization strategy. Conclusion: Mucosal immunization with CTB and PspA induced a local cellular immune response and systemic humoral immunity which resulted in effective reduction of pulmonary bacterial burden and complete protection against S. pneumoniae challenge. While induction of the pleiotropic cytokine IFN-γ likely contributes to control of infection through activation of effector pathways, it was not required for protection. Instead, immunization with PspA and CTB-induced S. pneumoniae-specific antibodies in the serum prior to infection that were sufficient to protect against mucosal challenge. PMID:28344805

  3. Antibody-mediated pure red cell aplasia (PRCA) on switching from darbepoetin alfa to epoetin beta: what are the implications?

    PubMed Central

    Assunção, José; Vinhas, José

    2008-01-01

    We report the development of antibody-mediated pure red cell aplasia (PRCA) in a 63-year-old man with end-stage renal disease following a switch from darbepoetin alfa to epoetin beta. Haemoglobin levels began to decrease 6 months after the switch. Increasing the epoetin beta dose produced no response and regular blood transfusions were required; PRCA was confirmed and epoetin beta was discontinued. The patient responded positively to immunosuppression; after 2 months on prednisone and cyclophosphamide, haemoglobin levels stabilized and no further transfusions were required. This case highlights the difficulty in establishing a cause-effect relationship where more than one erythropoiesis-stimulating agent is involved. PMID:25983889

  4. Antibody-mediated pure red cell aplasia (PRCA) on switching from darbepoetin alfa to epoetin beta: what are the implications?

    PubMed

    Assunção, José; Vinhas, José

    2008-08-01

    We report the development of antibody-mediated pure red cell aplasia (PRCA) in a 63-year-old man with end-stage renal disease following a switch from darbepoetin alfa to epoetin beta. Haemoglobin levels began to decrease 6 months after the switch. Increasing the epoetin beta dose produced no response and regular blood transfusions were required; PRCA was confirmed and epoetin beta was discontinued. The patient responded positively to immunosuppression; after 2 months on prednisone and cyclophosphamide, haemoglobin levels stabilized and no further transfusions were required. This case highlights the difficulty in establishing a cause-effect relationship where more than one erythropoiesis-stimulating agent is involved.

  5. Antibody-mediated immunity in CFW mice infected with Mycobacterium lepraemurium. Humoral immune response in murine leprosy.

    PubMed Central

    Rojas-Espinosa, O; Casoluengo-Méndez, M; Díaz, G V

    1976-01-01

    A depression in antibody-mediated immunity (AMI) measured both in terms of circulating antibody and plaque-forming cells in the spleen was observed in CFW mice infected with M. lepraemurium when sheep red blood cells (SRBC) and human gammaglobulin (HGG) were used as antigens. The impairment in AMI was evident only after 75 days of infection thereafter the antibody response to SRBC antigen progressively decreased until the last day of experimentation (135 days). Within the first 60 days of infection no alteration in AMI was observed with the HGG antigen while the response to the SRBC antigen was significantly higher in the infected animals than in uninfected controls. PMID:795574

  6. Analysis of Sera of Recipients with Allograft Rejection Indicates That Keratin 1 Is the Target of Anti-Endothelial Antibodies

    PubMed Central

    Guo, Xuli; Hu, Juan; Luo, Weiguang; Luo, Qizhi; Guo, Jing; Tian, Fang; Ming, Yingzi

    2017-01-01

    Anti-endothelial cell antibodies (AECAs) are usually directed against the surface antigens on the vascular endothelial cells. Clinical studies suggest a pathogenic role for nonhuman leukocyte antigen in antibody-mediated rejection; however, the antigens on the donor vascular endothelium that serve as the first-line targets for an immune response during allograft rejection have not been fully identified. Here, we used immunoprecipitation and mass spectrometry to identify antigens from the sera of kidney transplant recipients who were experiencing antibody-mediated rejection. Keratin 1 (KRT1) was identified as a novel antigenic target expressed on endothelial cells. To validate our finding, we produced recombinant proteins representing the three most common alleles of KRT1. The serum used for immunoprecipitation showed a strong reaction to KRT1 recombinants in western blot and ELISA. In the kidney transplant cohort, more AECA-positive recipients than AECA-negative recipients had KRT1 antibodies (32.2% versus 11.9%, p = 0.002). Sera from 255 renal recipients were tested by ELISA. Of the 77 recipients with deteriorating graft function (serum creatinine > 120 μmol/L), 23 had anti-KRT1 antibodies. KRT1-IgG positivity was, therefore, associated with a higher risk of kidney transplant rejection (29.9% (23/77) versus 16.9% (30/178), p = 0.0187). A better understanding of this antigenic target will improve long-term allograft survival. PMID:28265584

  7. Transfusion Induced Bone Marrow Transplant Rejection Due to Minor Histocompatibility Antigens

    PubMed Central

    Patel, Seema R; Zimring, James C

    2014-01-01

    Traditionally, alloimmunization to transfused blood products has focused exclusively upon recipient antibodies recognizing donor alloantigens present on the cell surface. Accordingly, the immunological sequelae of alloimmunization have been antibody mediated effects (i.e. hemolytic transfusion reactions, platelet refractoriness, anti-HLA and anti-HNA effects, etc.). However, in addition to the above sequelae, there is also a correlation between the number of antecedent transfusions in humans and the rate of bone marrow transplant (BMT) rejection - under reduced intensity conditioning with HLA matched or HLA identical marrow. BMT of this nature is the only existing cure for a series of non-malignant hematological diseases (e.g. sickle cell disease, thalassemias, etc.); however, rejection remains a clinical problem. It has been hypothesized that transfusion induces subsequent BMT rejection through immunization. Studies in animal models have observed the same effect and have demonstrated that transfusion induced BMT rejection can occur in response to alloimmunization. However, unlike traditional antibody responses, sensitization in this case results in cellular immune effects, involving populations such as T cell or NK cells. In this case, rejection occurs in the absence of alloantibodies, and would not be detected by existing immune-hematological methods. We review human and animal studies in light of the hypothesis that, for distinct clinical populations, enhanced rejection of BMT may be an unappreciated adverse consequence of transfusion which current blood bank methodologies are unable to detect. PMID:24090731

  8. Substitution of the precursor peptide prevents anti-prM antibody-mediated antibody-dependent enhancement of dengue virus infection.

    PubMed

    Wang, Ying; Si, Lu-Lu; Guo, Xiao-Lan; Cui, Guo-Hui; Fang, Dan-Yun; Zhou, Jun-Mei; Yan, Hui-Jun; Jiang, Li-Fang

    2017-02-02

    Antibody-dependent enhancement (ADE) is currently considered as the mechanism underlying the pathogenesis of severe dengue disease. Many studies have shown that precursor (pr) peptide-specific antibodies do not efficiently neutralize infection but potently promote ADE of dengue virus (DENV) infection. To explore the effect of pr peptide substitution on neutralization and ADE of DENV infection, the rabbit anti-prM polyclonal antibodies (pAbs) and anti-JEVpr/DENV-M pAbs were prepared, and the neutralization and ADE of these two pAbs were further compared. Here, we report that both anti-JEVpr/DENV-M and anti-prM pAbs exhibited broad cross-reactivity and only partial neutralization with four DENV serotypes and immature DENV. Rabbit anti-prM pAbs showed a significant enhancement in a broad range of serum dilutions. However, there was no statistically significant difference in the enhancing activity of rabbit anti-JEVpr/DENV-M pAbs at various levels of dilution. These results demonstrate that anti-prM antibody-mediated ADE can be prevented by JEV pr peptide replacement. The present study contribute further to research on the pathogenesis of DENV infection.

  9. The Perfect Storm: HLA Antibodies, Complement, FcγRs and Endothelium in Transplant Rejection

    PubMed Central

    Thomas, Kimberly A.; Valenzuela, Nicole M.; Reed, Elaine F.

    2015-01-01

    The pathophysiology of antibody-mediated rejection (AMR) in solid organ transplants is multi-faceted and predominantly caused by antibodies directed against polymorphic donor human leukocyte antigens (HLA). Despite the clearly detrimental impact of HLA antibodies (HLA-Ab) on graft function and survival, the prevention, diagnosis and treatment of AMR remain a challenge. Histological manifestations of AMR reflect signatures of HLA-Ab-triggered injury, specifically endothelial changes, recipient leukocytic infiltrate, and complement deposition. We review the interconnected mechanisms of HLA-Ab-mediated injury that might synergize in a “perfect storm” of inflammation. Characterization of antibody features that are critical for effector functions may help identify HLA-Ab more likely to cause rejection. We also highlight recent advancements that may pave the way for new, more effective therapeutics. PMID:25801125

  10. A case of accelerated acute rejection after ABO-compatible living unrelated kidney transplantation.

    PubMed

    Matsuo, Nanae; Yamamoto, Hiroyasu; Kobayashi, Akimitsu; Yamamoto, Izumi; Mitome, Jun; Maruyama, Yukio; Hayakawa, Hiroshi; Miyazaki, Yoichi; Utsunomiya, Yasunori; Hosoya, Tatsuo; Yamaguchi, Yutaka

    2009-08-01

    A 59-yr-old Japanese woman with chronic renal failure caused by IgA nephropathy and antineutrophil cytoplasmic antibody (ANCA)-related glomerulonephritis underwent kidney transplantation from a living unrelated spousal donor. The blood type was compatible, while the human leukocyte antigen (HLA) typing showed a 5/6 locus mismatch. She had become pregnant twice by her donor and had never received blood transfusions. Complement-dependent cytotoxicity cross-match, flow cytometry cross-match (FCXM), and flow panel reactive antibody (PRA) were negative. She initially underwent one week of immunosuppression with mycophenolate mofetil (MMF) and double filtration plasmapheresis (DFPP) immediately before transplantation to reduce the risk of antibody-mediated rejection. Induction therapy consisted of MMF, tacrolimus (TAC), methylprednisolone (MP), and basiliximab. The allograft function was excellent immediately after the operation. However, the urine output and platelet count declined rapidly on post-operative day (POD) 3, while the serum creatinine (sCr) and lactate dehydrogenase levels rose gradually. Subsequently, we could not detect the diastolic arterial flow on Doppler sonography. We diagnosed accelerated acute rejection and treated her with plasma exchange (PEX), intravenous MP pulse therapy, and rituximab. The first episode biopsy on POD 7 revealed acute vascular rejection and acute antibody-mediated rejection (Banff score AMR II). Her urinary excretion increased beginning on POD 13, while the sCr level decreased gradually and reached 0.9 mg/dL on POD 22. In our retrospective analysis, the LAB screen detected donor-specific antibody (DSA). This case suggested that, for successful kidney transplantation in highly sensitized recipients, such as husband-to-wife spousal kidney transplantation with a history of pregnancy, we should keep the risk of AMR in mind, even if the sensitive antibody detection tests are negative.

  11. Winter activity patterns of American martens (Martes americana): Rejection of the hypothesis of thermal-cost minimization

    USGS Publications Warehouse

    Drew, Gary S.; Bissonette, John A.

    1997-01-01

    Despite their temperate to subarctic geographic range, American martens (Martes americana) possess a thermally inefficient morphology. The lack of morphological adaptations for reducing thermal costs suggests that marten may use behavioral strategies to optimize thermal budgets. During the winters of 1989–1990 and 1990–1991, we radio-collared and monitored the diel activity of 7 martens. A log-linear model suggested that the presence or absence of light was the only factor associated with marten activity patterns (p < 0.001). A regression of the percentage of active fixes on ambient temperature failed to detect an association (b = −4.45, p = 0.084, n = 12). Contents of marten scats suggested that their activity was consistent with the prey-vulnerability hypothesis. While martens must balance multiple life requisites, their activity patterns suggest that they accept increased thermal costs in order to increase foraging efficiency. However, the nocturnal activity of martens during winter was also consistent with the hypothesis that they may be able to limit their own exposure to predation risk. The nocturnal habits of Newfoundland martens in the winter were consistent with the hypothesis of avoidance of predation risk.

  12. Enhanced pyrite rejection in coal flotation

    SciTech Connect

    Tao, D.P.; Lu, M.X.; Richardson, P.E.; Luttrell, G.H.; Adel, G.T.; Yoon, R.H.

    1994-12-31

    Difficulties in rejecting pyrite from coal by flotation primarily result from two mechanisms of particle recovery: attachment and middlings. Attachment of pyrite is the consequence of surface hydrophobicity induced by superficial oxidation; middlings that can float readily are caused by incomplete liberation of pyrite from coal. New flotation schemes have been developed to enhance pyrite rejection. They are referred to as Electrochemically-Enhanced Sulfur Rejection (EESR) and Polymer-Enhanced Sulfur Rejection (PESR) processes. In the EESR process, the formation of hydrophobic products is prevented by electrochemical techniques in which active metals are used as sacrificial anodes to cathodically protect pyrite from oxidation; in the PESR process, hydrophilic polymers is used to mask coal in middlings by specific adsorption on pyrite, and thus depress coal-pyrite middlings.

  13. The rapid rejection of allogeneic lymphocytes by a non-adaptive, cell-mediated mechanism (NK activity).

    PubMed Central

    Rolstad, B; Fossum, S; Bazin, H; Kimber, I; Marshall, J; Sparshott, S M; Ford, W L

    1985-01-01

    The fate of allogeneic lymphocytes (AO or DA) transferred to non-immune PVG recipients was studied in the light of previous evidence (Heslop & McNeilage, 1983; Rolstad & Ford, 1983) that allogeneic lymphocytes can be rapidly destroyed in certain strain combinations of rats and mice by a mechanism that is distinct from either T-cell mediated immunity or an alloantibody response. AO lymphocytes injected into PVG recipients were discriminated from syngeneic lymphocytes within 15-30 min of i.v. injection, as testified by the excess release of 51Cr into the lymph plasma of the recipient. The following experiments were intended to distinguish between natural antibody and natural killer (NK) cells as the mechanism responsible for the allogeneic lymphocyte cytotoxicity (ALC) displayed by PVG rats. Nude rats treated from birth with anti-mu chain serum and shown to be lacking B and T lymphocytes, as well as being profoundly deficient in immunoglobulin, displayed more aggressive ALC than did control nude rats which, in turn, showed stronger ALC than did euthymic rats. Serum from PVG nude rats exerted no inhibitory or destructive effect on allogeneic lymphocytes in an antibody-dependent cellular cytotoxicity system, an assay of graft-versus-host activity, or when injected into 3-4-week-old PVG rats which had not yet developed ALC. Treatment of nude rats with anti-asialo GM 1 antiserum depressed ALC and NK activity in parallel, thus adding to a wide range of circumstances in which ALC and NK activity are closely correlated. In conclusion, ALC is implemented by a non-adaptive, cell-mediated mechanism independent of immunoglobulin, but the precise identity of the effector cell in the recipients' lymphatic tissues remains to be settled. Images Figure 2 PMID:3972430

  14. The Impact of HLA Class I-Specific Killer Cell Immunoglobulin-Like Receptors on Antibody-Dependent Natural Killer Cell-Mediated Cytotoxicity and Organ Allograft Rejection

    PubMed Central

    Rajalingam, Raja

    2016-01-01

    Natural killer (NK) cells of the innate immune system are cytotoxic lymphocytes that play an important roles following transplantation of solid organs and hematopoietic stem cells. Recognition of self-human leukocyte antigen (HLA) class I molecules by inhibitory killer cell immunoglobulin-like receptors (KIRs) is involved in the calibration of NK cell effector capacities during the developmental stage, allowing the subsequent recognition and elimination of target cells with decreased expression of self-HLA class I (due to virus infection or tumor transformation) or HLA class I disparities (in the setting of allogeneic transplantation). NK cells expressing an inhibitory KIR-binding self-HLA can be activated when confronted with allografts lacking a ligand for the inhibitory receptor. Following the response of the adaptive immune system, NK cells can further destroy allograft endothelium by antibody-dependent cell-mediated cytotoxicity (ADCC), triggered through cross-linking of the CD16 Fc receptor by donor-specific antibodies bound to allograft. Upon recognizing allogeneic target cells, NK cells also secrete cytokines and chemokines that drive maturation of dendritic cells to promote cellular and humoral adaptive immune responses against the allograft. The cumulative activating and inhibitory signals generated by ligation of the receptors regulates mature NK cell killing of target cells and their production of cytokines and chemokines. This review summarizes the role of NK cells in allograft rejection and proposes mechanistic concepts that indicate a prominent role for KIR–HLA interactions in facilitating NK cells for Fc receptor-mediated ADCC effector function involved in antibody-mediated rejection of solid organ transplants. PMID:28066408

  15. The Impact of HLA Class I-Specific Killer Cell Immunoglobulin-Like Receptors on Antibody-Dependent Natural Killer Cell-Mediated Cytotoxicity and Organ Allograft Rejection.

    PubMed

    Rajalingam, Raja

    2016-01-01

    Natural killer (NK) cells of the innate immune system are cytotoxic lymphocytes that play an important roles following transplantation of solid organs and hematopoietic stem cells. Recognition of self-human leukocyte antigen (HLA) class I molecules by inhibitory killer cell immunoglobulin-like receptors (KIRs) is involved in the calibration of NK cell effector capacities during the developmental stage, allowing the subsequent recognition and elimination of target cells with decreased expression of self-HLA class I (due to virus infection or tumor transformation) or HLA class I disparities (in the setting of allogeneic transplantation). NK cells expressing an inhibitory KIR-binding self-HLA can be activated when confronted with allografts lacking a ligand for the inhibitory receptor. Following the response of the adaptive immune system, NK cells can further destroy allograft endothelium by antibody-dependent cell-mediated cytotoxicity (ADCC), triggered through cross-linking of the CD16 Fc receptor by donor-specific antibodies bound to allograft. Upon recognizing allogeneic target cells, NK cells also secrete cytokines and chemokines that drive maturation of dendritic cells to promote cellular and humoral adaptive immune responses against the allograft. The cumulative activating and inhibitory signals generated by ligation of the receptors regulates mature NK cell killing of target cells and their production of cytokines and chemokines. This review summarizes the role of NK cells in allograft rejection and proposes mechanistic concepts that indicate a prominent role for KIR-HLA interactions in facilitating NK cells for Fc receptor-mediated ADCC effector function involved in antibody-mediated rejection of solid organ transplants.

  16. Soothing the Sting of Rejection.

    ERIC Educational Resources Information Center

    Campbell, Joan Daniels

    1990-01-01

    Preventing rejection of a student by his/her peers and helping the child to cope with such rejection are ever-present challenges for teachers. Suggestions are given by teachers who have successfully dealt with students who were rejected by classmates. (IAH)

  17. Efficacy of Acute Cellular Rejection Treatment According to Banff Score in Kidney Transplant Recipients: A Systematic Review

    PubMed Central

    Lamarche, Caroline; Côté, Jean-Maxime; Sénécal, Lynne; Cardinal, Héloïse

    2016-01-01

    Background The poor prognosis classically associated with Banff grade 2 acute cell-mediated rejection (CMR) may be due to unrecognized antibody-mediated damage. We thus performed a systematic review of the literature to determine the rate of response to treatment in kidney transplant recipients with pure CMR, stratified by Banff class. Methods In addition to a manual search, databases interrogated included Excerpta Medica Database (EMBASE), Medical Literature Analysis and Retrieval System Online (MEDLINE), Evidence-Based Medicine (EBM) databases, Central, PubMed and CINAHL. Studies providing functional and/or histological response rates to the treatment of CMR rejection by Banff class (1997 or more recent) were included. Results Among the 746 articles identified, 5 articles were included in the final review. Two studies excluded some, and 2 excluded all features of antibody-mediated rejection, while providing data on functional recovery. The absence of functional recovery was reported in 4% of borderline, 15% for Banff grade 1A and IB pooled, 0% to 25% of Banff grade 1B alone, 11% to 20% of Banff grade 2A, and 38% of Banff grade 2B rejections. Conclusions The rate of functional recovery of pure Banff IIA CMR overlapped with that of Banff grade 1 CMR, whereas Banff grade 2B showed worse prognosis. There was important heterogeneity in the definition of response to treatment and paucity of data describing the histological response to treatment stratified by Banff class. There is a pressing need to standardize outcome metrics for the reversibility of rejection in kidney transplant recipients in order to design high-quality trials for novel therapeutic alternatives. PMID:27990480

  18. Δ9-Tetrahydrocannabinol attenuates allogeneic host-versus-graft response and delays skin graft rejection through activation of cannabinoid receptor 1 and induction of myeloid-derived suppressor cells

    PubMed Central

    Sido, Jessica M.; Nagarkatti, Prakash S.; Nagarkatti, Mitzi

    2015-01-01

    Immune cells have been shown to express cannabinoid receptors and to produce endogenous ligands. Moreover, activation of cannabinoid receptors on immune cells has been shown to trigger potent immunosuppression. Despite such studies, the role of cannabinoids in transplantation, specifically to prevent allograft rejection, has not, to our knowledge, been investigated previously. In the current study, we tested the effect of THC on the suppression of HvGD as well as rejection of skin allografts. To this end, we studied HvGD by injecting H-2k splenocytes into H-2b mice and analyzing the immune response in the draining ingLNs. THC treatment significantly reduced T cell proliferation and activation in draining LNs of the recipient mice and decreased early stage rejection-indicator cytokines, including IL-2 and IFN-γ. THC treatment also increased the allogeneic skin graft survival. THC treatment in HvGD mice led to induction of MDSCs. Using MDSC depletion studies as well as adoptive transfer experiments, we found that THC-induced MDSCs were necessary for attenuation of HvGD. Additionally, using pharmacological inhibitors of CB1 and CB2 receptors and CB1 and CB2 knockout mice, we found that THC was working preferentially through CB1. Together, our research shows, for the first time to our knowledge, that targeting cannabinoid receptors may provide a novel treatment modality to attenuate HvGD and prevent allograft rejection. PMID:26034207

  19. Δ⁹-Tetrahydrocannabinol attenuates allogeneic host-versus-graft response and delays skin graft rejection through activation of cannabinoid receptor 1 and induction of myeloid-derived suppressor cells.

    PubMed

    Sido, Jessica M; Nagarkatti, Prakash S; Nagarkatti, Mitzi

    2015-09-01

    Immune cells have been shown to express cannabinoid receptors and to produce endogenous ligands. Moreover, activation of cannabinoid receptors on immune cells has been shown to trigger potent immunosuppression. Despite such studies, the role of cannabinoids in transplantation, specifically to prevent allograft rejection, has not, to our knowledge, been investigated previously. In the current study, we tested the effect of THC on the suppression of HvGD as well as rejection of skin allografts. To this end, we studied HvGD by injecting H-2(k) splenocytes into H-2(b) mice and analyzing the immune response in the draining ingLNs. THC treatment significantly reduced T cell proliferation and activation in draining LNs of the recipient mice and decreased early stage rejection-indicator cytokines, including IL-2 and IFN-γ. THC treatment also increased the allogeneic skin graft survival. THC treatment in HvGD mice led to induction of MDSCs. Using MDSC depletion studies as well as adoptive transfer experiments, we found that THC-induced MDSCs were necessary for attenuation of HvGD. Additionally, using pharmacological inhibitors of CB1 and CB2 receptors and CB1 and CB2 knockout mice, we found that THC was working preferentially through CB1. Together, our research shows, for the first time to our knowledge, that targeting cannabinoid receptors may provide a novel treatment modality to attenuate HvGD and prevent allograft rejection.

  20. Complement and Antibody-Mediated Enhancement of Erythrocyte Invasion by Plasmodium Falciparum

    DTIC Science & Technology

    2016-04-01

    take place via antibody-dependent or independent mechanisms. Complement is activated during malaria infection (4), especially in the presence of...that complement activation during malaria infection enhances the invasion of RBCs by P. falciparum. In this research we tested our hypothesis by... infection have an enhancing effect on invasion and, if so, what is the mechanism. A - C3/C4 + C3/C4 % I n h ib it io n -10 -5 0 5 10 15 - C3/C4 + C3/C4

  1. Absence of Intragraft B Cells in Rejection Biopsies After Rituximab Induction Therapy: Consequences for Clinical Outcome

    PubMed Central

    van den Hoogen, Martijn W.F.; Steenbergen, Eric J.; Baas, Marije C.; Florquin, Sandrine; Hilbrands, Luuk B.

    2017-01-01

    Background The pathophysiological role of intragraft B cells during renal allograft rejection is unclear. Methods We studied B-cell infiltration during acute rejection in 53 patients who participated in a clinical trial in which adult renal transplant patients were randomized between a single intraoperative dose of rituximab (375 mg/m2) or placebo as induction therapy. Two independent pathologists scored all biopsies in a blinded fashion according to the Banff classification and scored for the presence of B cells and plasma cells using CD79a and CD138 as markers. Results The majority of acute rejections were T cell–mediated. The proportion of acute rejections with an antibody-mediated component tended to be lower in rituximab-treated patients (4/23, 17.4%) than in placebo-treated patients (11/30, 36.7%; P = 0.14). Biopsies of rituximab-treated patients had significantly lower scores for B cells (0.00; range, 0.00-0.50 vs 1.70; range, 0.60-3.30; P < 0.0001) and plasma cells (0.10; range, 0.00-1.90 vs 0.40; range, 0.00-7.50; P = 0.006). During acute rejection, intragraft clusters of B cells were not observed after rituximab induction therapy. However, the depletion of intragraft B cells during acute rejection did not affect steroid resistance, proteinuria, graft function at 2 years follow-up, or patient and graft survival at a median follow-up of 4.1 years (range, 2.0-6.2 years). Conclusions These data do not support a harmful influence of intragraft B cells present during acute allograft rejection on the clinical course within the first few years after renal transplantation.

  2. Patterns of Early Rejection in Renal Retransplantation: A Single-Center Experience

    PubMed Central

    Fu, Cheng; Lin, Kailin; Wang, Zhiqiang; Guo, Hui; Chen, Song; Lin, Zhengbin; Chen, Zhishui

    2016-01-01

    It has been reported that kidney retransplant patients had high rates of early acute rejection due to previous sensitization. In addition to the acute antibody-mediated rejection (ABMR) that has received widespread attention, the early acute T-cell-mediated rejection (TCMR) may be another important issue in renal retransplantation. In the current single-center retrospective study, we included 33 retransplant patients and 90 first transplant patients with similar protocols of induction and maintenance therapy. Analysis focused particularly on the incidence and patterns of early acute rejection episodes, as well as one-year graft and patient survival. Excellent short-term clinical outcomes were obtained in both groups, with one-year graft and patient survival rates of 93.9%/100% in the retransplant group and 92.2%/95.6% in the first transplant group. Impressively, with our strict immunological selection and desensitization criteria, the retransplant patients had a very low incidence of early acute ABMR (6.1%), which was similar to that in the first transplant patients (4.4%). However, a much higher rate of early acute TCMR was observed in the retransplant group than in the first transplant group (30.3% versus 5.6%, P < 0.001). Acute TCMR that develops early after retransplantation should be monitored in order to obtain better transplant outcomes. PMID:28058265

  3. Antibody-mediated targeted gene transfer to NMDA NR1-containing neurons in rat neocortex by helper virus-free HSV-1 vector particles containing a chimeric HSV-1 glycoprotein C-staphylococcus A protein.

    PubMed

    Cao, Haiyan; Zhang, Guo-Rong; Geller, Alfred I

    2010-09-10

    Because of the heterogeneous cellular composition of the brain, and especially the forebrain, cell type-specific expression will benefit many potential applications of direct gene transfer. The two prevalent approaches for achieving cell type-specific expression are using a cell type-specific promoter or targeting gene transfer to a specific cell type. Targeted gene transfer with Herpes Simplex Virus (HSV-1) vectors modifies glycoprotein C (gC) to replace the heparin binding domain, which binds to many cell types, with a binding activity for a specific cell surface protein. We previously reported targeted gene transfer to nigrostriatal neurons using chimeric gC-glial cell line-derived neurotrophic factor or gC-brain-derived neurotrophic factor protein. Unfortunately, this approach is limited to cells that express the cognate receptor for either neurotrophic factor. Thus, a general strategy for targeting gene transfer to many different types of neurons is desirable. Antibody-mediated targeted gene transfer has been developed for targeting specific virus vectors to specific peripheral cell types; a specific vector particle protein is modified to contain the Staphylococcus A protein ZZ domain, which binds immunoglobulin (Ig) G. Here, we report antibody-mediated targeted gene transfer of HSV-1 vectors to a specific type of forebrain neuron. We constructed a chimeric gC-ZZ protein, and showed this protein is incorporated into vector particles and binds Ig G. Complexes of these vector particles and an antibody to the NMDA receptor NR1 subunit supported targeted gene transfer to NR1-containing neocortical neurons in the rat brain, with long-term (2 months) expression.

  4. Complement and Antibody-Mediated Enhancement of Erythrocyte Invasion by Plasmodium Falciparum

    DTIC Science & Technology

    2015-09-01

    manuscript that is being prepared for publication. Page 13 of 50 Classification: BIOLOGICAL SCIENCES: Immunology and Inflammation; Microbiology...Landmesser1, Michelle D. Spring2, Christian F. Ockenhouse3, and José A. Stoute1,2,* 1The Department of Microbiology and Immunology , and the Department of...complement system is part of the innate immune response and is an important effector arm of humoral immunity. It can be activated via three main

  5. Heat rejection system

    DOEpatents

    Smith, Gregory C.; Tokarz, Richard D.; Parry, Jr., Harvey L.; Braun, Daniel J.

    1980-01-01

    A cooling system for rejecting waste heat consists of a cooling tower incorporating a plurality of coolant tubes provided with cooling fins and each having a plurality of cooling channels therein, means for directing a heat exchange fluid from the power plant through less than the total number of cooling channels to cool the heat exchange fluid under normal ambient temperature conditions, means for directing water through the remaining cooling channels whenever the ambient temperature rises above the temperature at which dry cooling of the heat exchange fluid is sufficient and means for cooling the water.

  6. Polyclonal antibodies mediated immobilization of a peroxidase from ammonium sulphate fractionated bitter gourd (Momordica charantia) proteins.

    PubMed

    Fatima, Aiman; Husain, Qayyum

    2007-06-01

    Polyclonal antibody bound Sepharose 4B support has been exploited for the immobilization of bitter gourd peroxidase directly from ammonium sulphate precipitated proteins. Immunoaffinity immobilized bitter gourd peroxidase exhibited high yield of immobilization. IgG-Sepharose 4B bound bitter gourd peroxidase showed a higher stability against heat, chaotropic agents (urea and guanidinium chloride), detergents (cetyl trimethyl ammonium bromide and Surf Excel), proteolytic enzyme (trypsin) and water-miscible organic solvents (propanol, THF and dioxane). The activity of immobilized bitter gourd peroxidase was significantly enhanced in the presence of cetyl trimethyl ammonium bromide and after treatment with trypsin as compared to soluble enzyme.

  7. Antibody-mediated neutralization of Ebola virus can occur by two distinct mechanisms

    SciTech Connect

    Shedlock, Devon J.; Bailey, Michael A.; Popernack, Paul M.; Cunningham, James M.; Burton, Dennis R.; Sullivan, Nancy J.

    2010-06-05

    Human Ebola virus causes severe hemorrhagic fever disease with high mortality and there is no vaccine or treatment. Antibodies in survivors occur early, are sustained, and can delay infection when transferred into nonhuman primates. Monoclonal antibodies (mAbs) from survivors exhibit potent neutralizing activity in vitro and are protective in rodents. To better understand targets and mechanisms of neutralization, we investigated a panel of mAbs shown previously to react with the envelope glycoprotein (GP). While one non-neutralizing mAb recognized a GP epitope in the nonessential mucin-like domain, the rest were specific for GP1, were neutralizing, and could be further distinguished by reactivity with secreted GP. We show that survivor antibodies, human KZ52 and monkey JP3K11, were specific for conformation-dependent epitopes comprising residues in GP1 and GP2 and that neutralization occurred by two distinct mechanisms; KZ52 inhibited cathepsin cleavage of GP whereas JP3K11 recognized the cleaved, fusion-active form of GP.

  8. Erythropoietin enhances nerve repair in anti-ganglioside antibody-mediated models of immune neuropathy.

    PubMed

    Zhang, Gang; Lehmann, Helmar C; Bogdanova, Nataliia; Gao, Tong; Zhang, Jiangyang; Sheikh, Kazim A

    2011-01-01

    Guillain-Barré syndrome (GBS) is a monophasic immune neuropathic disorder in which a significant proportion of patients have incomplete recovery. The patients with incomplete recovery almost always have some degree of failure of axon regeneration and target reinnervation. Anti-ganglioside antibodies (Abs) are the most commonly recognized autoimmune markers in all forms of GBS and specific Abs are associated with the slow/poor recovery. We recently demonstrated that specific anti-ganglioside Abs inhibit axonal regeneration and nerve repair in preclinical models by activation of small GTPase RhoA and its downstream effectors. The objective of this study was to determine whether erythropoietin (EPO), a pleiotropic cytokine with neuroprotective and neurotrophic properties, enhances nerve regeneration in preclinical cell culture and animal models of autoimmune neuropathy/nerve repair generated with monoclonal and patient derived Abs. Primary neuronal cultures and a standardized sciatic crush nerve model were used to assess the efficacy of EPO in reversing inhibitory effects of anti-ganglioside Abs on nerve repair. We found that EPO completely reversed the inhibitory effects of anti-ganglioside Abs on axon regeneration in cell culture models and significantly improved nerve regeneration/repair in an animal model. Moreover, EPO-induced proregenerative effects in nerve cells are through EPO receptors and Janus kinase 2/Signal transducer and activator of transcription 5 pathway and not via early direct modulation of small GTPase RhoA. These preclinical studies indicate that EPO is a viable candidate drug to develop further for neuroprotection and enhancing nerve repair in patients with GBS.

  9. Effect of cinnarizine on IgE antibody-mediated experimental allergic reactions in guinea pigs.

    PubMed

    Nagai, H; Yamada, H; Yakuo, I; Inagaki, N; Choi, S H; Koda, A; Daikoku, M

    1987-02-01

    The anti-allergic activity and mechanism of cinnarizine was investigated in guinea pigs. Nifedipine, a calcium antagonist, and tranilast, a potent, orally active anti-allergic agent, were used as comparative drugs. Cinnarizine protected against fatal systemic anaphylactic shock in guinea pigs passively sensitized with IgE antibody. Cinnarizine reduced many of the features of severe respiratory disorders. Nifedipine and tranilast showed similar effects. Cinnarizine and nifedipine inhibited the contractile response to antigen of sensitized tracheal smooth muscle when the challenge was carried out at low antigen concentrations. Tranilast showed a tendency to inhibit the antigen-induced contraction of tracheal smooth muscle. Cinnarizine and nifedipine inhibited Ca-induced contraction in potassium-depolarized tracheal smooth muscle, tranilast had no effect. Cinnarizine showed antagonistic action to the contraction by histamine or leukotriene D4 (LTD4) of tracheal muscle. Nifedipine showed similar antagonistic action, although its potency is lower than cinnarizine. Tranilast showed slight antagonistic action to LTD4. Antigen-induced release of histamine and slow reacting substance of anaphylaxis (SRS-A) from sensitized lung tissues was inhibited by nifedipine and tranilast but not by cinnarizine. The release of histamine and SRS-A from lung tissues by calcium ionophore A23187 was inhibited by nifedipine and tranilast but not by cinnarizine. These results suggest that the anti-allergic action of cinnarizine is mainly due to the antagonistic action to allergic mediators and not by interfering with the release of mediators. Cinnarizine's mechanism seems to be related to its antagonistic action to Ca in smooth muscle, but not to the transport of Ca in releasing the anaphylactic chemical mediators in mast cells and other target cells.

  10. Development of a selective biopharmaceutical from Herpes simplex virus type 1 glycoproteins E and I for blocking antibody mediated neutralization of oncolytic viruses.

    PubMed

    Bucurescu, Septimiu

    2010-12-01

    Future cancer therapies will be molecular cures. They will correct, block or destroy cancer cells by targeting molecular changes that lead to carcinogenesis. Destroying cancer cells can be done using oncolytic viruses. By blocking antibody mediated neutralization of oncolytic viruses, Herpes simplex virus type 1 glycoproteins E and I could be used in the adjuvant treatment of cancer for improving the chances of oncolytic viruses to kill cancer cells in vivo.

  11. Antibody-mediated inhibition of Nogo-A signaling promotes neurite growth in PC-12 cells

    PubMed Central

    Yazdi, Iman K; Taghipour, Nima; Hmaidan, Sarah; Palomba, Roberto; Scaria, Shilpa; Munoz, Alvaro; Boone, Timothy B; Tasciotti, Ennio

    2016-01-01

    The use of a monoclonal antibody to block the neurite outgrowth inhibitor Nogo-A has been of great interest for promoting axonal recovery as a treatment for spinal cord injury. While several cellular and non-cellular assays have been developed to quantify the bioactive effects of Nogo-A signaling, demand still exists for the development of a reliable approach to characterize the effectiveness of the anti-Nogo-A antibody. In this study, we developed and validated a novel cell-based approach to facilitate the biological quantification of a Nogo-A antibody using PC-12 cells as an in vitro neuronal cell model. Changes in the mRNA levels of the neuronal differentiation markers, growth-associated protein 43 and neurofilament light-polypeptide, suggest that activation of the Nogo-A pathway suppresses axonal growth and dendrite formation in the tested cell line. We found that application of anti-Nogo-A monoclonal antibody can significantly enhance the neuronal maturity of PC-12 cells by blocking the Nogo-A inhibitory effects, providing enhanced effects on neural maturity at the molecular level. No adverse effects were observed on cell viability. PMID:27027860

  12. Phagocytic cells contribute to the antibody-mediated elimination of pulmonary-infected SARS coronavirus.

    PubMed

    Yasui, Fumihiko; Kohara, Michinori; Kitabatake, Masahiro; Nishiwaki, Tetsu; Fujii, Hideki; Tateno, Chise; Yoneda, Misako; Morita, Kouichi; Matsushima, Kouji; Koyasu, Shigeo; Kai, Chieko

    2014-04-01

    While the 2002-2003 outbreak of severe acute respiratory syndrome (SARS) resulted in 774 deaths, patients who were affected with mild pulmonary symptoms successfully recovered. The objective of the present work was to identify, using SARS coronavirus (SARS-CoV) mouse infection models, immune factors responsible for clearing of the virus. The elimination of pulmonary SARS-CoV infection required the activation of B cells by CD4(+) T cells. Furthermore, passive immunization (post-infection) with homologous (murine) anti-SARS-CoV antiserum showed greater elimination efficacy against SARS-CoV than that with heterologous (rabbit) antiserum, despite the use of equivalent titers of neutralizing antibodies. This distinction was mediated by mouse phagocytic cells (monocyte-derived infiltrating macrophages and partially alveolar macrophages, but not neutrophils), as demonstrated both by adoptive transfer from donors and by immunological depletion of selected cell types. These results indicate that the cooperation of anti-SARS-CoV antibodies and phagocytic cells plays an important role in the elimination of SARS-CoV.

  13. Protooncogene bcl-2 gene transfer abrogates Fas/APO-1 antibody-mediated apoptosis of human malignant glioma cells and confers resistance to chemotherapeutic drugs and therapeutic irradiation.

    PubMed Central

    Weller, M; Malipiero, U; Aguzzi, A; Reed, J C; Fontana, A

    1995-01-01

    The majority of human malignant glioma cells express Fas/APO-1 and are susceptible to Fas/APO-1 antibody-mediated apoptosis in vitro. The sensitivity of Fas/APO-1-positive glioma cell lines to Fas/APO-1 antibody-mediated killing correlates inversely with the constitutive expression of the antiapoptotic protooncogene bcl-2. Here we report that BCL-2 protein expression of human glial tumors in vivo correlates with malignant transformation in that BCL-2 immunoreactive glioma cells were more abundant in WHO grade III/IV gliomas than in grade I/II gliomas. Fas/APO-1 antibody-sensitive human glioma cell lines stably transfected with a murine bcl-2 cDNA acquired resistance to Fas/APO-1 antibody-mediated apoptosis. Forced expression of bcl-2 also attenuated TNF alpha-mediated cytotoxicity of glioma cell lines in the presence of actinomycin D and cycloheximide and conferred partial protection from irradiation and the cancer chemotherapy drugs, cisplatin and BCNU. Preexposure of the glioma cell lines to the cytokines, IFN gamma and TNF alpha, which sensitize for Fas/APO-1-dependent killing, partially overcame bcl-2-mediated rescue from apoptosis, suggesting that multimodality immunotherapy involving cytokines and Fas/APO-1 targeting might eventually provide a promising approach to the treatment of human malignant gliomas. Images PMID:7539458

  14. Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia

    NASA Astrophysics Data System (ADS)

    Shingai, Masashi; Nishimura, Yoshiaki; Klein, Florian; Mouquet, Hugo; Donau, Olivia K.; Plishka, Ronald; Buckler-White, Alicia; Seaman, Michael; Piatak, Michael; Lifson, Jeffrey D.; Dimitrov, Dimiter; Nussenzweig, Michel C.; Martin, Malcolm A.

    2013-11-01

    Neutralizing antibodies can confer immunity to primate lentiviruses by blocking infection in macaque models of AIDS. However, earlier studies of anti-human immunodeficiency virus type 1 (HIV-1) neutralizing antibodies administered to infected individuals or humanized mice reported poor control of virus replication and the rapid emergence of resistant variants. A new generation of anti-HIV-1 monoclonal antibodies, possessing extraordinary potency and breadth of neutralizing activity, has recently been isolated from infected individuals. These neutralizing antibodies target different regions of the HIV-1 envelope glycoprotein including the CD4-binding site, glycans located in the V1/V2, V3 and V4 regions, and the membrane proximal external region of gp41 (refs 9, 10, 11, 12, 13, 14). Here we have examined two of the new antibodies, directed to the CD4-binding site and the V3 region (3BNC117 and 10-1074, respectively), for their ability to block infection and suppress viraemia in macaques infected with the R5 tropic simian-human immunodeficiency virus (SHIV)-AD8, which emulates many of the pathogenic and immunogenic properties of HIV-1 during infections of rhesus macaques. Either antibody alone can potently block virus acquisition. When administered individually to recently infected macaques, the 10-1074 antibody caused a rapid decline in virus load to undetectable levels for 4-7days, followed by virus rebound during which neutralization-resistant variants became detectable. When administered together, a single treatment rapidly suppressed plasma viraemia for 3-5weeks in some long-term chronically SHIV-infected animals with low CD4+ T-cell levels. A second cycle of anti-HIV-1 monoclonal antibody therapy, administered to two previously treated animals, successfully controlled virus rebound. These results indicate that immunotherapy or a combination of immunotherapy plus conventional antiretroviral drugs might be useful as a treatment for chronically HIV-1-infected

  15. Limitations of Murine Models for Assessment of Antibody-Mediated Therapies or Vaccine Candidates against Staphylococcus epidermidis Bloodstream Infection.

    PubMed

    Cole, Leah E; Zhang, Jinrong; Kesselly, Augustus; Anosova, Natalie G; Lam, Hubert; Kleanthous, Harry; Yethon, Jeremy A

    2016-04-01

    Staphylococcus epidermidis is normally a commensal colonizer of human skin and mucus membranes, but, due to its ability to form biofilms on indwelling medical devices, it has emerged as a leading cause of nosocomial infections. Bacteremia or bloodstream infection is a frequent and costly complication resulting from biofilm fouling of medical devices. Our goal was to develop a murine model of S. epidermidis infection to identify potential vaccine targets for the prevention of S. epidermidis bacteremia. However, assessing the contribution of adaptive immunity to protection against S. epidermidis challenge was complicated by a highly efficacious innate immune response in mice. Naive mice rapidly cleared S. epidermidis infections from blood and solid organs, even when the animals were immunocompromised. Cyclophosphamide-mediated leukopenia reduced the size of the bacterial challenge dose required to cause lethality but did not impair clearance after a nonlethal challenge. Nonspecific innate immune stimulation, such as treatment with a Toll-like receptor 4 (TLR4) agonist, enhanced bacterial clearance. TLR2 signaling was confirmed to accelerate the clearance of S. epidermidis bacteremia, but TLR2(-/-)mice could still resolve a bloodstream infection. Furthermore, TLR2 signaling played no role in the clearance of bacteria from the spleen. In conclusion, these data suggest that S. epidermidis bloodstream infection is cleared in a highly efficient manner that is mediated by both TLR2-dependent and -independent innate immune mechanisms. The inability to establish a persistent infection in mice, even in immunocompromised animals, rendered these murine models unsuitable for meaningful assessment of antibody-mediated therapies or vaccine candidates.

  16. Jet Transport Rejected Takeoffs.

    DTIC Science & Technology

    1977-02-01

    r _ _ _ _ _ _ N AD—A05 6 032 FEDERAL AVIATIO N ADMINISTRATION WASHINGTON 0 C FLIGHT—ETC FIG 1/2 ~,JET TRANSPORT REJECTED TAKEOFFS • (U)FED 77 0 S...AF~~16O-77-2 FOR FURTHER IRAN JET TRANSPORT R&JECTED TAKEDFFS DAVID W. OSTROWSKILI~~ H c ,~ ~~~~ C ...) ~~~~ O~ —1 w DDU FEB~JARY 1977U... FINAL...Pag. .po ,t No. 2 C.o.,,nm.rr, A c c . s s on No . 3. R.c ,pr. ns s Cat alog No. AFS-16~~-77-2_ j

  17. Antibody-mediated radiotherapy

    SciTech Connect

    Bloomer, W.D.; Lipsztein, R.; Dalton, J.F.

    1985-05-01

    Antibodies that react with antigens on the surface of tumor cells but not normal cells have great potential for cancer detection and therapy. If radiolabeled without loss of immunologic specificity, such antibodies may be able to deliver cytoxic amounts of radiation. Target- cell specificity and a high extraction coefficient are necessary with any radionuclide in order to minimize normal tissue irradiation. Tumor- cell-retention time and the rate of catabolized radionuclide will also influence ultimate applicability. Among the unanswered questions for choosing a radionuclide is the choice of particle emitter. Although classic beta emitters have been used in a number of clinical situations, they have not had a major impact on disease outcome except in diseases of the thyroid. Unfortunately, Auger emitters such as iodine 125 are cytotoxic only when localized within close proximity to the genome. On the other hand, alpha emitters such as astatine 211 eliminate the need for subcellular sequestration but not cell-specific localization. 34 references.

  18. Emotional responses to interpersonal rejection

    PubMed Central

    Leary, Mark R.

    2015-01-01

    A great deal of human emotion arises in response to real, anticipated, remembered, or imagined rejection by other people. Because acceptance by other people improved evolutionary fitness, human beings developed biopsychological mechanisms to apprise them of threats to acceptance and belonging, along with emotional systems to deal with threats to acceptance. This article examines seven emotions that often arise when people perceive that their relational value to other people is low or in potential jeopardy, including hurt feelings, jealousy, loneliness, shame, guilt, social anxiety, and embarrassment. Other emotions, such as sadness and anger, may occur during rejection episodes, but are reactions to features of the situation other than low relational value. The article discusses the evolutionary functions of rejection-related emotions, neuroscience evidence regarding the brain regions that mediate reactions to rejection, and behavioral research from social, developmental, and clinical psychology regarding psychological and behavioral concomitants of interpersonal rejection. PMID:26869844

  19. Emotional responses to interpersonal rejection.

    PubMed

    Leary, Mark R

    2015-12-01

    A great deal of human emotion arises in response to real, anticipated, remembered, or imagined rejection by other people. Because acceptance by other people improved evolutionary fitness, human beings developed biopsychological mechanisms to apprise them of threats to acceptance and belonging, along with emotional systems to deal with threats to acceptance. This article examines seven emotions that often arise when people perceive that their relational value to other people is low or in potential jeopardy, including hurt feelings, jealousy, loneliness, shame, guilt, social anxiety, and embarrassment. Other emotions, such as sadness and anger, may occur during rejection episodes, but are reactions to features of the situation other than low relational value. The article discusses the evolutionary functions of rejection-related emotions, neuroscience evidence regarding the brain regions that mediate reactions to rejection, and behavioral research from social, developmental, and clinical psychology regarding psychological and behavioral concomitants of interpersonal rejection.

  20. Private Information and Insurance Rejections

    PubMed Central

    Hendren, Nathaniel

    2013-01-01

    Across a wide set of non-group insurance markets, applicants are rejected based on observable, often high-risk, characteristics. This paper argues that private information, held by the potential applicant pool, explains rejections. I formulate this argument by developing and testing a model in which agents may have private information about their risk. I first derive a new no-trade result that theoretically explains how private information could cause rejections. I then develop a new empirical methodology to test whether this no-trade condition can explain rejections. The methodology uses subjective probability elicitations as noisy measures of agents beliefs. I apply this approach to three non-group markets: long-term care, disability, and life insurance. Consistent with the predictions of the theory, in all three settings I find significant amounts of private information held by those who would be rejected; I find generally more private information for those who would be rejected relative to those who can purchase insurance; and I show it is enough private information to explain a complete absence of trade for those who would be rejected. The results suggest private information prevents the existence of large segments of these three major insurance markets. PMID:24187381

  1. Do Scientists Really Reject God?

    ERIC Educational Resources Information Center

    Scott, Eugenie C.

    1998-01-01

    Suggests that the title of the recent Larson and Witham article in the journal Nature, "Leading Scientists Still Reject God", is premature and without reliable data upon which to base it. (Author/CCM)

  2. Space vehicle thermal rejection system

    NASA Technical Reports Server (NTRS)

    Tanzer, Herbert J. (Inventor)

    1989-01-01

    A space vehicle thermal heat rejection system 10 utilizing separate optimized heat pipe components for the functions of heat acquisition, heat transport, and heat rejection. A honeycomb panel heat pipe evaporator section 20 performs the function of heat acquisition, and forms a closed thermodynamic system with a dual channel heat pipe transport section 30, which performs the function of heat transport. A plurality of truss or channel core heat pipe rejection fins 41 form the condenser section 40, which performs the function of heat rejection. A common wall 32 separates the condenser section 40 from the transport section 30. Using the above heat pipe components and having efficient interfacing between them results in high performance factors for the overall system.

  3. Membrane rejection of nitrogen compounds

    NASA Technical Reports Server (NTRS)

    Lee, S.; Lueptow, R. M.

    2001-01-01

    Rejection characteristics of nitrogen compounds were examined for reverse osmosis, nanofiltration, and low-pressure reverse osmosis membranes. The rejection of nitrogen compounds is explained by integrating experimental results with calculations using the extended Nernst-Planck model coupled with a steric hindrance model. The molecular weight and chemical structure of nitrogen compounds appear to be less important in determining rejection than electrostatic properties. The rejection is greatest when the Donnan potential exceeds 0.05 V or when the ratio of the solute radius to the pore radius is greater than 0.8. The transport of solute in the pore is dominated by diffusion, although convective transport is significant for organic nitrogen compounds. Electromigration contributes negligibly to the overall solute transport in the membrane. Urea, a small organic compound, has lower rejection than ionic compounds such as ammonium, nitrate, and nitrite, indicating the critical role of electrostatic interaction in rejection. This suggests that better treatment efficiency for organic nitrogen compounds can be obtained after ammonification of urea.

  4. Early diagnosis of acute postoperative renal transplant rejection

    SciTech Connect

    Tisdale, P.L.; Collier, B.D.; Kauffman, H.M.; Adams, M.B.; Isitman, A.T.; Hellman, R.S.; Rao, S.A.; Joestgen, T.; Krohn, L.

    1985-05-01

    A prospective evaluation of In-111 labeled autologous platelet scintigraphy for the early diagnosis of acute postoperative renal transplant rejection was undertaken. To date, 28 consecutive patients between 7 and 14 days post-op have been injected with 500..mu..Ci of In-111 platelets followed by imaging at 24 and 48 hours. Activity within the renal transplant exceeding activity in the adjacent iliac vessels was considered to be evidence of rejection, and both chemical evidence and clinical impression of rejection at 5 days after completion of imaging was accepted as proof of ongoing or incipient rejection at the time of scintigraphy. In addition, to visual inspection, independent quantitative analysis compared the area-normalized activity over the transplant with the adjacent iliac vessels (normal <1.0). For 5 patients, positive In-111 scintigraphy was present before convincing clinical evidence of rejection. In-111 platelet scintigraphy is useful not only to confirm the clinical diagnosis of rejection but also to establish the early, pre-clinical diagnosis of incipient acute postoperative renal transplant rejection.

  5. Antibody-mediated complement C3b/iC3b binding to group B Streptococcus in paired mother and baby serum samples in a refugee population on the Thailand-Myanmar border.

    PubMed

    Herbert, Jenny; Thomas, Stephen; Brookes, Charlotte; Turner, Claudia; Turner, Paul; Nosten, Francois; Le Doare, Kirsty; Hudson, Michael; Heath, Paul T; Gorringe, Andrew; Taylor, Stephen

    2015-03-01

    Streptococcus agalactiae (group B streptococcus [GBS]) is the leading cause of neonatal sepsis and meningitis. In this study, we determined antibody-mediated deposition of complement C3b/iC3b onto the bacterial cell surface of GBS serotypes Ia, Ib, II, III, and V. This was determined for 520 mother and umbilical cord serum sample pairs obtained at the time of birth from a population on the Thailand-Myanmar border. Antibody-mediated deposition of complement C3b/iC3b was detected to at least one serotype in 91% of mothers, despite a known carriage rate in this population of only 12%. Antibody-mediated C3b/iC3b deposition corresponded to known carriage rates, with the highest levels of complement deposition observed onto the most prevalent serotype (serotype II) followed by serotypes Ia, III, V, and Ib. Finally, neonates born to mothers carrying serotype II GBS at the time of birth showed higher antibody-mediated C3b/iC3b deposition against serotype II GBS than neonates born to mothers with no serotype II carriage. Assessment of antibody-mediated C3b/iC3b deposition against GBS may provide insights into the seroepidemiology of anti-GBS antibodies in mothers and infants in different populations.

  6. Antibody-Mediated Complement C3b/iC3b Binding to Group B Streptococcus in Paired Mother and Baby Serum Samples in a Refugee Population on the Thailand-Myanmar Border

    PubMed Central

    Herbert, Jenny; Thomas, Stephen; Brookes, Charlotte; Turner, Claudia; Turner, Paul; Nosten, Francois; Le Doare, Kirsty; Hudson, Michael; Heath, Paul T.; Gorringe, Andrew

    2015-01-01

    Streptococcus agalactiae (group B streptococcus [GBS]) is the leading cause of neonatal sepsis and meningitis. In this study, we determined antibody-mediated deposition of complement C3b/iC3b onto the bacterial cell surface of GBS serotypes Ia, Ib, II, III, and V. This was determined for 520 mother and umbilical cord serum sample pairs obtained at the time of birth from a population on the Thailand-Myanmar border. Antibody-mediated deposition of complement C3b/iC3b was detected to at least one serotype in 91% of mothers, despite a known carriage rate in this population of only 12%. Antibody-mediated C3b/iC3b deposition corresponded to known carriage rates, with the highest levels of complement deposition observed onto the most prevalent serotype (serotype II) followed by serotypes Ia, III, V, and Ib. Finally, neonates born to mothers carrying serotype II GBS at the time of birth showed higher antibody-mediated C3b/iC3b deposition against serotype II GBS than neonates born to mothers with no serotype II carriage. Assessment of antibody-mediated C3b/iC3b deposition against GBS may provide insights into the seroepidemiology of anti-GBS antibodies in mothers and infants in different populations. PMID:25589553

  7. Lunar Dust on Heat Rejection System Surfaces: Problems and Prospects

    NASA Technical Reports Server (NTRS)

    Gaier, James R.; Jaworske, Donald A.

    2007-01-01

    Heat rejection from power systems will be necessary for human and robotic activity on the lunar surface. Functional operation of such heat rejection systems is at risk of degradation as a consequence of dust accumulation. The Apollo astronauts encountered marked degradation of performance in heat rejection systems for the lunar roving vehicle, science packages, and other components. Although ground testing of dust mitigation concepts in support of the Apollo mission identified mitigation tools, the brush concept adopted by the Apollo astronauts proved essentially ineffective. A better understanding of the issues associated with the impact of lunar dust on the functional performance of heat rejection systems and its removal is needed as planning gets underway for human and robotic missions to the Moon. Renewed emphasis must also be placed on ground testing of pristine and dust-covered heat rejection system surfaces to quantify degradation and address mitigation concepts. This paper presents a review of the degradation in performance of heat rejection systems encountered on the lunar surface to-date, and will discuss current activities underway to evaluate the durability of candidate heat rejection system surfaces and current dust mitigation concepts.

  8. Detection of cardiac transplant rejection with radiolabeled lymphocytes. [Rats

    SciTech Connect

    Bergmann, S.R.; Lerch, R.A.; Carlson, E.M.; Saffitz, J.E.; Sobel, B.E.

    1982-03-01

    To determine whether rejections of cardiac transplants could be detected specifically and non-invasively by lymphocytes labeled with indium-111 (111In), we studied 36 allogeneic and 14 isogeneic heterotopic cardiac transplants in rats. Allogeneic grafts accumulated autologous 111In-lymphocytes, detectable scintigraphically 24 hours after i.v. injection of the labeled cells. At the time of peak histologic rejection, the allogeneic grafts accumulated 92. +/- 4.8 times more activity than the native hearts (determined by well counting). The tissue-to-blood ratio in the rejecting transplants was 3.7 +/- 2.2; total uptake by the graft was 2.9 +/- 2.1% of the injected dose. Autoradiography confirmed that graft radioactivity was associated with labeled lymphocytes. In contrast, isogeneic grafts showed no signs of rejection and did not accumulate radioactivity. Because conventionally isolated and labeled lymphocytes are often contaminated with platelets, we prepared both 111In-platelets and purified 111In-lymphocytes for use in additional experiments. Allogeneic grafts accumulated platelets and purified lymphocytes independently. Thus, deposition of immunologically active cells in the rejecting graft representing specific pathophysiologic events can be detected. The results suggest that rejection of cardiac transplants can be detected noninvasively, potentially facilitating objective early clinical detection of rejection and titration of antirejection therapy.

  9. Separate neural representations for physical pain and social rejection

    PubMed Central

    Woo, Choong-Wan; Koban, Leonie; Kross, Ethan; Lindquist, Martin A.; Banich, Marie T.; Ruzic, Luka; Andrews-Hanna, Jessica R.; Wager, Tor D.

    2014-01-01

    Current theories suggest that physical pain and social rejection share common neural mechanisms, largely by virtue of overlapping functional magnetic resonance imaging (fMRI) activity. Here we challenge this notion by identifying distinct multivariate fMRI patterns unique to pain and rejection. Sixty participants experience painful heat and warmth and view photos of ex-partners and friends on separate trials. FMRI pattern classifiers discriminate pain and rejection from their respective control conditions in out-of-sample individuals with 92% and 80% accuracy. The rejection classifier performs at chance on pain, and vice versa. Pain-and rejection-related representations are uncorrelated within regions thought to encode pain affect (for example, dorsal anterior cingulate) and show distinct functional connectivity with other regions in a separate resting-state data set (N = 91). These findings demonstrate that separate representations underlie pain and rejection despite common fMRI activity at the gross anatomical level. Rather than co-opting pain circuitry, rejection involves distinct affective representations in humans. PMID:25400102

  10. Separate neural representations for physical pain and social rejection.

    PubMed

    Woo, Choong-Wan; Koban, Leonie; Kross, Ethan; Lindquist, Martin A; Banich, Marie T; Ruzic, Luka; Andrews-Hanna, Jessica R; Wager, Tor D

    2014-11-17

    Current theories suggest that physical pain and social rejection share common neural mechanisms, largely by virtue of overlapping functional magnetic resonance imaging (fMRI) activity. Here we challenge this notion by identifying distinct multivariate fMRI patterns unique to pain and rejection. Sixty participants experience painful heat and warmth and view photos of ex-partners and friends on separate trials. FMRI pattern classifiers discriminate pain and rejection from their respective control conditions in out-of-sample individuals with 92% and 80% accuracy. The rejection classifier performs at chance on pain, and vice versa. Pain- and rejection-related representations are uncorrelated within regions thought to encode pain affect (for example, dorsal anterior cingulate) and show distinct functional connectivity with other regions in a separate resting-state data set (N = 91). These findings demonstrate that separate representations underlie pain and rejection despite common fMRI activity at the gross anatomical level. Rather than co-opting pain circuitry, rejection involves distinct affective representations in humans.

  11. Hypervigilance to Rejecting Stimuli in Rejection Sensitive Individuals: Behavioral and Neurocognitive Evidence.

    PubMed

    Ehrlich, Katherine B; Gerson, Sarah A; Vanderwert, Ross E; Cannon, Erin N; Fox, Nathan A

    2015-10-01

    Individuals who are high in rejection sensitivity are vigilant toward social cues that signal rejection, and they exhibit attention biases towards information that confirms expectations of rejection. Little is known, however, about the neural correlates of rejection sensitivity. The present study examined whether rejection sensitivity is associated with individuals' neural responses to rejection-relevant information. Female participants, classified as high or average in rejection sensitivity, completed a modified dot-probe task in which a neutral face was paired with either another neutral face or a gaze-averted ("rejecting") face while EEG was collected and ERP components were computed. Behavioral results indicated that average rejection sensitive participants showed an attention bias away from rejecting faces, while high rejection sensitive participants were equally vigilant to neutral and rejecting faces. High rejection sensitivity was associated with ERP components signaling elevated attention and arousal to faces. These findings suggest that rejection sensitivity shapes behavioral and neurocognitive responses to faces.

  12. IgE and IgGa antibody-mediated release of histamine from rat peritoneal cells. II. Interaction of IgGa and IgE at the targe cell.

    PubMed

    Bach, M K; Block, K J; Austen, K F

    1971-04-01

    IgGa, in contrast to IgE, antibodies mediated the antigen-induced release of histamine from rat peritoneal mast cells without a requirement for a latent period and without the capacity to bind firmly to the target cell. Nonetheless, IgGa anti-DNP antibody interfered with the capacity of rat anti-N. brasiliensis antiserum rich in IgE antibodies to prepare the target cells for histamine release by worm antigen. Further, interaction of IgE antibody-prepared cells with IgGa anti-DNP antibody and DNP-BSA at 0 degrees C so as to achieve sterile activation, or at 30 degrees C to permit histamine release, inactivated such cells as determined by the subsequent failure to release histamine upon challenge with worm antigen. Thus, although IgE and IgGa antibodies are immunochemically distinct homologous immunoglobulins and exhibit different functional characteristics, their interaction at the target cell involves a common receptor and at least one common point in the pathway to the release of pharmacologic agents from the cell.

  13. Allorecognition by T Lymphocytes and Allograft Rejection

    PubMed Central

    Marino, Jose; Paster, Joshua; Benichou, Gilles

    2016-01-01

    Recognition of donor antigens by recipient T cells in secondary lymphoid organs initiates the adaptive inflammatory immune response leading to the rejection of allogeneic transplants. Allospecific T cells become activated through interaction of their T cell receptors with intact allogeneic major histocompatibility complex (MHC) molecules on donor cells (direct pathway) and/or donor peptides presented by self-MHC molecules on recipient antigen-presenting cells (APCs) (indirect pathway). In addition, recent studies show that alloreactive T cells can also be stimulated through recognition of allogeneic MHC molecules displayed on recipient APCs (MHC cross-dressing) after their transfer via cell–cell contact or through extracellular vesicles (semi-direct pathway). The specific allorecognition pathway used by T cells is dictated by intrinsic and extrinsic factors to the allograft and can influence the nature and magnitude of the alloresponse and rejection process. Consequently, various organs and tissues such as skin, cornea, and solid organ transplants are recognized differently by pro-inflammatory T cells through these distinct pathways, which may explain why these grafts are rejected in a different fashion. On the other hand, the mechanisms by which anti-inflammatory regulatory T cells (Tregs) recognize alloantigen and promote transplantation tolerance are still unclear. It is likely that thymic Tregs are activated through indirect allorecognition, while peripheral Tregs recognize alloantigens in a direct fashion. As we gain insights into the mechanisms underlying allorecognition by pro-inflammatory and Treg cells, novel strategies are being designed to prevent allograft rejection in the absence of ongoing immunosuppressive drug treatment in patients. PMID:28018349

  14. Antagonism of antiviral and allogeneic activity of a human public CTL clonotype by a single altered peptide ligand: implications for allograft rejection

    SciTech Connect

    Ely, Lauren K.; Green, Katherine J.; Beddoe, Travis; Clements, Craig S.; Miles, John J.; Bottomley, Stephen P.; Zernich, Danielle; Kjer-Nielsen, Lars; Purcell, Anthony W.; McCluskey, James; Rossjohn, Jamie; Burrows, Scott R.

    2010-06-30

    Alloreactive T lymphocytes are central mediators of graft-versus-host disease and allograft rejection. A public CTL clonotype with specificity for the alloantigens HLA-B*4402 and B*4405 is often expanded to large numbers in healthy HLA-B*0801{sup +} individuals, driven by cross-reactive stimulation with the common, persistent herpesvirus EBV. Since such alloreactive memory CTL expansions have the potential to influence transplantation outcome, altered peptide ligands (APLs) of the target HLA-B*0801-binding EBV peptide, FLRGRAYGL, were screened as specific antagonists for this immunodominant clonotype. One APL, FLRGRFYGL, exerted powerful antagonism of a prototypic T cell clone expressing this immunodominant TCR when costimulated with target cells presenting HLA-B*0801{sup FLRGRAYGL}. Significantly, this APL also reduced the lysis of allogeneic target cells expressing HLA-B*4402 by up to 99%. The affinities of the agonist and antagonist complexes for the public TCR, measured using solution and solid-phase assays, were 8 and 138 {micro}M, respectively. Surprisingly, the half-life of the agonist and antagonist complexes was similar, yet the association rate for the antagonist complex was significantly slower. These observations were further supported by structural studies that suggested a large conformational hurdle was required to ligate the immunodominant TCR to the HLA-B*0801 antagonist complex. By defining an antagonist APL against an immunodominant alloreactive TCR, these findings raise the prospect of exploiting such peptides to inhibit clinical alloreactivity, particularly against clonal T cell expansions that react with alloantigens.

  15. Characteristics of recursive backstepping algorithm and active damping of oscillations in feedback linearization for electromechanical system with extended stability analysis and perturbation rejection.

    PubMed

    Anand, V; Narendran, R

    2016-09-01

    In this paper, a technique for estimation of state variables and control of a class of electromechanical system is proposed. Initially, an attempt is made on rudimentary pole placement technique for the control of rotor position and angular velocity profiles of Permanent Magnet Stepper Motor. Later, an alternative approach is analyzed using feedback linearization method to reduce the error in tracking performances. A damping control scheme was additionally incorporated into the feedback linearization system in order to nullify the persistent oscillations present in the system. Furthermore, a robust backstepping controller with high efficacy is put forth to enhance the overall performance and to carry out disturbance rejection. The predominant advantage of this control technique is that it does not require the DQ Transformation of the motor dynamics. A Lyapunov candidate was employed to ensure global asymptotical stability criterion. Also, a nonlinear observer is presented to estimate the unknown states namely load torque and rotor angular velocity, even under load uncertainty conditions. Finally, the performances of all the aforementioned control schemes and estimation techniques are compared and analyzed extensively through simulation.

  16. Hypervigilance to Rejecting Stimuli in Rejection Sensitive Individuals: Behavioral and Neurocognitive Evidence

    PubMed Central

    Ehrlich, Katherine B.; Gerson, Sarah A.; Vanderwert, Ross E.; Cannon, Erin N.; Fox, Nathan A.

    2015-01-01

    Individuals who are high in rejection sensitivity are vigilant toward social cues that signal rejection, and they exhibit attention biases towards information that confirms expectations of rejection. Little is known, however, about the neural correlates of rejection sensitivity. The present study examined whether rejection sensitivity is associated with individuals’ neural responses to rejection-relevant information. Female participants, classified as high or average in rejection sensitivity, completed a modified dot-probe task in which a neutral face was paired with either another neutral face or a gaze-averted (“rejecting”) face while EEG was collected and ERP components were computed. Behavioral results indicated that average rejection sensitive participants showed an attention bias away from rejecting faces, while high rejection sensitive participants were equally vigilant to neutral and rejecting faces. High rejection sensitivity was associated with ERP components signaling elevated attention and arousal to faces. These findings suggest that rejection sensitivity shapes behavioral and neurocognitive responses to faces. PMID:26213434

  17. Late acute humoral rejection in low-risk renal transplant recipients induced with an interleukin-2 receptor antagonist and maintained with standard therapy: preliminary communication.

    PubMed

    Morales, J; Contreras, L; Zehnder, C; Pinto, V; Elberg, M; Araneda, S; Herzog, C; Calabran, L; Aguiló, J; Ferrario, M; Buckel, E; Fierro, J A

    2011-01-01

    Low-risk renal transplant recipients treated with standard immunosuppressive therapy including interleukin-2 receptor (IL-2R) antagonist show a low incidence of early rejection episodes but few reports have examined the incidence and severity of late rejection processes. This study evaluated retrospectively cellular and antibody-mediated rejection (AMR) among 42 recipients selected because they showed low panel-reactive-antibodies, short cold ischemia time, no delayed graft function, and therapy including basiliximab (Simulect) induction. The mean observation time was 6.6 years. Sixty-seven percent of donors were deceased. Ten-year patient and death-censored graft survivals were 81% and 78%, respectively. Seven patients lost their kidneys due to nonimmunologic events. The seven recipients who experienced cellular rejection episodes during the first posttransplant year had them reversed with steroids. Five patients displayed late acute AMR causing functional deterioration in four cases including 1 graft loss. De novo sensitization occurred in 48% of recipients including patients without clinical rejection. In conclusion, long-term follow-up of kidney transplant recipients selected by a low immunologic risk showed a persistent risk of de novo sensitization evolving to acute AMR in 11% of cases. Although immunologic events were related to late immunosuppressive reduction, most graft losses were due to nonimmunologic factors.

  18. Control of Immune Response to Allogeneic Embryonic Stem Cells by CD3 Antibody-Mediated Operational Tolerance Induction.

    PubMed

    Calderon, D; Prot, M; You, S; Marquet, C; Bellamy, V; Bruneval, P; Valette, F; de Almeida, P; Wu, J C; Pucéat, M; Menasché, P; Chatenoud, L

    2016-02-01

    Implantation of embryonic stem cells (ESCs) and their differentiated derivatives into allogeneic hosts triggers an immune response that represents a hurdle to clinical application. We established in autoimmunity and in transplantation that CD3 antibody therapy induces a state of immune tolerance. Promising results have been obtained with CD3 antibodies in the clinic. In this study, we tested whether this strategy can prolong the survival of undifferentiated ESCs and their differentiated derivatives in histoincompatible hosts. Recipients of either mouse ESC-derived embryoid bodies (EBs) or cardiac progenitors received a single short tolerogenic regimen of CD3 antibody. In immunocompetent mice, allogeneic EBs and cardiac progenitors were rejected within 20-25 days. Recipients treated with CD3 antibody showed long-term survival of implanted cardiac progenitors or EBs. In due course, EBs became teratomas, the growth of which was self-limited. Regulatory CD4(+)FoxP3(+) T cells and signaling through the PD1/PDL1 pathway played key roles in the CD3 antibody therapeutic effect. Gene profiling emphasized the importance of TGF-β and the inhibitory T cell coreceptor Tim3 to the observed effect. These results demonstrate that CD3 antibody administered alone promotes prolonged survival of allogeneic ESC derivatives and thus could prove useful for enhancing cell engraftment in the absence of chronic immunosuppression.

  19. Augmented orbiter heat rejection study

    NASA Technical Reports Server (NTRS)

    Hixon, C. W.

    1981-01-01

    Spacecraft radiator concepts are presented that relieve attitude restrictions required by the shuttle orbiter space radiator for baseline and extended capability STS missions. Cost effective heat rejection kits are considered which add additional capability in the form of attached spacelab radiators or a deployable radiator module.

  20. Response to abdominal hysterectomy with bilateral salpingo-oophorectomy in postmenopausal woman with anti-yo antibody mediated paraneoplastic cerebellar degeneration.

    PubMed

    Bhargava, Amita; Bhushan, Bharat; Kasundra, Gaurav M; Shubhakaran, Khichar; Pujar, Guruprasad S; Banakar, Basavaraj

    2014-07-01

    Paraneoplastic cerebellar degeneration (PCD) is a rare neurological disorder characterized by a widespread loss of Purkinje cells associated with a progressive pancerebellar dysfunction. PCD often precedes the cancer diagnosis by months to years. Here, we report a case of 44-year old postmenopausal woman who presented with PCD symptoms and high levels of anti-Yo antibodies titer since 8 months. We failed to conclude any neoplastic focus after thorough laboratory and imaging study. She minimally responded to methylprednisolone and immunoglobulin therapies. Despite therapy she was severely disabled. Planned abdominal hysterectomy with bilateral salpingo-oophorectomy (AHBSO) was done, histology revealed grade IIA borderline serous papillary carcinoma of ovary. Her neurological deficit responded dramatically to AHBSO. It is first case report who emphasize the response of AHBSO with presentation of anti-Yo antibody-mediated PCD and hidden nidus in post menopausal women.

  1. Anti-Fas/APO-1 antibody-mediated apoptosis of cultured human glioma cells. Induction and modulation of sensitivity by cytokines.

    PubMed Central

    Weller, M; Frei, K; Groscurth, P; Krammer, P H; Yonekawa, Y; Fontana, A

    1994-01-01

    Fas/APO-1 is a transmembrane protein of the nerve growth factor/TNF alpha receptor family which signals apoptotic cell death in susceptible target cells. We have investigated the susceptibility of seven human malignant glioma cell lines to Fas/APO-1-dependent apoptosis. Sensitivity to Fas/APO-1 antibody-mediated cell killing correlated with cell surface expression of Fas/APO-1. Expression of Fas/APO-1 as well as Fas/APO-1-dependent cytotoxicity were augmented by preexposure of human malignant glioma cells to IFN gamma and TNF alpha. Further, pretreatment with TGF beta 2, IL1 and IL8 enhanced Fas/APO-1 antibody-induced glioma cell apoptosis whereas other cytokines including TNF beta, IL6, macrophage colony-stimulating factor, IL10 and IL13 had no such effect. None of the human malignant glioma cell lines was susceptible to TNF alpha-induced cytotoxicity. Fas/APO-1 antibody-sensitive glioma cell lines (n = 5), but not Fas/APO-1 antibody-resistant glioma cell lines (n = 2), became sensitive to TNF alpha when co-treated with inhibitors of RNA and protein synthesis. Resistance of human glioma cells to Fas/APO-1 antibody-mediated apoptosis was mainly related to low level expression of Fas/APO-1 and appeared not to be linked to overexpression of the anti-apoptotic protooncogene, bcl-2. Given the resistance of human malignant glioma to surgery, irradiation, chemotherapy and immunotherapy, we propose that Fas/APO-1 may be a promising target for a novel locoregionary approach to human malignant glioma. This strategy gains support from the demonstration of Fas/APO-1 expression in ex vivo human malignant glioma specimens and from the absence of Fas/APO-1 in normal human brain parenchyma. Images PMID:7521890

  2. Does chronic classroom peer rejection predict the development of children's classroom participation during the grade school years?

    PubMed

    Ladd, Gary W; Herald-Brown, Sarah L; Reiser, Mark

    2008-01-01

    A sample of 398 children was followed up from ages 5 to 12 to investigate the relation between peer group rejection and classroom participation. The participation trajectories of individuals and groups of children who were rejected for differing periods of time were examined both during and after rejection using piecewise growth curve analyses. The results showed that whereas during periods of rejection, children exhibited negative or negligible growth in participation, when nonrejected, they manifested positive growth. These findings corroborated the hypothesis that (a) peer rejection creates constraints that inhibit children's classroom participation and (b) the cessation of rejection enables children to become more active and cooperative participants in classroom activities.

  3. Two distinct pathways of immuno-modulation improve potency of p53 immunization in rejecting established tumors.

    PubMed

    Daftarian, Pirouz; Song, Guang-Yun; Ali, Saima; Faynsod, Moshe; Longmate, Jeff; Diamond, Don J; Ellenhorn, Joshua D I

    2004-08-01

    The p53 gene product is overexpressed by almost 50% of cancers, making it an ideal target for cancer immunotherapy. We previously demonstrated rejection of established p53-overexpressing tumors without stimulating autoimmunity by immunization with modified vaccinia Ankara-expressing murine p53 (MVAp53). Tumor rejection was enhanced through antibody-mediated CTL-associated antigen 4 (CTLA-4) blockade. We examined the role of synthetic oligodeoxynucleotides (ODN) containing unmethylated cytosine-phosphate-guanine (CpG) motifs (CpG ODN) in enhancing MVAp53-mediated tumor rejection. CpG ODN with MVAp53 resulted in tumor rejection in BALB/c mice bearing poorly immunogenic 11A-1 murine mammary carcinomas or Meth A sarcomas and C57Bl/6 mice bearing MC-38 colon carcinomas. The effect was similar to that seen in tumor-bearing mice treated with MVAp53 along with CTLA-4 blockade. Monoclonal antibody depletion experiments demonstrated that the adjuvant effects of CpG ODN and CTLA-4 blockades were CD8 dependent. CpG ODN were partially natural killer cell dependent and ineffective in Toll-like Receptor 9(-/-) and interleukin 6(-/-) mice, whereas CTLA-4 blockade was partially CD4 dependent and functional in Toll-like Receptor 9(-/-) and interleukin 6(-/-) mice. In addition, when administered with MVAp53, both adjuvants enhanced p53-specific cytotoxicity and demonstrated an additive effect when combined. The combination of CpG ODN and CTLA-4 blockade worked synergistically to reject palpable 11A-1 and MC-38 tumors. These experiments demonstrate the potential for augmenting MVAp53-mediated antitumor immunity using CpG ODN and CTLA-4 blockade. This cell-free immunotherapy approach is a candidate for evaluation in cancer patients.

  4. GPS antenna multipath rejection performance

    NASA Astrophysics Data System (ADS)

    Dinius, A. M.

    1995-08-01

    A GPS antenna multipath rejection performance evaluation was conducted. Ground reference station antennas and aviation patches were tested for their ability to reject a multipath signal. Different types of ground plane structures were used such as choke rings, ground planes, and mock sections of fuselage. Frequencies transmitted were L1 (1575 MHz), L2 (1227 MHz), and the median GLONASS frequency (1609 MHz). Receive amplitude and phase were measured on each antenna. Subsequently, these data were converted to absolute gain for a right hand and left hand circularly polarized signal as a function of satellite elevation angle. Two types of multipath signals were considered: ground bounce multipath and building or structure bounce multipath. Ground bounce multipath typically occurs at low satellite elevation angles while structure bounce multipath can occur at any satellite elevation angle. Separate analysis methods were used to assess an antenna's ability to reject either type of multipath. This report describes the data collection methods, data reduction and analysis, and the results.

  5. 7 CFR 58.136 - Rejected milk.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 3 2013-01-01 2013-01-01 false Rejected milk. 58.136 Section 58.136 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Standards... Milk § 58.136 Rejected milk. A plant shall reject specific milk from a producer if the milk fails...

  6. 7 CFR 58.136 - Rejected milk.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 3 2014-01-01 2014-01-01 false Rejected milk. 58.136 Section 58.136 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Standards... Milk § 58.136 Rejected milk. A plant shall reject specific milk from a producer if the milk fails...

  7. 7 CFR 58.136 - Rejected milk.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 3 2012-01-01 2012-01-01 false Rejected milk. 58.136 Section 58.136 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Standards... Milk § 58.136 Rejected milk. A plant shall reject specific milk from a producer if the milk fails...

  8. Peer Group Rejection and Children's Outgroup Prejudice

    ERIC Educational Resources Information Center

    Nesdale, Drew; Durkin, Kevin; Maass, Anne; Kiesner, Jeff; Griffiths, Judith; Daly, Josh; McKenzie, David

    2010-01-01

    Two simulation studies examined the effect of peer group rejection on 7 and 9 year old children's outgroup prejudice. In Study 1, children (n = 88) pretended that they were accepted or rejected by their assigned group, prior to competing with a lower status outgroup. Results indicated that rejected versus accepted children showed increased…

  9. 7 CFR 58.136 - Rejected milk.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 3 2010-01-01 2010-01-01 false Rejected milk. 58.136 Section 58.136 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Standards... Milk § 58.136 Rejected milk. A plant shall reject specific milk from a producer if the milk fails...

  10. 7 CFR 58.136 - Rejected milk.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 3 2011-01-01 2011-01-01 false Rejected milk. 58.136 Section 58.136 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Standards... Milk § 58.136 Rejected milk. A plant shall reject specific milk from a producer if the milk fails...

  11. Study of Background Rejection Systems for the IXO Mission.

    NASA Astrophysics Data System (ADS)

    Laurent, Philippe; Limousin, O.; Tatischeff, V.

    2009-01-01

    The scientific performances of the IXO mission will necessitate a very low detector background level. This will imply thorough background simulations, and efficient background rejection systems. It necessitates also a very good knowledge of the detectors to be shielded. In APC, Paris, and CEA, Saclay, we got experience on these activities by conceiving and optimising in parallel the high energy detector and the active and passive background rejection system of the Simbol-X mission. Considering that this work may be naturally extended to other X-ray missions, we have initiated with CNES a R&D project on the study of background rejection systems mainly in view the IXO project. We will detail this activity in the poster.

  12. Bortezomib for antibody mediated rejection treatment: experience at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in Mexico City.

    PubMed

    Leyva, Sergio; Marino-Vázquez, Lluvia A; Reyes-Loaeza, Jorge A; Vega, Olynka; Uribe-Uribe, Norma; Alberú, Josefina; Morales-Buenrostro, Luis E

    2009-01-01

    The use of bortezomib as a treatment modality of AHR improved and stabilized graft function (clinical response) in the majority of patients. Its use in single dose, even combined with rituximab, does not seem to be useful to obtain a sustained clinical response neither to reduce HLAabs level. The use of 4 doses of bortezomib in days 1, 4, 7, and 10 (1.3 mg/m2 BSA each) plus plasmapheresis produced both a good clinical response and a reduction in DSA. Moving forward, it will necessary to define the long-term effectiveness of bortezomib and whether rituximab administration is indispensable to achieve this goal.

  13. Collagen Sponge Functionalized with Chimeric Anti-BMP-2 Monoclonal Antibody Mediates Repair of Critical-Size Mandibular Continuity Defects in a Nonhuman Primate Model

    PubMed Central

    Xie, Yilin; Su, Yingying; Tang, Jianxia; Goh, Bee Tin; Saigo, Leonardo; Zhang, Chunmei; Wang, Jinsong; Khojasteh, Arash; Wang, Songlin

    2017-01-01

    Antibody-mediated osseous regeneration (AMOR) has been introduced by our research group as a tissue engineering approach to capture of endogenous growth factors through the application of specific monoclonal antibodies (mAbs) immobilized on a scaffold. Specifically, anti-Bone Morphogenetic Protein- (BMP-) 2 mAbs have been demonstrated to be efficacious in mediating bone repair in a number of bone defects. The present study sought to investigate the application of AMOR for repair of mandibular continuity defect in nonhuman primates. Critical-sized mandibular continuity defects were created in Macaca fascicularis locally implanted with absorbable collagen sponges (ACS) functionalized with chimeric anti-BMP-2 mAb or isotype control mAb. 2D and 3D analysis of cone beam computed tomography (CBCT) imaging demonstrated increased bone density and volume observed within mandibular continuity defects implanted with collagen scaffolds functionalized with anti-BMP-2 mAb, compared with isotype-matched control mAb. Both CBCT imaging and histologic examination demonstrated de novo bone formation that was in direct apposition to the margins of the resected bone. It is hypothesized that bone injury may be necessary for AMOR. This is evidenced by de novo bone formation adjacent to resected bone margins, which may be the source of endogenous BMPs captured by anti-BMP-2 mAb, in turn mediating bone repair.

  14. Development of PET Imaging to Visualize Activated Macrophages Accumulated in the Transplanted iPSc-Derived Cardiac Myocytes of Allogeneic Origin for Detecting the Immune Rejection of Allogeneic Cell Transplants in Mice

    PubMed Central

    Kashiyama, Noriyuki; Miyagawa, Shigeru; Fukushima, Satsuki; Kawamura, Takuji; Kawamura, Ai; Yoshida, Shohei; Harada, Akima; Watabe, Tadashi; Kanai, Yasukazu; Toda, Koichi; Hatazawa, Jun; Sawa, Yoshiki

    2016-01-01

    Allogeneic transplantation (Tx) of induced pluripotent stem cells (iPSCs) is a promising tissue regeneration therapy. However, this inevitably induces macrophage-mediated immune response against the graft, limiting its therapeutic efficacy. Monitoring the magnitude of the immune response using imaging tools would be useful for prolonging graft survival and increasing the therapy longevity. Minimally invasive quantitative detection of activated macrophages by medical imaging technologies such as positron emission tomography (PET) imaging targets translocator protein (TSPO), which is highly expressed on mitochondrial membrane, especially in activated macrophage. N,N-diethyl-2-[4-(2-fluoroethoxy) phenyl]-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide (DPA-714) is known as a TSPO ligand used in clinical settings. We herein hypothesized that immune rejection of the transplanted iPSC-derived cardiomyocytes (iPSC-CMs) of allogeneic origin may be quantitated using 18F-DPA-714-PET imaging study. iPSC-CM cell-sheets of C57BL/6 mice origin were transplanted on the surface of the left ventricle (LV) of C57BL/6 mice as a syngeneic cell-transplant model (syngeneic Tx group), or Balb/c mice as an allogeneic model (allogeneic Tx group). 18F-DPA-714-PET was used to determine the uptake ratio, calculated as the maximum standardized uptake value in the anterior and septal wall of the LV. The uptake ratio was significantly higher in the allogeneic Tx group than in the syngeneic group or the sham group at days 7 and day 10 after the cell transplantation. In addition, the immunochemistry showed significant presence of CD68 and CD3-positive cells at day 7 and 10 in the transplanted graft of the allogeneic Tx group. The expression of TSPO, CD68, IL-1 beta, and MCP-1 was significantly higher in the allogeneic Tx group than in the syngeneic Tx and the sham groups at day 7. The 18F-DPA-714-PET imaging study enabled quantitative visualization of the macrophages-mediated immune rejection of

  15. Fate of articles rejected by Indian Pediatrics.

    PubMed

    Dewan, Pooja; Gupta, Piyush; Shah, Dheeraj

    2010-12-01

    The present study was conducted to determine the fate of manuscripts rejected by Indian Pediatrics (IP), and to identify the factors facilitating publication of a rejected manuscript elsewhere. Database (PubMed, IndMed) and Google searches were performed to trace the manuscripts published elsewhere any time after rejection by Indian Pediatrics in the year 2002. Eighteen per cent of the rejected submissions (62 out of 347) were eventually (till July 2009) published elsewhere. These manuscripts subsequently appeared in 33 different journals; Indian Journal of Pediatrics published the maximum numbers (n=22). Seventy four per cent of the rejected papers were published in journals with a impact factor lesser than Indian Pediatrics. Rejection before initiating peer-review, and rejection on the grounds of over-interpretation of results or poor statistical analysis diminished the chances of subsequent publication, whereas manuscripts rejected on grounds of poor originality or poor language had greater chances of being published elsewhere. Rejection of a manuscript by IP does not preclude publication, but rejected manuscripts are published more often in non-pediatric journals or journals with a lower impact factor, although the occasional exception exists.

  16. B Lymphocytes Differentially Influence Acute and Chronic Allograft Rejection in Mice1

    PubMed Central

    DiLillo, David J.; Griffiths, Robert; Seshan, Surya V.; Magro, Cynthia M.; Ruiz, Phillip; Coffman, Thomas M.; Tedder, Thomas F.

    2013-01-01

    The relative contributions of B lymphocytes and plasma cells during allograft rejection remain unclear. Therefore, the effects of B cell depletion on acute cardiac rejection, chronic renal rejection, and skin graft rejection were compared using CD20 or CD19 mAbs. Both CD20 and CD19 mAbs effectively depleted mature B cells, while CD19 mAb treatment depleted plasmablasts and some plasma cells. B cell depletion did not affect acute cardiac allograft rejection, although CD19 mAb treatment prevented allograft-specific IgG production. Strikingly, CD19 mAb treatment significantly reduced renal allograft rejection and abrogated allograft-specific IgG development, while CD20 mAb treatment did not. By contrast, B cell depletion exacerbated skin allograft rejection and augmented the proliferation of adoptively transferred alloantigen-specific CD4+ T cells, demonstrating that B cells can also negatively regulate allograft rejection. Thereby, B cells can either positively or negatively regulate allograft rejection depending on the nature of the allograft and the intensity of the rejection response. Moreover, CD19 mAb may represent a new approach for depleting both B cells and plasma cells to concomitantly impair T cell activation, inhibit the generation of new allograft-specific Abs, or reduce preexisting allograft-specific Ab levels in transplant patients. PMID:21248259

  17. Annexin A2 is involved in antiphospholipid antibody-mediated pathogenic effects in vitro and in vivo.

    PubMed

    Romay-Penabad, Zurina; Montiel-Manzano, Maria Guadalupe; Shilagard, Tuya; Papalardo, Elizabeth; Vargas, Gracie; Deora, Arun B; Wang, Michael; Jacovina, Andrew T; Garcia-Latorre, Ethel; Reyes-Maldonado, Elba; Hajjar, Katherine A; Pierangeli, Silvia S

    2009-10-01

    Antiphospholipid (aPL) antibodies recognize receptor-bound beta(2) glycoprotein I (beta(2)GPI) on target cells, and induce an intracellular signaling and a procoagulant/proinflammatory phenotype that leads to thrombosis. Evidence indicates that annexin A2 (A2), a receptor for tissue plasminogen activator and plasminogen, binds beta(2)GPI on target cells. However, whether A2 mediates pathogenic effects of aPL antibodies in vivo is unknown. In this work, we studied the effects of human aPL antibodies in A2-deficient (A2(-/-)) mice. A2(-/-) and A2(+/+) mice were injected with immunoglobulin G (IgG) isolated from either a patient with antiphospholipid syndrome (IgG-APS), a healthy control subject (IgG-normal human serum), a monoclonal anti-beta(2)GPI antibody (4C5), an anti-A2 monoclonal antibody, or monoclonal antibody of irrelevant specificity as control. We found that, after IgG-APS or 4C5 injections and vascular injury, mean thrombus size was significantly smaller and tissue factor activity was significantly less in A2(-/-) mice compared with A2(+/+) mice. The expression of vascular cell adhesion molecule-1 induced by IgG-APS or 4C5 in explanted A2(-/-) aorta was also significantly reduced compared with A2(+/+) mice. Interestingly, anti-A2 monoclonal antibody significantly decreased aPL-induced expression of intercellular cell adhesion molecule-1, E-selectin, and tissue factor activity on cultured endothelial cells. Together, these data indicate for the first time that A2 mediates the pathogenic effects of aPL antibodies in vivo and in vitro APS.

  18. CD40 agonist antibody mediated improvement of chronic Cryptosporidium infection in patients with X- linked hyper IgM syndrome

    PubMed Central

    Fan, Xiying; Upadhyaya, Bhaskar; Wu, Liming; Koh, Christopher; Santín-Durán, Mónica; Pittaluga, Stefania; Uzel, Gulbu; Kleiner, David; Williams, Ester; Ma, Chi A.; Bodansky, Aaron; Oliveira, Joao B.; Edmonds, Pamela; Hornung, Ronald; Wong, Duane W.; Fayer, Ronald; Fleisher, Tom; Heller, Theo; Prussin, Calman; Jain, Ashish

    2012-01-01

    X-linked hyper-IgM syndrome (XHM) is a combined immune deficiency disorder caused by mutations in CD40 ligand. We tested CP-870,893, a human CD40 agonist monoclonal antibody, in the treatment of two XHM patients with biliary Cryptosporidiosis. CP-870,893 activated B cells and APCs in vitro, restoring class switch recombination in XHM B cells and inducing cytokine secretion by monocytes. CP-870,893 infusions were well tolerated and showed significant activity in vivo, decreasing leukocyte concentration in peripheral blood. Although specific antibody responses were lacking, frequent dosing in one subject primed T cells to secrete IFN-g and suppressed oocyst shedding in the stool. Nevertheless, relapse occurred after discontinuation of therapy. The CD40 receptor was rapidly internalized following binding with CP-870,893, potentially explaining the limited capacity of CP-870,893 to mediate immune reconstitution. This study demonstrates that CP-870,893 suppressed oocysts shedding in XHM patients with biliary cryptosporidiosis. The continued study of CD40 agonists in XHM is warranted. PMID:22459705

  19. Renal allograft rejection: sonography and scintigraphy

    SciTech Connect

    Singh, A.; Cohen, W.N.

    1980-07-01

    A total of 30 renal allograft patients who had sonographic B scanning and radionuclide studies of the transplant was studied as to whether: (1) the allograft rejection was associated with any consistent and reliable sonographic features and (2) the sonograms complemented the radionuclide studies. Focal areas of decreased parenchymal echogenicity were the most striking and consistent sonographic finding in chymal echogenicity were the most striking and consistens sonographic finding in allograft rejection. This was observed in most of the patients exhibiting moderate or severe rejection, but was frequently absent with mild rejection. Areas of decreased parenchymal echogenicity were not seen during episodes of acute tubular necrosis. Therefore, sonography showing zones of decreased parenchymal echogenicity was complementary to radionuclide studies in the diagnosis of allograft rejection versus acute tubular necrosis. Corticomedullary demarcation was difficult to interpret because of technical variables, and was inconsistently related to rejection in this series.

  20. Failure to diagnose cardiac treatment rejection with Tc99m-PYP images

    SciTech Connect

    McKillop, J.H.; McDougall, I.R.; Goris, M.L.; Mason, J.W.; Reitz, B.A.

    1981-08-01

    The possibility of diagnosing transplant rejection using Tc-99m-PYP imaging was examined in 12 cardiac transplant recipients. Two patients were studied on two occasions. The presence or absence of active rejection was established by endomyocardial biopsy. The intensity and pattern of myocardial uptake of the tracer did not differ significantly in the two patients studied at the time of rejection compared to the remainder. It is concluded that a single Tc-99m-PYP study cannot be used to diagnose cardiac transplant rejection.

  1. Graft-infiltrating host dendritic cells play a key role in organ transplant rejection

    PubMed Central

    Zhuang, Quan; Liu, Quan; Divito, Sherrie J.; Zeng, Qiang; Yatim, Karim M.; Hughes, Andrew D.; Rojas-Canales, Darling M.; Nakao, A.; Shufesky, William J.; Williams, Amanda L.; Humar, Rishab; Hoffman, Rosemary A.; Shlomchik, Warren D.; Oberbarnscheidt, Martin H.; Lakkis, Fadi G.; Morelli, Adrian E.

    2016-01-01

    Successful engraftment of organ transplants has traditionally relied on preventing the activation of recipient (host) T cells. Once T-cell activation has occurred, however, stalling the rejection process becomes increasingly difficult, leading to graft failure. Here we demonstrate that graft-infiltrating, recipient (host) dendritic cells (DCs) play a key role in driving the rejection of transplanted organs by activated (effector) T cells. We show that donor DCs that accompany heart or kidney grafts are rapidly replaced by recipient DCs. The DCs originate from non-classical monocytes and form stable, cognate interactions with effector T cells in the graft. Eliminating recipient DCs reduces the proliferation and survival of graft-infiltrating T cells and abrogates ongoing rejection or rejection mediated by transferred effector T cells. Therefore, host DCs that infiltrate transplanted organs sustain the alloimmune response after T-cell activation has already occurred. Targeting these cells provides a means for preventing or treating rejection. PMID:27554168

  2. [Tubulointerstitial rejection of renal allografts].

    PubMed

    Malušková, Jana; Honsová, Eva

    2015-01-01

    Tubulo-intersticial rejection represents T-cell mediated rejection of kidney allografts with the morphology of immune-mediated interstitial nephritis. Diagnosis is dependent on the histopathological evaluation of a graft biopsy sample. The key morphological features are interstitial inflammatory infiltrate and damage to tubular epithelial cell which in severe cases can result in the ruptures of the tubular basement membranes. The differential diagnosis of tubulo-interstitial rejection includes acute interstitial nephritis and viral inflammatory kidney diseases, mainly polyomavirus nephropathy.

  3. Solar collector apparatus having increased energy rejection during stagnation

    DOEpatents

    Moore, S.W.

    1981-01-16

    An active solar collector having increased energy rejection during stagnation is disclosed. The collector's glazing is brought into substantial contact with absorber during stagnation to increase re-emittance and thereby to maintan lower temperatures when the collector is not in operation.

  4. Solar collector apparatus having increased energy rejection during stagnation

    DOEpatents

    Moore, Stanley W.

    1983-07-12

    The disclosure relates to an active solar collector having increased energy rejection during stagnation. The collector's glazing is brought into substantial contact with absorber during stagnation to increase re-emittance and thereby to maintain lower temperatures when the collector is not in operation.

  5. Antibody-mediated targeted gene transfer of helper virus-free HSV-1 vectors to rat neocortical neurons that contain either NMDA receptor 2B or 2A subunits.

    PubMed

    Cao, Haiyan; Zhang, Guo-rong; Geller, Alfred I

    2011-09-30

    Because of the numerous types of neurons in the brain, and particularly the forebrain, neuron type-specific expression will benefit many potential applications of direct gene transfer. The two most promising approaches for achieving neuron type-specific expression are targeted gene transfer to a specific type of neuron and using a neuron type-specific promoter. We previously developed antibody-mediated targeted gene transfer with Herpes Simplex Virus (HSV-1) vectors by modifying glycoprotein C (gC) to replace the heparin binding domain, which mediates the initial binding of HSV-1 particles to many cell types, with the Staphylococcus A protein ZZ domain, which binds immunoglobulin (Ig) G. We showed that a chimeric gC-ZZ protein is incorporated into vector particles and binds IgG. As a proof-of-principle for antibody-mediated targeted gene transfer, we isolated complexes of these vector particles and an anti-NMDA NR1 subunit antibody, and demonstrated targeted gene transfer to neocortical cells that contain NR1 subunits. However, because most forebrain neurons contain NR1, we obtained only a modest increase in the specificity of gene transfer, and this targeting specificity is of limited utility for physiological experiments. Here, we report efficient antibody-mediated targeted gene transfer to NMDA NR2B- or NR2A-containing cells in rat postrhinal cortex, and a neuron-specific promoter further restricted recombinant expression to neurons. Of note, because NR2A-containing neurons are relatively rare, these results show that antibody-mediated targeted gene transfer with HSV-1 vectors containing neuron type-specific promoters can restrict recombinant expression to specific types of forebrain neurons of physiological significance.

  6. The absence of IgE antibody-mediated augmentation of immune responses in CD23-deficient mice.

    PubMed Central

    Fujiwara, H; Kikutani, H; Suematsu, S; Naka, T; Yoshida, K; Yoshida, K; Tanaka, T; Suemura, M; Matsumoto, N; Kojima, S

    1994-01-01

    The CD23 antigen, a low-affinity receptor for IgE (Fc epsilon RII), is a type II membrane-bound glycoprotein expressed on various cells, particularly mature B cells. A number of functions have been ascribed to CD23, including specific regulation of IgE production, IgE-mediated cytotoxicity and release of mediators, IgE-dependent antigen focusing, promotion of B-cell growth, prevention of germinal center B cells from apoptosis, proliferation of myeloid precursors, and maturation of early thymocytes. It is not clear whether these activities represent in vivo functions. To explore in vivo functions of CD23, we have produced CD23-deficient mice. These mice displayed normal lymphocyte differentiation and could mount normal antibody responses, including IgE responses upon immunization with T-dependent antigens and infection with Nippostrongyrus brasiliensis. Germinal center formation after immunization and in vitro proliferative response of B cells were not affected in mutant mice. However, antigen-specific IgE-mediated enhancement of antibody responses was severely impaired. Images PMID:8041705

  7. Blocking by anti-idiotypic antibodies of monoclonal antibody-mediated protection against lethal Semliki Forest virus in mice.

    PubMed

    Oosterlaken, T A; Harmsen, M; Kraaijeveld, C A; Snippe, H

    1990-02-01

    Semliki Forest virus-(SEV) neutralizing monoclonal antibodies (MoAbs), produced after fusion of spleen cells from BALB/c mice and myeloma cell line P3-X63-AG8. 653 or SP2/0, were used for anti-idiotypic immunization of female BALB/c mice. Two intracutaneous immunizations (2 x 40 micrograms per animal), 3 weeks apart, with keyhole limpet haemocyanin-conjugated MoAbs mixed with the saponin Quil A were sufficient to induce high levels of anti-idiotypic antibodies in the circulation of these mice with the capacity to block specifically in vitro MoAb-mediated virus neutralization. Anti-idiotypic antibodies against SFV-neutralizing MoAbs, either passively transferred or actively acquired by immunization, are also able to abrogate (specifically) passive immunity, mediated by critical protective doses of MoAb, in mice against infection with a lethal strain of SFV. Furthermore we confirmed by intervention with anti-idiotypic serum in vivo that an SFV-neutralizing MoAb exerts its greatest protective effect during the first 2 days of infection.

  8. Maternal Antibody-Mediated Disease Enhancement in Type I Interferon-Deficient Mice Leads to Lethal Disease Associated with Liver Damage.

    PubMed

    Martínez Gómez, Julia María; Ong, Li Ching; Lam, Jian Hang; Binte Aman, Siti Amanlina; Libau, Eshele Anak; Lee, Pei Xuan; St John, Ashley L; Alonso, Sylvie

    2016-03-01

    Epidemiological studies have reported that most of the severe dengue cases occur upon a secondary heterologous infection. Furthermore, babies born to dengue immune mothers are at greater risk of developing severe disease upon primary infection with a heterologous or homologous dengue virus (DENV) serotype when maternal antibodies reach sub-neutralizing concentrations. These observations have been explained by the antibody mediated disease enhancement (ADE) phenomenon whereby heterologous antibodies or sub-neutralizing homologous antibodies bind to but fail to neutralize DENV particles, allowing Fc-receptor mediated entry of the virus-antibody complexes into host cells. This eventually results in enhanced viral replication and heightened inflammatory responses. In an attempt to replicate this ADE phenomenon in a mouse model, we previously reported that upon DENV2 infection 5-week old type I and II interferon (IFN) receptors-deficient mice (AG129) born to DENV1-immune mothers displayed enhancement of disease severity characterized by increased virus titers and extensive vascular leakage which eventually led to the animals' death. However, as dengue occurs in immune competent individuals, we sought to reproduce this mouse model in a less immunocompromised background. Here, we report an ADE model that is mediated by maternal antibodies in type I IFN receptor-deficient A129 mice. We show that 5-week old A129 mice born to DENV1-immune mothers succumbed to a DENV2 infection within 4 days that was sub-lethal in mice born to naïve mothers. Clinical manifestations included extensive hepatocyte vacuolation, moderate vascular leakage, lymphopenia, and thrombocytopenia. Anti-TNFα therapy totally protected the mice and correlated with healthy hepatocytes. In contrast, blocking IL-6 did not impact the virus titers or disease outcome. This A129 mouse model of ADE may help dissecting the mechanisms involved in dengue pathogenesis and evaluate the efficacy of vaccine and

  9. Increased infectivity in human cells and resistance to antibody-mediated neutralization by truncation of the SIV gp41 cytoplasmic tail.

    PubMed

    Kuwata, Takeo; Kaori, Takaki; Enomoto, Ikumi; Yoshimura, Kazuhisa; Matsushita, Shuzo

    2013-01-01

    The role of antibodies in protecting the host from human immunodeficiency virus type 1 (HIV-1) infection is of considerable interest, particularly because the RV144 trial results suggest that antibodies contribute to protection. Although infection of non-human primates with simian immunodeficiency virus (SIV) is commonly used as an animal model of HIV-1 infection, the viral epitopes that elicit potent and broad neutralizing antibodies to SIV have not been identified. We isolated a monoclonal antibody (MAb) B404 that potently and broadly neutralizes various SIV strains. B404 targets a conformational epitope comprising the V3 and V4 loops of Env that intensely exposed when Env binds CD4. B404-resistant variants were obtained by passaging viruses in the presence of increasing concentration of B404 in PM1/CCR5 cells. Genetic analysis revealed that the Q733stop mutation, which truncates the cytoplasmic tail of gp41, was the first major substitution in Env during passage. The maximal inhibition by B404 and other MAbs were significantly decreased against a recombinant virus with a gp41 truncation compared with the parental SIVmac316. This indicates that the gp41 truncation was associated with resistance to antibody-mediated neutralization. The infectivities of the recombinant virus with the gp41 truncation were 7,900-, 1,000-, and 140-fold higher than those of SIVmac316 in PM1, PM1/CCR5, and TZM-bl cells, respectively. Immunoblotting analysis revealed that the gp41 truncation enhanced the incorporation of Env into virions. The effect of the gp41 truncation on infectivity was not obvious in the HSC-F macaque cell line, although the resistance of viruses harboring the gp41 truncation to neutralization was maintained. These results suggest that viruses with a truncated gp41 cytoplasmic tail were selected by increased infectivity in human cells and by acquiring resistance to neutralizing antibody.

  10. Maternal Antibody-Mediated Disease Enhancement in Type I Interferon-Deficient Mice Leads to Lethal Disease Associated with Liver Damage

    PubMed Central

    Lam, Jian Hang; Binte Aman, Siti Amanlina; Libau, Eshele Anak; Lee, Pei Xuan; St. John, Ashley L.; Alonso, Sylvie

    2016-01-01

    Epidemiological studies have reported that most of the severe dengue cases occur upon a secondary heterologous infection. Furthermore, babies born to dengue immune mothers are at greater risk of developing severe disease upon primary infection with a heterologous or homologous dengue virus (DENV) serotype when maternal antibodies reach sub-neutralizing concentrations. These observations have been explained by the antibody mediated disease enhancement (ADE) phenomenon whereby heterologous antibodies or sub-neutralizing homologous antibodies bind to but fail to neutralize DENV particles, allowing Fc-receptor mediated entry of the virus-antibody complexes into host cells. This eventually results in enhanced viral replication and heightened inflammatory responses. In an attempt to replicate this ADE phenomenon in a mouse model, we previously reported that upon DENV2 infection 5-week old type I and II interferon (IFN) receptors-deficient mice (AG129) born to DENV1-immune mothers displayed enhancement of disease severity characterized by increased virus titers and extensive vascular leakage which eventually led to the animals’ death. However, as dengue occurs in immune competent individuals, we sought to reproduce this mouse model in a less immunocompromised background. Here, we report an ADE model that is mediated by maternal antibodies in type I IFN receptor-deficient A129 mice. We show that 5-week old A129 mice born to DENV1-immune mothers succumbed to a DENV2 infection within 4 days that was sub-lethal in mice born to naïve mothers. Clinical manifestations included extensive hepatocyte vacuolation, moderate vascular leakage, lymphopenia, and thrombocytopenia. Anti-TNFα therapy totally protected the mice and correlated with healthy hepatocytes. In contrast, blocking IL-6 did not impact the virus titers or disease outcome. This A129 mouse model of ADE may help dissecting the mechanisms involved in dengue pathogenesis and evaluate the efficacy of vaccine and

  11. Sensitivity of scintigraphy with /sup 111/In-lymphocytes for detection of cardiac allograft rejection

    SciTech Connect

    Eisenberg, S.B.; Eisen, H.J.; Sobel, B.E.; Bergmann, S.R.; Bolman, R.M. 3d.

    1988-12-01

    We recently demonstrated the feasibility of noninvasive detection of cardiac allograft rejection after administration of indium-111-labeled lymphocytes. To determine the sensitivity and specificity of the technique, as well as its value for delineating the severity of rejection, we studied 16 dogs with heterotopic thoracic cardiac allografts. Five animals were evaluated while exposed to immunosuppressive agents. Animals were scanned sequentially after administration of 100-400 microCi of indium-111-labeled autologous lymphocytes. Myocardial lymphocyte infiltration was expressed as the indium excess (IE), defined as the ratio of indium activity of the transplant or native heart compared with that in blood. Scintigraphic results were compared with characteristics of simultaneously obtained endomyocardial biopsies. Among 17 biopsy documented episodes of rejection, 16 were detected scintigraphically. Among 18 biopsies with no evidence of rejection, scintigraphy was uniformly negative. Thus, the sensitivity and specificity of scintigraphy were 94 and 100%, respectively. Biopsies graded as showing no rejection were associated with an IE of 0.3 +/- 0.5 (+/- SD); those graded as mild, 2.8 +/- 1.7; those as moderate, 10.7 +/- 7.2; and those graded as indicative of severe rejection, 14.2 +/- 4.5. Thus, scintigraphy with indium-111-labeled lymphocytes sensitively and specifically detects cardiac allograft rejection and delineates the intensity of the rejection process. It should be useful clinically for assessing potential allograft rejection noninvasively.

  12. 21 CFR 1230.47 - Rejected containers.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Rejected containers. 1230.47 Section 1230.47 Food... FEDERAL CAUSTIC POISON ACT Imports § 1230.47 Rejected containers. (a) In all cases where the containers... notification to the importer that the containers must be exported under customs supervision within 3...

  13. Rejection and Depression: Prospective and Contemporaneous Analyses.

    ERIC Educational Resources Information Center

    Lefkowitz, Monroe M.; Tesiny, Edward P.

    1984-01-01

    Three studies explore the relationship between parental rejection during childhood and manifestations of depression both then and in young adulthood. With regard to rejection, findings support the general hypothesis that deprivation is an etiological factor in adult depression. (Author/RH)

  14. Rapid heartbeat, but dry palms: reactions of heart rate and skin conductance levels to social rejection

    PubMed Central

    Iffland, Benjamin; Sansen, Lisa M.; Catani, Claudia; Neuner, Frank

    2014-01-01

    Background: Social rejection elicits negative mood, emotional distress, and neural activity in networks that are associated with physical pain. However, studies assessing physiological reactions to social rejection are rare and results of these studies were found to be ambiguous. Therefore, the present study aimed to examine and specify physiological effects of social rejection. Methods: Participants (n = 50) were assigned to either a social exclusion or inclusion condition of a virtual ball-tossing game (Cyberball). Immediate and delayed physiological [skin conductance level (SCL) and heart rate] reactions were recorded. In addition, subjects reported levels of affect, emotional states, and fundamental needs. Results: Subjects who were socially rejected showed increased heart rates. However, social rejection had no effect on subjects' SCLs. Both conditions showed heightened arousal on this measurement. Furthermore, psychological consequences of social rejection indicated the validity of the paradigm. Conclusions: Our results reveal that social rejection evokes an immediate physiological reaction. Accelerated heart rates indicate that behavior activation rather than inhibition is associated with socially threatening events. In addition, results revealed gender-specific response patterns suggesting that sample characteristics such as differences in gender may account for ambiguous findings of physiological reactions to social rejection. PMID:25221535

  15. Abdominal Wall Transplantation: Skin as a Sentinel Marker for Rejection.

    PubMed

    Gerlach, U A; Vrakas, G; Sawitzki, B; Macedo, R; Reddy, S; Friend, P J; Giele, H; Vaidya, A

    2016-06-01

    Abdominal wall transplantation (AWTX) has revolutionized difficult abdominal closure after intestinal transplantation (ITX). More important, the skin of the transplanted abdominal wall (AW) may serve as an immunological tool for differential diagnosis of bowel dysfunction after transplant. Between August 2008 and October 2014, 29 small bowel transplantations were performed in 28 patients (16 male, 12 female; aged 41 ± 13 years). Two groups were identified: the solid organ transplant (SOT) group (n = 15; 12 ITX and 3 modified multivisceral transplantation [MMVTX]) and the SOT-AWTX group (n = 14; 12 ITX and 2 MMVTX), with the latter including one ITX-AWTX retransplantation. Two doses of alemtuzumab were used for induction (30 mg, 6 and 24 h after reperfusion), and tacrolimus (trough levels 8-12 ng/mL) was used for maintenance immunosuppression. Patient survival was similar in both groups (67% vs. 61%); however, the SOT-AWTX group showed faster posttransplant recovery, better intestinal graft survival (79% vs. 60%), a lower intestinal rejection rate (7% vs. 27%) and a lower rate of misdiagnoses in which viral infection was mistaken and treated as rejection (14% vs. 33%). The skin component of the AW may serve as an immune modulator and sentinel marker for immunological activity in the host. This can be a vital tool for timely prevention of intestinal graft rejection and, more important, avoidance of overimmunosuppression in cases of bowel dysfunction not related to graft rejection.

  16. Teaching requesting and rejecting sequences to four children with developmental disabilities using augmentative and alternative communication.

    PubMed

    Choi, Hayoung; O'Reilly, Mark; Sigafoos, Jeff; Lancioni, Giulio

    2010-01-01

    The purpose of this study was to evaluate the feasibility of teaching an integrated requesting-rejecting sequence. Four children with developmental disabilities were taught to request missing items and reject wrong items using either speech-generating devices (SGD) or picture-exchange (PE) communication. Data showed that the introduction of the teaching procedures were associated with acquisition of the targeted requesting and rejecting responses. The newly acquired rejecting responses generalized across two untrained activities and were maintained for up to four weeks following intervention for three of the four participants. The missing-item and wrong-item formats can be successfully combined to teach an integrated sequence of requesting and rejecting to students with developmental disabilities who use speech-generating devices (SGD) or picture-exchange (PE) communication.

  17. Mechanisms of chronic rejection in cardiothoracic transplantation

    PubMed Central

    Weiss, Matthew J.; Madsen, Joren C.; Rosengard, Bruce R.; Allan, James S.

    2010-01-01

    Despite significant improvements in early post-transplantation survival rates, long-term patient and graft survival have remained poor, due in large part to the vexing problem of chronic allograft rejection. Attempts to combat this problem with intensification of immunosuppression have led to concomitant increases in the rates of fatal malignancies and infections. In cardiac transplantation, chronic rejection is manifested primarily by a disease entity known as cardiac allograft vasculopathy, an occlusive narrowing of the coronary vessels. In lung transplantation, chronic rejection is typified by obliterative bronchiolitis, an airflow limiting narrowing of the bronchioles. From an immunologic standpoint, chronic rejection is believed to be the end result of repeated immune and non-immune insults to the graft. This review examines the pathophysiology of heart and lung chronic, with emphasis on both immune and non-immune causes. PMID:17981771

  18. Applying the Cognitive-Affective Processing Systems Approach to Conceptualizing Rejection Sensitivity

    PubMed Central

    Ayduk, Özlem; Gyurak, Anett

    2009-01-01

    The Cognitive-Affective Processing Systems or CAPS theory (Mischel & Shoda, 1995) was proposed to account for the processes that explain why and how people’s behavior varies stably across situations. Research on Rejection Sensitivity is reviewed as a programmatic attempt to illustrate how personality dispositions can be studied within the CAPS framework. This research reveals an if … then … (e.g., if situation X, he does A, but if situation Y, he does B) pattern of rejection sensitivity such that high rejection sensitive people’s goal to prevent rejection can lead to accommodating behavior; yet, the failure to achieve this goal can lead to aggression, reactivity, and lack of self-concept clarity. These situation–behavior relations or personality signatures reflect a stable activation network of distinctive personality processing dynamics. These dynamics link fears and expectations of rejection, perceptions/attributions of rejection, and affective/behavioral overreactions to perceived rejection. Self-regulatory and attentional mechanisms may interact with these dynamics as buffers against high rejection sensitivity, illustrating how multiple processes within a CAPS network play out in behavior. PMID:19890458

  19. Prevention of peer rejection through a classroom-level intervention in middle school.

    PubMed

    Mikami, Amori Yee; Boucher, Margaret A; Humphreys, Keith

    2005-01-01

    This project evaluated an intervention for preventing peer rejection in middle school that promoted social acceptance in the classroom environment. The systems-level and preventive focus of this intervention differed markedly from traditional interventions that target putative deficits within individual rejected children. In collaboration with 24 teachers and their classrooms, the intervention team led mixed groups of accepted and rejected children in cooperative games that required teamwork and mutual respect among all members in order to succeed. To reinforce these alliances between children, as well as to prevent future peer rejection, teachers were encouraged to use cooperative, teamwork-based group activities for academic instruction. The intervention was evaluated using a randomized control (waitlist) design. Results suggested that the intervention reduced the amount of self-reported peer rejection in classrooms. Implications for the further development and evaluation of systems-level interventions to prevent peer rejection are discussed. EDITORS' STRATEGIC IMPLICATIONS: The use of a systems-based prevention program shows promise for the prevention of children's perceived peer rejection. The authors demonstrate a model of university-community collaboration with a plan for sustainability and a focus on low-income and minority populations. Educators, school administrators, and researchers will be intrigued by the positive experiences of non-rejected peers and teachers in promoting a socially accepting school climate.

  20. How to get your paper rejected.

    PubMed

    Chernick, Victor

    2008-03-01

    This paper focuses on the main problems that authors of rejected papers have had in their submissions to Pediatric Pulmonology over the past 5 years or so. It is intended as a teaching tool for residents, fellows, allied health personnel, practicing physicians and even some academic physicians who need a refresher on what goes wrong and how they may avoid rejection of their labor. The approach is somewhat lighthearted but nevertheless the message is quite serious.

  1. Thallium kinetics in rat cardiac transplant rejection

    SciTech Connect

    Barak, J.H.; LaRaia, P.J.; Boucher, C.A.; Fallon, J.T.; Buckley, M.J.

    1988-04-01

    Cardiac transplant rejection is a very complex process involving both cellular and vascular injury. Recently, thallium imaging has been used to assess acute transplant rejection. It has been suggested that changes in thallium kinetics might be a sensitive indicator of transplant rejection. Accordingly, thallium kinetics were assessed in vivo in acute untreated rat heterotopic (cervical) transplant rejection. Male Lewis rats weighing 225-250 g received heterotopic heart transplants from syngeneic Lewis rats (group A; n = 13), or allogeneic Brown Norway rats (group B; n = 11). Rats were imaged serially on the 2nd and the 7th postoperative days. Serial cardiac thallium content was determined utilizing data collected every 150 sec for 2 hr. The data were fit to a monoexponential curve and the decay rate constant (/sec) derived. By day 7 all group B hearts had histological evidence of severe acute rejection, and demonstrated decreased global contraction. Group A hearts showed normal histology and contractility. However, thallium uptakes and washout of the two groups were the same. Peak thallium uptake of group B was +/- 3758 1166 counts compared with 3553 +/- 950 counts in the control group A (P = 0.6395); The 2-hr percentage of washout was 12.1 +/- 1.04 compared with 12.1 +/- 9.3 (P = 1.0000); and the decay constant was -0.00002065 +/- 0.00001799 compared with -0.00002202 +/- 0.00001508 (P = 0.8409). These data indicate that in vivo global thallium kinetics are preserved during mild-to-severe acute transplant rejection. These findings suggest that the complex cellular and extracellular processes of acute rejection limit the usefulness of thallium kinetics in the detection of acute transplant rejection.

  2. The fate of triaged and rejected manuscripts.

    PubMed

    Zoccali, Carmine; Amodeo, Daniela; Argiles, Angel; Arici, Mustafa; D'arrigo, Graziella; Evenepoel, Pieter; Fliser, Danilo; Fox, Jonathan; Gesualdo, Loreto; Jadoul, Michel; Ketteler, Markus; Malyszko, Jolanta; Massy, Ziad; Mayer, Gert; Ortiz, Alberto; Sever, Mehmet; Vanholder, Raymond; Vinck, Caroline; Wanner, Christopher; Więcek, Andrzej

    2015-12-01

    In 2011, Nephrology Dialysis and Transplantation (NDT) established a more restrictive selection process for manuscripts submitted to the journal, reducing the acceptance rate from 25% (2008-2009) to currently about 12-15%. To achieve this goal, we decided to score the priority of manuscripts submitted to NDT and to reject more papers at triage than in the past. This new scoring system allows a rapid decision for the authors without external review. However, the risk of such a restrictive policy may be that the journal might fail to capture important studies that are eventually published in higher-ranked journals. To look into this problem, we analysed random samples of papers (∼10%) rejected by NDT in 2012. Of the papers rejected at triage and those rejected after regular peer review, 59 and 61%, respectively, were accepted in other journals. A detailed analysis of these papers showed that only 4 out of 104 and 7 out of 93 of the triaged and rejected papers, respectively, were published in journals with an impact factor higher than that of NDT. Furthermore, for all these papers, independent assessors confirmed the evaluation made by the original reviewers. The number of citations of these papers was similar to that typically obtained by publications in the corresponding journals. Even though the analyses seem reassuring, previous observations made by leading journals warn that the risk of 'big misses', resulting from selective editorial policies, remains a real possibility. We will therefore continue to maintain a high degree of alertness and will periodically track the history of manuscripts rejected by NDT, particularly papers that are rejected at triage by our journal.

  3. A QSAR model for predicting rejection of emerging contaminants (pharmaceuticals, endocrine disruptors) by nanofiltration membranes.

    PubMed

    Yangali-Quintanilla, Victor; Sadmani, Anwar; McConville, Megan; Kennedy, Maria; Amy, Gary

    2010-01-01

    A quantitative structure activity relationship (QSAR) model has been produced for predicting rejection of emerging contaminants (pharmaceuticals, endocrine disruptors, pesticides and other organic compounds) by polyamide nanofiltration (NF) membranes. Principal component analysis, partial least square regression and multiple linear regressions were used to find a general QSAR equation that combines interactions between membrane characteristics, filtration operating conditions and compound properties for predicting rejection. Membrane characteristics related to hydrophobicity (contact angle), salt rejection, and surface charge (zeta potential); compound properties describing hydrophobicity (log K(ow), log D), polarity (dipole moment), and size (molar volume, molecular length, molecular depth, equivalent width, molecular weight); and operating conditions namely flux, pressure, cross flow velocity, back diffusion mass transfer coefficient, hydrodynamic ratio (J(o)/k), and recovery were identified as candidate variables for rejection prediction. An experimental database produced by the authors that accounts for 106 rejection cases of emerging contaminants by NF membranes as result of eight experiments with clean and fouled membranes (NF-90, NF-200) was used to produce the QSAR model. Subsequently, using the QSAR model, rejection predictions were made for external experimental databases. Actual rejections were compared against predicted rejections and acceptable R(2) correlation coefficients were found (0.75 and 0.84) for the best models. Additionally, leave-one-out cross-validation of the models achieved a Q(2) of 0.72 for internal validation. In conclusion, a unified general QSAR equation was able to predict rejections of emerging contaminants during nanofiltration; moreover the present approach is a basis to continue investigation using multivariate analysis techniques for understanding membrane rejection of organic compounds.

  4. Peer acceptance and rejection through the eyes of youth: pupillary, eyetracking and ecological data from the Chatroom Interact task

    PubMed Central

    Stroud, Laura R.; Siegle, Greg J.; Dahl, Ronald E.; Lee, Kyung Hwa; Nelson, Eric E.

    2012-01-01

    We developed an ecologically valid virtual peer interaction paradigm—the Chatroom Interact Task in which 60 pre-adolescents and adolescents (ages 9–17 years) were led to believe that they were interacting with other youth in a simulated internet chatroom. Youth received rejection and acceptance feedback from virtual peers. Findings revealed increased pupil dilation, an index of increased activity in cognitive and affective processing regions of the brain, to rejection compared to acceptance trials, which was greater for older youth. Data from a cell-phone Ecological Momentary Assessment (EMA) protocol completed following the task indicated that increased pupillary reactivity to rejection trials was associated with lower feelings of social connectedness with peers in daily life. Eyetracking analyses revealed attentional biases toward acceptance feedback and away from rejection feedback. Biases toward acceptance feedback were stronger for older youth. Avoidance of rejection feedback was strongest among youth with increased pupillary reactivity to rejection, even in the seconds leading up to and following rejection feedback. These findings suggest that adolescents are sensitive to rejection feedback and seek to anticipate and avoid attending to rejection stimuli. Furthermore, the salience of social rejection and acceptance feedback appears to increase during adolescence. PMID:21775386

  5. Neural responses to witnessing peer rejection after being socially excluded: fMRI as a window into adolescents’ emotional processing

    PubMed Central

    Masten, Carrie L.; Eisenberger, Naomi I.; Pfeifer, Jennifer H.; Dapretto, Mirella

    2013-01-01

    During adolescence, concerns about peer rejection and acceptance become increasingly common. Adolescents regularly experience peer rejection firsthand and witness these behaviors among their peers. In the current study, neuroimaging techniques were employed to conduct a preliminary investigation of the affective and cognitive processes involved in witnessing peer acceptance and rejection—specifically when these witnessed events occur in the immediate aftermath of a firsthand experience with rejection. During an fMRI scan, twenty-three adolescents underwent a simulated experience of firsthand peer rejection. Then, immediately following this experience they watched as another adolescent was ostensibly first accepted and then rejected. Findings indicated that in the immediate aftermath of being rejected by peers, adolescents displayed neural activity consistent with distress when they saw another peer being accepted, and neural activity consistent with emotion regulation and mentalizing (e.g., perspective-taking) processes when they saw another peer being rejected. Furthermore, individuals displaying a heightened sensitivity to firsthand rejection were more likely to show neural activity consistent with distress when observing a peer being accepted. Findings are discussed in terms of how witnessing others being accepted or rejected relates to adolescents’ interpretations of both firsthand and observed experiences with peers. Additionally, the potential impact that witnessed events might have on the broader perpetuation of bullying at this age is also considered. PMID:24033579

  6. Reward, addiction, and emotion regulation systems associated with rejection in love.

    PubMed

    Fisher, Helen E; Brown, Lucy L; Aron, Arthur; Strong, Greg; Mashek, Debra

    2010-07-01

    Romantic rejection causes a profound sense of loss and negative affect. It can induce clinical depression and in extreme cases lead to suicide and/or homicide. To begin to identify the neural systems associated with this natural loss state, we used functional magnetic resonance imaging to study 10 women and 5 men who had recently been rejected by a partner but reported they were still intensely "in love." Participants alternately viewed a photograph of their rejecting beloved and a photograph of a familiar, individual, interspersed with a distraction-attention task. Their responses while looking at their rejecter included love, despair, good, and bad memories, and wondering why this happened. Activation specific to the image of the beloved occurred in areas associated with gains and losses, craving and emotion regulation and included the ventral tegmental area (VTA) bilaterally, ventral striatum, medial and lateral orbitofrontal/prefrontal cortex, and cingulate gyrus. Compared with data from happily-in-love individuals, the regional VTA activation suggests that mesolimbic reward/survival systems are involved in romantic passion regardless of whether one is happily or unhappily in love. Forebrain activations associated with motivational relevance, gain/loss, cocaine craving, addiction, and emotion regulation suggest that higher-order systems subject to experience and learning also may mediate the rejection reaction. The results show activation of reward systems, previously identified by monetary stimuli, in a natural, endogenous, negative emotion state. Activation of areas involved in cocaine addiction may help explain the obsessive behaviors associated with rejection in love.

  7. Rejection of pharmaceuticals by nanofiltration (NF) membranes: Effect of fouling on rejection behaviour

    NASA Astrophysics Data System (ADS)

    Mahlangu, T. O.; Msagati, T. A. M.; Hoek, E. M. V.; Verliefde, A. R. D.; Mamba, B. B.

    The aim of this study was to investigate the effects of membrane fouling by sodium alginate, latex and a combination of alginate + latex on the rejection behaviour of salts and organics. Sodium chloride and caffeine were selected to represent salts and organics, respectively. The effects of the presence of calcium chloride on the fouling behaviour and rejection of solutes were investigated. The results revealed that the salt rejection by virgin membranes was 47% while that of caffeine was 85%. Fouling by alginate, latex and combined alginate-latex resulted in flux decline of 25%, 37% and 17%, respectively. The addition of Ca2+ aggravated fouling and resulted in further flux decline to 37%. Fouling decreased salt rejection, an observation that was further aggravated by the addition on Ca2+. However, it was also observed that fouling with alginate and calcium and with latex and calcium minimised salt rejection by 30% and 31%, respectively. This reduction in salt rejection was attributed to the decrease in permeate flux (since rejection is a function of flux). There was a slight increase in caffeine rejection when the membrane was fouled with latex particles. Moreover, the presence of foulants on the membrane resulted in a decrease in the surface charge of the membrane. The results of this study have shown that the NF 270 membrane can be used to treat water samples contaminated with caffeine and other organic compounds that have physicochemical properties similar to those of caffeine.

  8. Taste rejection of nonnutritive sweeteners in cats.

    PubMed

    Bartoshuk, L M; Jacobs, H L; Nichols, T L; Hoff, L A; Ryckman, J J

    1975-10-01

    Cats reject saccharin and cyclamate and are indifferent to dulcin, although they, like other mammals, prefer sucrose. The rejection threshold for saccharin found in this experiments, .0001 M, is about 2 log steps lower than a previously reported rejection threshold for sodium saccharin. Water produces a taste in cats adapted to their own saliva. The high sodium saccharin threshold may have resulted because the taste of the sodium saccharin was masked by the taste of the water solvent; however, saccharin may also be somewhat more aversive to the cat than sodium saccharin. Saccharin may produce an aversive taste because it stimulates receptor sites sensitive to substances bitter to man as well as those sensitive to sugars. In addition, saccharin may not be an effective stimulus for all sugar-sensitive sites.

  9. Solar dynamic space power system heat rejection

    NASA Technical Reports Server (NTRS)

    Carlson, A. W.; Gustafson, E.; Mclallin, K. L.

    1986-01-01

    A radiator system concept is described that meets the heat rejection requirements of the NASA Space Station solar dynamic power modules. The heat pipe radiator is a high-reliability, high-performance approach that is capable of erection in space and is maintainable on orbit. Results are present of trade studies that compare the radiator system area and weight estimates for candidate advanced high performance heat pipes. The results indicate the advantages of the dual-slot heat pipe radiator for high temperature applications as well as its weight-reduction potential over the range of temperatures to be encountered in the solar dynamic heat rejection systems.

  10. Prefrontal Recruitment During Social Rejection Predicts Greater Subsequent Self-Regulatory Imbalance and Impairment: Neural and Longitudinal Evidence

    PubMed Central

    Chester, David S.; DeWall, C. Nathan

    2014-01-01

    Social rejection impairs self-regulation, yet the neural mechanisms underlying this relationship remain unknown. The right ventrolateral prefrontal cortex (rVLPFC) facilitates self-regulation and plays a robust role in regulating the distress of social rejection. However, recruiting this region’s inhibitory function during social rejection may come at a self-regulatory cost. As supported by prominent theories of self-regulation, we hypothesized that greater rVLPFC recruitment during rejection would predict a subsequent self-regulatory imbalance that favored reflexive impulses (i.e., cravings), which would then impair self-regulation. Supporting our hypotheses, rVLPFC activation during social rejection was associated with greater subsequent nucleus accumbens (NAcc) activation and lesser functional connectivity between the NAcc and rVLPFC to appetitive cues. Over seven days, the effect of daily felt rejection on daily self-regulatory impairment was exacerbated among participants who showed a stronger rVLPFC response to social rejection. This interactive effect was mirrored in the effect of daily felt rejection on heightened daily alcohol cravings. Our findings suggest that social rejection likely impairs self-regulation by recruiting the rVLPFC, which then tips the regulatory balance towards reward-based impulses. PMID:25094019

  11. Rejection of trace organic compounds by high-pressure membranes.

    PubMed

    Kim, T U; Amy, G; Drewes, J E

    2005-01-01

    High-pressure membranes, encompassing reverse osmosis (RO), nanofiltration (NF), and low-pressure RO, may provide an effective treatment barrier for trace organic compounds including disinfection by-products (DBPs), pesticides, solvents, endocrine disrupting compounds (EDCs) and pharmaceutically active compounds (PhACs). The objective is to develop a mechanistic understanding of the rejection of trace organic compounds by high-pressure membranes, based on an integrated framework of compound properties, membrane properties, and operational conditions. Eight trace organic compounds, four DBPs and four chlorinated (halogenated) solvents, are being emphasized during an initial study, based on considerations of compound properties, occurrence, and health effects (regulations). Four polyamide FilmTec membranes; three reverse osmosis/RO (BW-400, LE-440, XLE-440) and one nanofiltration/NF (NF-90); are being characterized according to pure water permeability (PWP), molecular weight cutoff (MWCO), hydrophobicity (contact angle), and surface charge (zeta potential). It is noteworthy that rejections of compounds of intermediate hydrophobicity by the candidate membranes were observed to be less than salt rejections reported for these membranes, suggesting that transport of these solutes through these membranes is facilitated by solute-membrane interactions. We are continuing with diffusion cell measurements to describe solute-membrane interactions by estimation of diffusion coefficients through membranes pores, either hindered or facilitated.

  12. B-Cell-Mediated Strategies to Fight Chronic Allograft Rejection

    PubMed Central

    Dalloul, Ali

    2013-01-01

    Solid organs have been transplanted for decades. Since the improvement in graft selection and in medical and surgical procedures, the likelihood of graft function after 1 year is now close to 90%. Nonetheless even well-matched recipients continue to need medications for the rest of their lives hence adverse side effects and enhanced morbidity. Understanding Immune rejection mechanisms, is of increasing importance since the greater use of living-unrelated donors and genetically unmatched individuals. Chronic rejection is devoted to T-cells, however the role of B-cells in rejection has been appreciated recently by the observation that B-cell depletion improve graft survival. By contrast however, B-cells can be beneficial to the grafted tissue. This protective effect is secondary to either the secretion of protective antibodies or the induction of B-cells that restrain excessive inflammatory responses, chiefly by local provision of IL-10, or inhibit effector T-cells by direct cellular interactions. As a proof of concept B-cell-mediated infectious transplantation tolerance could be achieved in animal models, and evidence emerged that the presence of such B-cells in transplanted patients correlate with a favorable outcome. Among these populations, regulatory B-cells constitute a recently described population. These cells may develop as a feedback mechanism to prevent uncontrolled reactivity to antigens and inflammatory stimuli. The difficult task for the clinician, is to quantify the respective ratios and functions of “tolerant” vs. effector B-cells within a transplanted organ, at a given time point in order to modulate B-cell-directed therapy. Several receptors at the B-cell membrane as well as signaling molecules, can now be targeted for this purpose. Understanding the temporal expansion of regulatory B-cells in grafted patients and the stimuli that activate them will help in the future to implement specific strategies aimed at fighting chronic allograft

  13. Antimyosin imaging in cardiac transplant rejection

    SciTech Connect

    Johnson, L.L.; Cannon, P.J. )

    1991-09-01

    Fab fragments of antibodies specific for cardiac myosin have been labeled with indium-111 and injected intravenously into animals and into patients with heart transplants. The antibodies, developed by Khaw, Haber, and co-workers, localize in cardiac myocytes that have been damaged irreversibly by ischemia, myocarditis, or the rejection process. After clearance of the labeled antibody from the cardiac blood pool, planar imaging or single photon emission computed tomography is performed. Scintigrams reveal the uptake of the labeled antimyosin in areas of myocardium undergoing transplant rejection. In animal studies, the degree of antimyosin uptake appears to correlate significantly with the degree of rejection assessed at necropsy. In patients, the correlation between scans and pathologic findings from endomyocardial biopsy is not as good, possibly because of sampling error in the endomyocardial biopsy technique. The scan results at 1 year correlate with either late complications (positive) or benign course (negative). Current limitations of the method include slow blood clearance, long half-life of indium-111, and hepatic uptake. Overcoming these limitations represents a direction for current research. It is possible that from these efforts a noninvasive approach to the diagnosis and evaluation of cardiac transplantation may evolve that will decrease the number of endomyocardial biopsies required to evaluate rejection. This would be particularly useful in infants and children. 31 references.

  14. Automatic Rejection Of Multimode Laser Pulses

    NASA Technical Reports Server (NTRS)

    Tratt, David M.; Menzies, Robert T.; Esproles, Carlos

    1991-01-01

    Characteristic modulation detected, enabling rejection of multimode signals. Monitoring circuit senses multiple longitudinal mode oscillation of transversely excited, atmospheric-pressure (TEA) CO2 laser. Facility developed for inclusion into coherent detection laser radar (LIDAR) system. However, circuit described of use in any experiment where desireable to record data only when laser operates in single longitudinal mode.

  15. Development of enhanced sulfur rejection processes

    SciTech Connect

    Yoon, R.H.; Luttrell, G.; Adel, G.; Richardson, P.E.

    1993-03-23

    Research at Virginia Tech led to two complementary concepts for improving the removal of inorganic sulfur from much of the Eastern US coals. One controls the surface properties of coal pyrite (FeS[sub 2]) by electrochemical-.potential control, referred to as the Electrochemically Enhanced Sulfur Rejection (EESR) Process: The second controls the flotation of middlings, i.e., particles composed of pyrite with coal inclusions by using polymeric reagents to react with pyrite and convert the middlings to hydrophilic particles, and is termed the Polymer Enhanced Sulfur Rejection (PESR) Process. These new concepts are based on recent research establishing the two main reasons why flotation fails to remove more than about 50% of the pyritic sulfur from coal: superficial oxidization of liberated pyrite to form polysulfide oxidation products so that a part of the liberated pyrite floats with the coal; and hydrophobic coal inclusions in the middlings dominating their flotation so that the middlings also float with the coal. These new pyritic-sulfur rejection processes do not require significant modifications of existing coal preparation facilities, enhancing their adoptability by the coal industry. It is believed that they can be used simultaneously to achieve both free pyrite and locked pyrite rejection.

  16. Development of enhanced sulfur rejection processes

    SciTech Connect

    Yoon, R.H.; Luttrell, G.H.; Adel, G.T.; Richardson, P.E.

    1996-03-01

    Research at Virginia Tech led to the development of two complementary concepts for improving the removal of inorganic sulfur from many eastern U.S. coals. These concepts are referred to as Electrochemically Enhanced Sulfur Rejection (EESR) and Polymer Enhanced Sulfur Rejection (PESR) processes. The EESR process uses electrochemical techniques to suppress the formation of hydrophobic oxidation products believed to be responsible for the floatability of coal pyrite. The PESR process uses polymeric reagents that react with pyrite and convert floatable middlings, i.e., composite particles composed of pyrite with coal inclusions, into hydrophilic particles. These new pyritic-sulfur rejection processes do not require significant modifications to existing coal preparation facilities, thereby enhancing their adoptability by the coal industry. It is believed that these processes can be used simultaneously to maximize the rejection of both well-liberated pyrite and composite coal-pyrite particles. The project was initiated on October 1, 1992 and all technical work has been completed. This report is based on the research carried out under Tasks 2-7 described in the project proposal. These tasks include Characterization, Electrochemical Studies, In Situ Monitoring of Reagent Adsorption on Pyrite, Bench Scale Testing of the EESR Process, Bench Scale Testing of the PESR Process, and Modeling and Simulation.

  17. Changes in Self-Definition Impede Recovery From Rejection.

    PubMed

    Howe, Lauren C; Dweck, Carol S

    2016-01-01

    Previous research highlights how adept people are at emotional recovery after rejection, but less research has examined factors that can prevent full recovery. In five studies, we investigate how changing one's self-definition in response to rejection causes more lasting damage. We demonstrate that people who endorse an entity theory of personality (i.e., personality cannot be changed) report alterations in their self-definitions when reflecting on past rejections (Studies 1, 2, and 3) or imagining novel rejection experiences (Studies 4 and 5). Further, these changes in self-definition hinder post-rejection recovery, causing individuals to feel haunted by their past, that is, to fear the recurrence of rejection and to experience lingering negative affect from the rejection. Thus, beliefs that prompt people to tie experiences of rejection to self-definition cause rejection's impact to linger.

  18. Large Solar-Rejection Filter

    NASA Technical Reports Server (NTRS)

    Roberts, William; Sheikh, David; Patrick, Brian

    2007-01-01

    analogous to a bird on a high voltage power wire. Recent analysis confirms that positive floating potentials, ionospheric currents to the EVA suit, can be hazardous. The analysis is wrong in that the ionospheric plasma itself can close the circuit. Parametric analysis of very low voltage exposures (2 to 15 volts) could cause pain and/or involuntary muscle tetani or spinal cord shock. NASA worked with the Naval Health Research Center Detachment Directed Energy Bioeffects Laboratory to examine the affects electrical hazards could have on extravehicular activity using two models. The results of the two computational models were combined to predict areas of the body in which neurons of different diameters would be excited. They predicted that physiologically active current could be conducted across the crew member causing catastrophic hazards. Future work to analyze additional current paths was proposed. The FUSE spectrum of BB Dor, observed in a high state, is modeled with an accretion disk with a very low inclination (possibly lower than 10 degrees). Assuming an average WD mass of 0.8 solar mass leads to a distance of the order of approximately 650pc, consistent with the extremely low galactic reddening in its direction, and a mass accretion rate of 10 (exp -9) solar mass a year. The spectrum presents some broad and deep silicon and sulfur absorption lines, indicating that these elements are over-abundant: silicon is 3 times solar, and sulfur is 20 times solar. The FUSE spectrum of BB Dor, observed in a high state, is modeled with an accretion disk with a very low inclination (possibly lower than 10 degrees). Assuming an average WD mass of 0.8 solar mass leads to a distance of the order of approximately 650pc, consistent with the extremely low galactic reddening in its direction, and a mass accretion rate of 10 (exp -9) solar mass a year. The spectrum presents some broad and deep silicon and sulfur absorption lines, indicating that these elements are over-abundant: silicon is

  19. Kin rejection: social signals, neural response and perceived distress during social exclusion.

    PubMed

    Sreekrishnan, Anirudh; Herrera, Tania A; Wu, Jia; Borelli, Jessica L; White, Lars O; Rutherford, Helena J V; Mayes, Linda C; Crowley, Michael J

    2014-11-01

    Across species, kin bond together to promote survival. We sought to understand the dyadic effect of exclusion by kin (as opposed to non-kin strangers) on brain activity of the mother and her child and their subjective distress. To this end, we probed mother-child relationships with a computerized ball-toss game Cyberball. When excluded by one another, rather than by a stranger, both mothers and children exhibited a significantly pronounced frontal P2. Moreover, upon kin rejection versus stranger rejection, both mothers and children showed incremented left frontal positive slow waves for rejection events. Children reported more distress upon exclusion than their own mothers. Similar to past work, relatively augmented negative frontal slow wave activity predicted greater self-reported ostracism distress. This effect, generalized to the P2, was limited to mother- or child-rejection by kin, with comparable magnitude of effect across kin identity (mothers vs. children). For both mothers and children, the frontal P2 peak was significantly pronounced for kin rejection versus stranger rejection. Taken together, our results document the rapid categorization of social signals as kin relevant and the specificity of early and late neural markers for predicting felt ostracism.

  20. Allospecific rejection of MHC class I-deficient bone marrow by CD8 T cells

    PubMed Central

    Haspot, Fabienne; Li, Hao Wei; Lucas, Carrie L.; Fehr, Thomas; Beyaz, Semir; Sykes, Megan

    2014-01-01

    Avoidance of long-term immunosuppression is a desired goal in organ transplantation. Mixed chimerism offers a promising approach to tolerance induction, and we have aimed to develop low-toxicity, non-immunodepleting approaches to achieve this outcome. In a mouse model achieving fully MHC-mismatched allogeneic bone marrow engraftment with minimal conditioning (3 Gy total body irradiation followed by anti-CD154 and T cell-depleted allogeneic bone marrow cells), CD4 T cells in the recipient are required to promote tolerance of pre-existing alloreactive recipient CD8 T cells and thereby permit chimerism induction. We now demonstrate that mice devoid of CD4 T cells and NK cells reject MHC class-I deficient and class I/class II-deficient marrow in a CD8 T cell-dependent manner. This rejection is specific for donor alloantigens, since recipient hematopoiesis is not affected by donor marrow rejection and MHC class-I deficient bone marrow that is syngeneic to the recipient is not rejected. Recipient CD8 T cells are activated and develop cytotoxicity against MHC class I-deficient donor cells in association with rejection. These data implicate a novel CD8 T cell-dependent bone marrow rejection pathway, wherein recipient CD8 T cells indirectly activated by donor alloantigens promote direct killing, in a TCR-independent manner, of class I-deficient donor cells. PMID:24304495

  1. To Accept or Reject? The Impact of Adolescent Rejection Sensitivity on Early Adult Romantic Relationships

    PubMed Central

    Hafen, Christopher A.; Spilker, Ann; Chango, Joanna; Marston, Emily S.; Allen, Joseph P.

    2013-01-01

    Successfully navigating entry into romantic relationships is a key task in adolescence, which sensitivity to rejection can make difficult to accomplish. This study uses multi-informant data from a community sample of 180 adolescents assessed repeatedly from age 16 to 22. Individuals with elevated levels of rejection sensitivity at age 16 were less likely to have a romantic partner at age 22, reported more anxiety and avoidance when they did have relationships, and were observed to be more negative in their interactions with romantic partners. In addition, females whose rejection sensitivity increased during late adolescence were more likely to adopt a submissive pattern within adult romantic relationships, further suggesting a pattern in which rejection sensitivity forecasts difficulties. PMID:24729668

  2. Detection of rejection of canine orthotopic cardiac allografts with indium-111 lymphocytes and gamma scintigraphy

    SciTech Connect

    Eisen, H.J.; Rosenbloom, M.; Laschinger, J.C.; Saffitz, J.E.; Cox, J.L.; Sobel, B.E.; Bolman, R.M. III; Bergmann, S.R.

    1988-07-01

    Previous studies have demonstrated the feasibility of detecting canine heterotopic cardiac allograft rejection scintigraphically after administration of 111In lymphocytes. To determine whether the approach is capable of detecting rejection in orthotopic cardiac transplants in which labeled lymphocytes circulating in the blood pool may reduce sensitivity, the present study was performed in which canine orthotopic cardiac transplants were evaluated in vivo. Immunosuppression was maintained with cyclosporine A (10-20 mg/kg/day) and prednisone (1 mg/kg/day) for 2 wk after transplantation. Subsequently, therapy was tapered. Five successful allografts were evaluated scintigraphically every 3 days after administration of 100-350 microCi 111In autologous lymphocytes. Correction for labeled lymphocytes circulating in the blood pool, but not actively sequestered in the allografts was accomplished by administering 3-6 mCi 99mTc autologous erythrocytes and employing a previously validated blood-pool activity correction technique. Cardiac infiltration of labeled lymphocytes was quantified as percent indium excess (%IE), scintigraphically detectable 111In in the transplant compared with that in blood, and results were compared with those of concomitantly performed endomyocardial biopsy. Scintigraphic %IE for hearts not undergoing rejection manifest histologically was 0.7 +/- 0.4. Percent IE for rejecting hearts was 6.8 +/- 4.0 (p less than 0.05). Scintigraphy detected each episode of rejection detected by biopsy. Scintigraphic criteria for rejection (%IE greater than 2 s.d. above normal) were not manifest in any study in which biopsies did not show rejection. Since scintigraphic results with 111In-labeled lymphocytes were concordant with biopsy results in orthotopic cardiac transplants, noninvasive detection of graft rejection in patients should be attainable with the approach developed.

  3. Inflammatory triggers of acute rejection of organ allografts

    PubMed Central

    Mori, Daniel N.; Kreisel, Daniel; Fullerton, James N.; Gilroy, Derek W.; Goldstein, Daniel R.

    2014-01-01

    Summary Solid organ transplantation is a vital therapy for end stage diseases. Decades of research has established that the components of the adaptive immune system are critical for transplant rejection, but the role of the innate immune system in organ transplantation is just emerging. Accumulating evidence indicates that the innate immune system is activated at the time of organ implantation by the release of endogenous inflammatory triggers. This review discusses the nature of these triggers in organ transplantation and also potential mediators that may enhance inflammation resolution after organ implantation. PMID:24517430

  4. An observer with controller to detect and reject disturbances

    NASA Astrophysics Data System (ADS)

    de Jesús Rubio, José; Meléndez, Fidel; Figueroa, Maricela

    2014-03-01

    In this paper, a novel states observer is designed. This observer not only estimates the states, but also detects the disturbances by creating estimated signals. Then, both the observed states and detected disturbances are used in a control law to reject the disturbances, avoiding the requirement to know the states and disturbances. The observer is designed by the combination of the poles assignation and geometric techniques. Both the observer and controller work simultaneously. The proposed method is applied in an active suspension system and a liquid-level hydraulic system.

  5. Mechanisms of allograft rejection of corneal endothelium

    SciTech Connect

    Tagawa, Y.; Silverstein, A.M.; Prendergast, R.A.

    1982-07-01

    The local intraocular graft-vs.-host (GVH) reaction, involving the destruction of the corneal endothelial cells of the rabbit host by sensitized donor lymphoid cells, has been used to study the mechanism of corneal allograft rejection. Pretreatment of donor cells with a specific mouse monoclonal hybridoma anti-T cell antibody and complement suppresses the destructive reaction, suggesting that a cellular-immune mechanism is primarily involved. Pretreatment of donor cells with mitomycin-C completely abolishes the local GVH reaction, indicating that the effector lymphocytes must undergo mitosis within the eye before they can engage in target cell destruction. Finally, studies of the local GVH reaction in irradiated leukopenic recipients or in preinflamed rabbit eyes suggest that host leukocytes may contribute nonspecifically to enhance the destructive process. These studies show that the local ocular GVH reaction may provide a useful model for the study of the mechanisms involved in the rejection of corneal allografts.

  6. Background Rejection in the ARA Experiment

    NASA Astrophysics Data System (ADS)

    Pfendner, Carl

    2017-03-01

    The Askaryan Radio Array (ARA) is a radio frequency observatory under construction at the South Pole that is searching for ultrahigh energy neutrinos via the Askaryan effect. Thermal fluctuations currently dominate the trigger-level background for the observatory and anthropogenic sources also introduce a significant source of noise. By taking advantage of the observatory's regular geometry and the expected coincident nature of the RF signals arriving from neutrino-induced events, this background can be filtered efficiently. This contribution will discuss techniques developed for the ARA analyses to reject these thermal signals, to reject anthropogenic backgrounds, and to search for neutrino-induced particle showers in the Antarctic ice. The results of a search for neutrinos from GRBs using the prototype station using some of these techniques will be presented.

  7. Children reject inequity out of spite.

    PubMed

    McAuliffe, Katherine; Blake, Peter R; Warneken, Felix

    2014-12-01

    When confronted with inequality, human children and adults sacrifice personal gain to reduce the pay-offs of other individuals, exhibiting apparently spiteful motivations. By contrast, sacrifice of personal gain by non-human animals is often interpreted as frustration. Spite may thus be a uniquely human motivator. However, to date, no empirical study has demonstrated that psychological spite actually drives human behaviour, leaving the motivation for inequity aversion unclear. Here, we ask whether 4- to 9-year-old children and adults reject disadvantageous inequity (less for self, more for peer) out of spite or frustration. We show that children, but not adults, are more likely to reject disadvantageous allocations when doing so deprives their peer of a better reward (spite) than when their peer has already received the better reward (frustration). Spiteful motivations are thus present early in childhood and may be a species-specific component of humans' developing cooperative and competitive behaviour.

  8. Optical communication noise rejection using corelated photons

    NASA Technical Reports Server (NTRS)

    Jackson, D.; Hockney, G. M.; Dowling, J. P.

    2002-01-01

    This paper describes a completely new way to perform noise rejection using photons correlated through quantum entanglement to improve an optical communications link in the presence of uncorrelated noise. In particular, a detailed analysis is made of the case where a classical link would be saturated by an intense background, such as when a satellite is in front of the sun, and identifies where the quantum correlating system has superior performance.

  9. 43 CFR 3141.6-6 - Rejection of bid.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ..., DEPARTMENT OF THE INTERIOR MINERALS MANAGEMENT (3000) LEASING IN SPECIAL TAR SAND AREAS Leasing in Special Tar Sand Areas § 3141.6-6 Rejection of bid. If the high bid is rejected for failure by the...

  10. 43 CFR 3141.6-6 - Rejection of bid.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ..., DEPARTMENT OF THE INTERIOR MINERALS MANAGEMENT (3000) LEASING IN SPECIAL TAR SAND AREAS Leasing in Special Tar Sand Areas § 3141.6-6 Rejection of bid. If the high bid is rejected for failure by the...

  11. 43 CFR 3141.6-6 - Rejection of bid.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ..., DEPARTMENT OF THE INTERIOR MINERALS MANAGEMENT (3000) LEASING IN SPECIAL TAR SAND AREAS Leasing in Special Tar Sand Areas § 3141.6-6 Rejection of bid. If the high bid is rejected for failure by the...

  12. 43 CFR 3141.6-6 - Rejection of bid.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ..., DEPARTMENT OF THE INTERIOR MINERALS MANAGEMENT (3000) LEASING IN SPECIAL TAR SAND AREAS Leasing in Special Tar Sand Areas § 3141.6-6 Rejection of bid. If the high bid is rejected for failure by the...

  13. Gender-based rejection sensitivity and academic self-silencing in women.

    PubMed

    London, Bonita; Downey, Geraldine; Romero-Canyas, Rainer; Rattan, Aneeta; Tyson, Diana

    2012-05-01

    Building on prior work on rejection sensitivity, we propose a social-cognitive model of gender-based rejection sensitivity (Gender RS) to account for individual differences in how women perceive and cope with gender-based evaluative threats in competitive, historically male institutions. Study 1 develops a measure of Gender RS, defined as anxious expectations of gender-based rejection. Studies 2-5 support the central predictions of the model: Gender RS is associated with increased perceptions of gender-based threats and increased coping by self-silencing--responses that reinforce feelings of alienation and diminished motivation. Study 2 shows that Gender RS is distinct from overall sensitivity to rejection or perceiving the world through the lens of gender. Study 3 shows that Gender RS becomes activated specifically when gender-based rejection is a plausible explanation for negative outcomes. Study 4 provides experimental evidence that Gender RS predicts lower academic self-confidence, greater expectations of bias, and avoidance of opportunities for further help from a weakness-focused expert evaluator. Study 5 tests the Gender RS model in situ, using daily diaries to track women's experiences during the first weeks in a highly competitive law school. Implications for women's coping with the subtle nature of contemporary sexism are discussed as well as the importance of institution-level checks to prevent the costs of gender-based rejection.

  14. Parental Acceptance-Rejection Theory and the Phylogenetic Model.

    ERIC Educational Resources Information Center

    Rohner, Ronald P.

    Guided by specific theoretical and methodological points of view--the phylogenetic perspective and the universalistic approach respectively--this paper reports on a worldwide study of the antecedents and effects of parental acceptance and rejection. Parental acceptance-rejection theory postulates that rejected children throughout our species share…

  15. Paying To Belong: When Does Rejection Trigger Ingratiation?

    PubMed Central

    Romero-Canyas, Rainer; Downey, Geraldine; Reddy, Kavita S.; Rodriguez, Sylvia; Cavanaugh, Timothy J.; Pelayo, Rosemary

    2010-01-01

    Societies and social scientists have long held the belief that exclusion induces ingratiation and conformity, an idea in contradiction with robust empirical evidence linking rejection with hostility and aggression. The classic literatures on ingratiation and conformity help resolve this contradiction by identifying circumstances under which rejection may trigger efforts to ingratiate. Jointly, findings from these literatures suggest that when people are given an opportunity to impress their rejecters, ingratiation is likely after rejection experiences that are harsh and that occur in important situations that threaten the individual’s self-definition. Four studies tested the hypothesis that people high in rejection sensitivity, and therefore dispositionally concerned about rejection, will utilize opportunities to ingratiate after harsh rejection in situations that are self-defining. In three studies of situations that are particularly self-defining for men, rejection predicted ingratiation among men (but not women) who were high in rejection sensitivity. In a fourth study, harsh rejection in a situation particularly self-defining for women predicted ingratiation among highly rejection-sensitive women (but not men). These findings help identify the specific circumstances under which people are willing to act in socially desirable ways toward those who have rejected them harshly. PMID:20649367

  16. Cultural Rejection and Re-identification in Minority Group Members.

    ERIC Educational Resources Information Center

    Diller, Jerry V.

    There is little consistent research available on cultural rejection and re-identification in minority group members, but this report uses case study material to extrapolate three general factors precipitating rejection: self-hatred and negative chauvinism, quality of ethnic experience and rejection of religious experience. A four-step model for…

  17. 28 CFR 540.13 - Notification of rejections.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... CONTACT WITH PERSONS IN THE COMMUNITY Correspondence § 540.13 Notification of rejections. When correspondence is rejected, the Warden shall notify the sender in writing of the rejection and the reasons for... shall refer an appeal to an official other than the one who originally disapproved the...

  18. 28 CFR 540.13 - Notification of rejections.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... CONTACT WITH PERSONS IN THE COMMUNITY Correspondence § 540.13 Notification of rejections. When correspondence is rejected, the Warden shall notify the sender in writing of the rejection and the reasons for... shall refer an appeal to an official other than the one who originally disapproved the...

  19. 28 CFR 540.13 - Notification of rejections.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... CONTACT WITH PERSONS IN THE COMMUNITY Correspondence § 540.13 Notification of rejections. When correspondence is rejected, the Warden shall notify the sender in writing of the rejection and the reasons for... shall refer an appeal to an official other than the one who originally disapproved the...

  20. 28 CFR 540.13 - Notification of rejections.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... CONTACT WITH PERSONS IN THE COMMUNITY Correspondence § 540.13 Notification of rejections. When correspondence is rejected, the Warden shall notify the sender in writing of the rejection and the reasons for... shall refer an appeal to an official other than the one who originally disapproved the...

  1. 28 CFR 540.13 - Notification of rejections.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... CONTACT WITH PERSONS IN THE COMMUNITY Correspondence § 540.13 Notification of rejections. When correspondence is rejected, the Warden shall notify the sender in writing of the rejection and the reasons for... shall refer an appeal to an official other than the one who originally disapproved the...

  2. Nitration and Inactivation of Manganese Superoxide Dismutase in Chronic Rejection of Human Renal Allografts

    NASA Astrophysics Data System (ADS)

    MacMillan-Crow, L. A.; Crow, John P.; Kerby, Jeffrey D.; Beckman, Joseph S.; Thompson, John A.

    1996-10-01

    Inflammatory processes in chronic rejection remain a serious clinical problem in organ transplantation. Activated cellular infiltrate produces high levels of both superoxide and nitric oxide. These reactive oxygen species interact to form peroxynitrite, a potent oxidant that can modify proteins to form 3-nitrotyrosine. We identified enhanced immunostaining for nitrotyrosine localized to tubular epithelium of chronically rejected human renal allografts. Western blot analysis of rejected tissue demonstrated that tyrosine nitration was restricted to a few specific polypeptides. Immunoprecipitation and amino acid sequencing techniques identified manganese superoxide dismutase, the major antioxidant enzyme in mitochondria, as one of the targets of tyrosine nitration. Total manganese superoxide dismutase protein was increased in rejected kidney, particularly in the tubular epithelium; however, enzymatic activity was significantly decreased. Exposure of recombinant human manganese superoxide dismutase to peroxynitrite resulted in a dose-dependent (IC50 = 10 μ M) decrease in enzymatic activity and concomitant increase in tyrosine nitration. Collectively, these observations suggest a role for peroxynitrite during development and progression of chronic rejection in human renal allografts. In addition, inactivation of manganese superoxide dismutase by peroxynitrite may represent a general mechanism that progressively increases the production of peroxynitrite, leading to irreversible oxidative injury to mitochondria.

  3. Immunological analogy between allograft rejection, recurrent abortion and pre-eclampsia - the same basic mechanism?

    PubMed

    Wilczyński, Jacek R

    2006-07-01

    There are still controversies concerning the role of immunological mechanisms engaged both in recurrent abortions (RA) and pre-eclampsia (PE). According to some opinions, recurrent miscarriage is comparable to organ-specific autoimmune disease. Analysis of immune reactions shows that graft rejection shares many similar mechanisms with RA and PE. This fact allows us to conclude that rejection of transplanted alloantigenic organs and pregnancy loss have probably the same evolutionary origin. Subsets and functions of immunocompetent cells (T CD4, suppressor gammadeltaT, cytotoxic T CD8, Treg, Tr1, uterine NK cells), over-activation of innate immunity (activation of NK cytotoxic cells, macrophages, neutrophils and complement), changes of Th1/Th2 cytokine balance (IL-2, IL-12, IL-15, IL-18, IFNgamma, TNFalpha vs. IL-4, IL-10, TGFbeta), importance of HLA-G molecule, CD200/CD200R interaction, over-expression of adhesion molecules, fgl2 prothrombinase activation and stimulation of IDO and HO expression, all suggest that RA and PE are syndromes of fetal allograft rejection, and not organ-specific autoimmune diseases. According to that supposition, an analogy might exist between acute graft rejection and recurrent abortion, and between chronic graft rejection and pre-eclampsia.

  4. Genetic Polymorphism of Interferon Regulatory Factor 5 (IRF5) Correlates with Allograft Acute Rejection of Liver Transplantation

    PubMed Central

    Yu, Xiaobo; Wei, Bajin; Dai, Yifan; Zhang, Min; Wu, Jian; Xu, Xiao; Jiang, Guoping; Zheng, Shusen; Zhou, Lin

    2014-01-01

    Background Although liver transplantation is one of the most efficient curative therapies of end stage liver diseases, recipients may suffer liver graft loss opst-operation. IRF-5, a member of Interferon Regulatory Factors, functions as a key regulator in TLR4 cascade, and is capable of inducing inflammatory cytokines. Although TLR4 has been proved to contribute to acute allograft rejection, including after liver transplantation, the correlation between IRF5 gene and acute rejection has not been elucidated yet. Methods The study enrolled a total of 289 recipients, including 39 females and 250 males, and 39 recipients developed acute allograft rejection within 6 months post-transplantation. The allograft rejections were diagnosed by liver biopsies. Genome DNA of recipients was extracted from pre-operative peripheral blood. Genotyping of IRF-5, including rs3757385, rs752637 and rs11761199, was performed, followed by SNP frequency and Hardy-Weinberg equilibrium analysis. Results The genetic polymorphism of rs3757385 was found associated with acute rejection. G/G homozygous individuals were at higher risk of acute rejection, with a P value of 0.042 (OR = 2.34 (1.07–5.10)). Conclusions IRF5, which transcriptionally activates inflammatory cytokines, is genetically associated with acute rejection and might function as a risk factor for acute rejection of liver transplantations. PMID:24788560

  5. LATE ACUTE REJECTION IN LIVER TRANSPLANT: A SYSTEMATIC REVIEW

    PubMed Central

    NACIF, Lucas Souto; PINHEIRO, Rafael Soares; PÉCORA, Rafael Antônio de Arruda; DUCATTI, Liliana; ROCHA-SANTOS, Vinicius; ANDRAUS, Wellington; D'ALBUQUERQUE, Luiz Carneiro

    2015-01-01

    Introduction: Late acute rejection leads to worse patient and graft survival after liver transplantation. Aim: To analyze the reported results published in recent years by leading transplant centers in evaluating late acute rejection and update the clinical manifestations, diagnosis and treatment of liver transplantation. Method: Systematic literature review through Medline-PubMed database with headings related to late acute rejection in articles published until November 2013 was done. Were analyzed demographics, immunosuppression, rejection, infection and graft and patient survival rates. Results: Late acute rejection in liver transplantation showed poor results mainly regarding patient and graft survival. Almost all of these cohort studies were retrospective and descriptive. The incidence of late acute rejection varied from 7-40% in these studies. Late acute rejection was one cause for graft loss and resulted in different outcomes with worse patient and graft survival after liver transplant. Late acute rejection has been variably defined and may be a cause of chronic rejection with worse prognosis. Late acute rejection occurs during a period in which the goal is to maintain lower immunosuppression after liver transplantation. Conclusion: The current articles show the importance of late acute rejection. The real benefit is based on early diagnosis and adequate treatment at the onset until late follow up after liver transplantation. PMID:26537150

  6. Dispositional mindfulness and rejection sensitivity: The critical role of nonjudgment.

    PubMed

    Peters, Jessica R; Eisenlohr-Moul, Tory A; Smart, Laura M

    2016-04-01

    The pain of rejection is a crucial component of normal social functioning; however, heightened sensitivity to rejection can be impairing in numerous ways. Mindfulness-based interventions have been effective with several populations characterized by elevated sensitivity to rejection; however, the relationship between mindfulness and rejection sensitivity has been largely unstudied. The present study examines associations between rejection sensitivity and multiple dimensions of dispositional mindfulness, with the hypothesis that a nonjudgmental orientation to inner experiences would be both associated with decreased rejection sensitivity and attenuate the impact of sensitivity to rejection on general negative affect. A cross-sectional sample of undergraduates (n = 451) completed self-report measures of rejection sensitivity, dispositional mindfulness, and trait-level negative affect. Significant zero-order correlations and independent effects were observed between most facets of dispositional mindfulness and rejection sensitivity, with nonjudging demonstrating the largest effects. As predicted, rejection sensitivity was associated with negative affectivity for people low in nonjudging (β = .27, t = 5.12, p < .001) but not for people high in nonjudging (β = .06, t = .99, p = .324). These findings provide preliminary support for mindfulness, specifically the nonjudging dimension, as a protective factor against rejection sensitivity and its effects on affect.

  7. Using Compton scattering for random coincidence rejection

    NASA Astrophysics Data System (ADS)

    Kolstein, M.; Chmeissani, M.

    2016-12-01

    The Voxel Imaging PET (VIP) project presents a new approach for the design of nuclear medicine imaging devices by using highly segmented pixel CdTe sensors. CdTe detectors can achieve an energy resolution of ≈ 1% FWHM at 511 keV and can be easily segmented into submillimeter sized voxels for optimal spatial resolution. These features help in rejecting a large part of the scattered events from the PET coincidence sample in order to obtain high quality images. Another contribution to the background are random events, i.e., hits caused by two independent gammas without a common origin. Given that 60% of 511 keV photons undergo Compton scattering in CdTe (i.e. 84% of all coincidence events have at least one Compton scattering gamma), we present a simulation study on the possibility to use the Compton scattering information of at least one of the coincident gammas within the detector to reject random coincidences. The idea uses the fact that if a gamma undergoes Compton scattering in the detector, it will cause two hits in the pixel detectors. The first hit corresponds to the Compton scattering process. The second hit shall correspond to the photoelectric absorption of the remaining energy of the gamma. With the energy deposition of the first hit, one can calculate the Compton scattering angle. By measuring the hit location of the coincident gamma, we can construct the geometric angle, under the assumption that both gammas come from the same origin. Using the difference between the Compton scattering angle and the geometric angle, random events can be rejected.

  8. Mechanisms of solute rejection in solvent resistant nanofiltration: the effect of solvent on solute rejection.

    PubMed

    Darvishmanesh, Siavash; Degrève, Jan; Van der Bruggen, Bart

    2010-10-28

    The separation performance of solvent resistant nanofiltration (SRNF) membranes was studied in a systematic way to elucidate the complex mechanisms involved in rejection of solutes. Rejection of three dyes (Sudan II, Sudan Black, Sudan 408) from common organic solvents (methanol, ethanol, acetone, methyl ethyl ketone, toluene and n-hexane) through a polyimide based SRNF membrane, STARMEM™122, was studied. It was found that the rejection of the STARMEM™122 membrane was lower than that indicated by the manufacturer. The experimental observations for Sudan II were not promising for the rejection study as they were lower than expected. Sudan Black and Sudan 408, which are larger solutes than Sudan II, provided more interesting insights. The effects of the solvent on the membrane and solute were studied separately. A higher permeation rate of ketones and alcohols was observed, while permeabilities of non-polar solvents were low which shows that this membrane shows higher affinity toward semi-polar solvents (alcohols, ketones). The effect of the solvent on the solute's rejection, based on the results for Sudan Black and Sudan 408, was studied for solvents in the same chemical groups, since the membrane showed a similar separation performance for solvents with similar functional groups (e.g. alcohols). The effect of solvent on solute molecular size was investigated by using simulation with Molecular Dynamics. It was shown that the effective size of a molecule is dependent on the solvent due to solvation and hydration of the solute by the solvent. The size of the solute in the solvent belonging to a similar family was studied separately. It was clear that the rejection was influenced by molecular size of the solute in the same group of solvents. A surprising negative rejection of solutes was achieved for n-hexane. Although solutes in n-hexane have higher volume compared to those in other solvents, the affinity between the solute and membrane increases the solute

  9. Rejected asylum seekers: the problem of return.

    PubMed

    Noll, G

    1999-01-01

    "During this decade the return of rejected asylum seekers has become an issue of increasing concern to major asylum states in the industrialized world. This article exposes the various political and legal approaches taken by returning states as well as the constraints emerging from human rights law. As a rigid control paradigm and related enforcement practices entail a considerable risk of human rights violations, it seems reasonable to focus on measures enhancing the voluntary compliance of all actors involved with norms governing return." (EXCERPT)

  10. Confidence and rejection in automatic speech recognition

    NASA Astrophysics Data System (ADS)

    Colton, Larry Don

    Automatic speech recognition (ASR) is performed imperfectly by computers. For some designated part (e.g., word or phrase) of the ASR output, rejection is deciding (yes or no) whether it is correct, and confidence is the probability (0.0 to 1.0) of it being correct. This thesis presents new methods of rejecting errors and estimating confidence for telephone speech. These are also called word or utterance verification and can be used in wordspotting or voice-response systems. Open-set or out-of-vocabulary situations are a primary focus. Language models are not considered. In vocabulary-dependent rejection all words in the target vocabulary are known in advance and a strategy can be developed for confirming each word. A word-specific artificial neural network (ANN) is shown to discriminate well, and scores from such ANNs are shown on a closed-set recognition task to reorder the N-best hypothesis list (N=3) for improved recognition performance. Segment-based duration and perceptual linear prediction (PLP) features are shown to perform well for such ANNs. The majority of the thesis concerns vocabulary- and task-independent confidence and rejection based on phonetic word models. These can be computed for words even when no training examples of those words have been seen. New techniques are developed using phoneme ranks instead of probabilities in each frame. These are shown to perform as well as the best other methods examined despite the data reduction involved. Certain new weighted averaging schemes are studied but found to give no performance benefit. Hierarchical averaging is shown to improve performance significantly: frame scores combine to make segment (phoneme state) scores, which combine to make phoneme scores, which combine to make word scores. Use of intermediate syllable scores is shown to not affect performance. Normalizing frame scores by an average of the top probabilities in each frame is shown to improve performance significantly. Perplexity of the wrong

  11. Solar Rejection Filter for Large Telescopes

    NASA Technical Reports Server (NTRS)

    Hemmati, Hamid; Lesh, James

    2009-01-01

    To reject solar radiation photons at the front aperture for large telescopes, a mosaic of large transmission mode filters is placed in front of the telescope or at the aperture of the dome. Filtering options for effective rejection of sunlight include a smaller filter down-path near the focus of the telescope, and a large-diameter filter located in the front of the main aperture. Two types of large filters are viable: reflectance mode and transmittance mode. In the case of reflectance mode, a dielectric coating on a suitable substrate (e.g. a low-thermal-expansion glass) is arranged to reflect only a single, narrow wavelength and to efficiently transmit all other wavelengths. These coatings are commonly referred to as notch filter. In this case, the large mirror located in front of the telescope aperture reflects the received (signal and background) light into the telescope. In the case of transmittance mode, a dielectric coating on a suitable substrate (glass, sapphire, clear plastic, membrane, and the like) is arranged to transmit only a single wavelength and to reject all other wavelengths (visible and near IR) of light. The substrate of the large filter will determine its mass. At first glance, a large optical filter with a diameter of up to 10 m, located in front of the main aperture, would require a significant thickness to avoid sagging. However, a segmented filter supported by a structurally rugged grid can support smaller filters. The obscuration introduced by the grid is minimal because the total area can be made insignificant. This configuration can be detrimental to a diffraction- limited telescope due to diffraction effects at the edges of each sub-panel. However, no discernable degradation would result for a 20 diffraction-limit telescope (a photon bucket). Even the small amount of sagging in each subpanel should have minimal effect in the performance of a non-diffraction limited telescope because the part has no appreciable optical power. If the

  12. Relating rejection of trace organic contaminants to membrane properties in forward osmosis: measurements, modelling and implications.

    PubMed

    Xie, Ming; Nghiem, Long D; Price, William E; Elimelech, Menachem

    2014-02-01

    This study elucidates the relationship between membrane properties and the rejection of trace organic contaminants (TrOCs) in forward osmosis (FO). An asymmetric cellulose triacetate (CTA) and a thin-film composite (TFC) polyamide FO membrane were used for this investigation. The effective average pore radius (rp), selective barrier thickness over porosity parameter (l/ε), surface charge, support layer structural parameter (S), pure water permeability coefficient (A) and salt (NaCl) permeability coefficient (B) of the two membranes were systematically characterised. Results show that measured rejection of TrOCs as a function of permeate water flux can be well described by the pore hindrance transport model. This observation represents the first successful application of this model, which was developed for pressure-driven nanofiltration, to an osmotically-driven membrane process. The rejection of charged TrOCs by the CTA and TFC membranes was high and was governed by both electrostatic repulsion and steric hindrance. The TFC membrane exhibited higher rejection of neutral TrOCs with low molecular weight than the CTA membrane, although the estimated pore size of the TFC membrane (0.42 nm) was slightly larger than that of the CTA membrane (0.37 nm). This higher rejection of neutral TrOCs by the TFC membrane is likely attributed to its active layer properties, namely a more effective active layer structure, as indicated by a larger l/ε parameter, and pore hydration induced by the negative surface charge.

  13. Role of Memory T Cells in Allograft Rejection and Tolerance

    PubMed Central

    Benichou, Gilles; Gonzalez, Bruno; Marino, Jose; Ayasoufi, Katayoun; Valujskikh, Anna

    2017-01-01

    Memory T cells are characterized by their low activation threshold, robust effector functions, and resistance to conventional immunosuppression and costimulation blockade. Unlike their naïve counterparts, memory T cells reside in and recirculate through peripheral non-lymphoid tissues. Alloreactive memory T cells are subdivided into different categories based on their origins, phenotypes, and functions. Recipients whose immune systems have been directly exposed to allogeneic major histocompatibility complex (MHC) molecules display high affinity alloreactive memory T cells. In the absence of any prior exposure to allogeneic MHC molecules, endogenous alloreactive memory T cells are regularly generated through microbial infections (heterologous immunity). Regardless of their origin, alloreactive memory T cells represent an essential element of the allograft rejection process and a major barrier to tolerance induction in clinical transplantation. This article describes the different subsets of alloreactive memory T cells involved in transplant rejection and examine their generation, functional properties, and mechanisms of action. In addition, we discuss strategies developed to target deleterious allospecific memory T cells in experimental animal models and clinical settings. PMID:28293238

  14. The 'fine line' of heat rejection.

    PubMed

    Carruthers, Phillip

    2010-09-01

    Selection of heat rejection equipment has traditionally entailed a choice between the higher energy consumption of an air-cooled solution, and the high water consumption of a water-cooled solution. This paper examines advancement in heat rejection technology and the way it can be applied to air conditioning and refrigeration plant in healthcare and other facilities. It also examines field difficulties encountered in pipework design as the knowledge and experience levels of engineers designing systems with remote condensers diminish. With plant larger than 1,000 kW, the only option previously has been water-cooled solutions using an array of cooling towers, or perhaps an evaporative condenser, since air-cooled plant involved massive volumes of chemical refrigerant, which posed a problem ecologically. An additional hurdle was problems associated with limitations on pipe lengths for refrigeration plant. The advent of adiabatically pre-cooled closed circuit coolers and air-cooled condensers has introduced an alternative to cooling towers that offers the potential for "water-cooled performance" from an air-cooled solution with no serious threat of Legionella contamination. However, each application needs to be considered on a case-by-case basis. The paper examines, in detail, the impact of adiabatic pre-cooling, with recent examples of its application in sub-tropical Brisbane providing evidence of the potential performance achievable.

  15. Frontal-Brainstem Pathways Mediating Placebo Effects on Social Rejection.

    PubMed

    Koban, Leonie; Kross, Ethan; Woo, Choong-Wan; Ruzic, Luka; Wager, Tor D

    2017-03-29

    Placebo treatments can strongly affect clinical outcomes, but research on how they shape other life experiences and emotional well-being is in its infancy. We used fMRI in humans to examine placebo effects on a particularly impactful life experience, social pain elicited by a recent romantic rejection. We compared these effects with placebo effects on physical (heat) pain, which are thought to depend on pathways connecting prefrontal cortex and periaqueductal gray (PAG). Placebo treatment, compared with control, reduced both social and physical pain, and increased activity in the dorsolateral prefrontal cortex (dlPFC) in both modalities. Placebo further altered the relationship between affect and both dlPFC and PAG activity during social pain, and effects on behavior were mediated by a pathway connecting dlPFC to the PAG, building on recent work implicating opioidergic PAG activity in the regulation of social pain. These findings suggest that placebo treatments reduce emotional distress by altering affective representations in frontal-brainstem systems.SIGNIFICANCE STATEMENT Placebo effects are improvements due to expectations and the socio-medical context in which treatment takes place. Whereas they have been extensively studied in the context of somatic conditions such as pain, much less is known of how treatment expectations shape the emotional experience of other important stressors and life events. Here, we use brain imaging to show that placebo treatment reduces the painful feelings associated with a recent romantic rejection by recruiting a prefrontal-brainstem network and by shifting the relationship between brain activity and affect. Our findings suggest that this brain network may be important for nonspecific treatment effects across a wide range of therapeutic approaches and mental health conditions.

  16. Immune response to UV-induced tumors: mediation of progressor tumor rejection by natural killer cells

    SciTech Connect

    Streeter, P.R.; Fortner, G.W.

    1986-03-01

    Skin tumors induced in mice by chronic ultraviolet (UV) irradiation are highly antigenic and can induce a state of transplantation immunity in syngeneic animals. In the present study, the authors compared the in vitro cytolytic activity of splenic lymphocytes from mice immunized with either regressor or progressor UV-tumors. The results of this comparison implicated tumor-specific cytolytic T (Tc) lymphocytes in rejection of regressor UV-tumors, and revealed that immunization with the progressor UV-tumor 2237 failed to elicit detectable levels of progressor tumor-specific Tc cells even as the tumors rejected. Following in vitro resensitization of spleen cells from either regressor or progressor tumor immune animals, the authors found NK-like lymphocytes with anti-tumor activity. As the authors had not detected cells with this activity in splenic lymphocyte preparations prior to in vitro resensitization, the authors examined lymphocytes from the local tumor environment during the course of progressor tumor rejection for this activity. This analysis revealed NK lymphocytes exhibiting significant levels of cytolytic activity against UV-tumors. These results implicate NK cells as potential effector cells in the rejection of progressor UV-tumors by immune animals, and suggests that these cells may be regulated by T lymphocytes.

  17. CD28 Family and Chronic Rejection: “To Belatacept...and Beyond!”

    PubMed Central

    Silva, Marcos V.; Machado, Juliana R.; Rocha, Laura P.; Castellano, Lúcio R.; Reis, Marlene A.; Corrêa, Rosana R. M.

    2012-01-01

    Kidneys are one of the most frequently transplanted human organs. Immunosuppressive agents may prevent or reverse most acute rejection episodes; however, the graft may still succumb to chronic rejection. The immunological response involved in the chronic rejection process depends on both innate and adaptive immune response. T lymphocytes have a pivotal role in chronic rejection in adaptive immune response. Meanwhile, we aim to present a general overview on the state-of-the-art knowledge of the strategies used for manipulating the lymphocyte activation mechanisms involved in allografts, with emphasis on T-lymphocyte costimulatory and coinhibitory molecules of the B7-CD28 superfamily. A deeper understanding of the structure and function of these molecules improves both the knowledge of the immune system itself and their potential action as rejection inducers or tolerance promoters. In this context, the central role played by CD28 family, especially the relationship between CD28 and CTLA-4, becomes an interesting target for the development of immune-based therapies aiming to increase the survival rate of allografts and to decrease autoimmune phenomena. Good results obtained by the recent development of abatacept and belatacept with potential clinical use aroused better expectations concerning the outcome of transplanted patients. PMID:22720132

  18. Single-chain antibody-mediated intracellular retention of ErbB-2 impairs Neu differentiation factor and epidermal growth factor signaling.

    PubMed Central

    Graus-Porta, D; Beerli, R R; Hynes, N E

    1995-01-01

    ErbB-2 becomes rapidly phosphorylated and activated following treatment of many cell lines with epidermal growth factor (EGF) or Neu differentiation factor (NDF). However, these factors do not directly bind ErbB-2, and its activation is likely to be mediated via transmodulation by other members of the type I/EGF receptor (EGFR)-related family of receptor tyrosine kinases. The precise role of ErbB-2 in the transduction of the signals elicited by EGF and NDF is unclear. We have used a novel approach to study the role of ErbB-2 in signaling through this family of receptors. An ErbB-2-specific single-chain antibody, designed to prevent transit through the endoplasmic reticulum and cell surface localization of ErbB-2, has been expressed in T47D mammary carcinoma cells, which express all four known members of the EGFR family. We show that cell surface expression of ErbB-2 was selectively suppressed in these cells and that the activation of the mitogen-activated protein kinase pathway and p70/p85S6K, induction of c-fos expression, and stimulation of growth by NDF were dramatically impaired. Activation of mitogen-activated protein kinase and p70/p85S6K and induction of c-fos expression by EGF were also significantly reduced. We conclude that in T47D cells, ErbB-2 is a major NDF signal transducer and a potentiator of the EGF signal. Thus, our observations demonstrate that ErbB-2 plays a central role in the type I/EGFR-related family of receptors and that receptor transmodulation represents a crucial step in growth factor signaling. PMID:7532277

  19. Memory Distortion and Its Avoidance: An Event-Related Potentials Study on False Recognition and Correct Rejection

    PubMed Central

    Beato, Maria Soledad

    2016-01-01

    Memory researchers have long been captivated by the nature of memory distortions and have made efforts to identify the neural correlates of true and false memories. However, the underlying mechanisms of avoiding false memories by correctly rejecting related lures remains underexplored. In this study, we employed a variant of the Deese/Roediger-McDermott paradigm to explore neural signatures of committing and avoiding false memories. ERP were obtained for True recognition, False recognition, Correct rejection of new items, and, more importantly, Correct rejection of related lures. With these ERP data, early-frontal, left-parietal, and late right-frontal old/new effects (associated with familiarity, recollection, and monitoring processes, respectively) were analysed. Results indicated that there were similar patterns for True and False recognition in all three old/new effects analysed in our study. Also, False recognition and Correct rejection of related lures activities seemed to share common underlying familiarity-based processes. The ERP similarities between False recognition and Correct rejection of related lures disappeared when recollection processes were examined because only False recognition presented a parietal old/new effect. This finding supported the view that actual false recollections underlie false memories, providing evidence consistent with previous behavioural research and with most ERP and neuroimaging studies. Later, with the onset of monitoring processes, False recognition and Correct rejection of related lures waveforms presented, again, clearly dissociated patterns. Specifically, False recognition and True recognition showed more positive going patterns than Correct rejection of related lures signal and Correct rejection of new items signature. Since False recognition and Correct rejection of related lures triggered familiarity-recognition processes, our results suggest that deciding which items are studied is based more on recollection

  20. A hybrid disturbance rejection control solution for variable valve timing system of gasoline engines.

    PubMed

    Xie, Hui; Song, Kang; He, Yu

    2014-07-01

    A novel solution for electro-hydraulic variable valve timing (VVT) system of gasoline engines is proposed, based on the concept of active disturbance rejection control (ADRC). Disturbances, such as oil pressure and engine speed variations, are all estimated and mitigated in real-time. A feed-forward controller was added to enhance the performance of the system based on a simple and static first principle model, forming a hybrid disturbance rejection control (HDRC) strategy. HDRC was validated by experimentation and compared with an existing manually tuned proportional-integral (PI) controller. The results show that HDRC provided a faster response and better tolerance of engine speed and oil pressure variations.

  1. Total lymphoid irradiation for treatment of intractable cardiac allograft rejection

    SciTech Connect

    Hunt, S.A.; Strober, S.; Hoppe, R.T.; Stinson, E.B. )

    1991-03-01

    The ability of postoperative total lymphoid irradiation to reverse otherwise intractable cardiac allograft rejection was examined in a group of 10 patients in whom conventional rejection therapy (including pulsed steroids and monoclonal or polyclonal anti-T-cell antibody therapy) had failed to provide sustained freedom from rejection. Follow-up periods range from 73 to 1119 days since the start of total lymphoid irradiation. No patient died or sustained serious morbidity because of the irradiation. Three patients have had no further rejection (follow-up periods, 105 to 365 days). Two patients died--one in cardiogenic shock during the course of total lymphoid irradiation, the other with recurrent rejection caused by noncompliance with his medical regimen. Total lymphoid irradiation appears to be a safe and a moderately effective immunosuppressive modality for 'salvage' therapy of cardiac allograft rejection unresponsive to conventional therapy.

  2. The relations between secrecy, rejection sensitivity and autonomy-connectedness.

    PubMed

    Wismeijer, Andreas A J; Van Assen, Marcel A L M; Bekker, Marrie H J

    2014-01-01

    The aim of this study was to examine the effects of two attachment-related variables on secrecy: rejection sensitivity and autonomy-connectedness. We hypothesized that rejection sensitivity is positively associated with secrecy, and autonomy-connectedness negatively with rejection sensitivity and secrecy. These hypotheses were generally corroborated in a sample of 303 university students. Moreover, we found that autonomy-connectedness at least partly explained the association between rejection sensitivity and secrecy. Self-awareness was negatively related to secrecy, suggesting that being aware of what one needs and thinks and being able to realize one's needs in social interactions reduce the tendency to keep secrets. In addition, interesting gender effects were found suggesting that men have a higher tendency to have secrets than women after controlling for the effects of autonomy-connectedness and rejection sensitivity. Our findings deepen the insight into possible reasons behind established associations between rejection sensitivity and secrecy, and may have clinical implications.

  3. Associations among Pubertal Development, Empathic Ability, and Neural Responses While Witnessing Peer Rejection in Adolescence

    ERIC Educational Resources Information Center

    Masten, Carrie L.; Eisenberger, Naomi I.; Pfeifer, Jennifer H.; Colich, Natalie L.; Dapretto, Mirella

    2013-01-01

    Links among concurrent and longitudinal changes in pubertal development and empathic ability from ages 10 to 13 and neural responses while witnessing peer rejection at age 13 were examined in 16 participants. More advanced pubertal development at age 13, and greater longitudinal increases in pubertal development, related to increased activity in…

  4. Rejection Sensitivity, Jealousy, and the Relationship to Interpersonal Aggression.

    PubMed

    Murphy, Anna M; Russell, Gemma

    2016-01-21

    The development and maintenance of interpersonal relationships lead individuals to risk rejection in the pursuit of acceptance. Some individuals are predisposed to experience a hypersensitivity to rejection that is hypothesized to be related to jealous and aggressive reactions within interpersonal relationships. The current study used convenience sampling to recruit 247 young adults to evaluate the relationship between rejection sensitivity, jealousy, and aggression. A mediation model was used to test three hypotheses: Higher scores of rejection sensitivity would be positively correlated to higher scores of aggression (Hypothesis 1); higher scores of rejection sensitivity would be positively correlated to higher scores of jealousy (Hypothesis 2); jealousy would mediate the relationship between rejection sensitivity and aggression (Hypothesis 3). Study results suggest a tendency for individuals with high rejection sensitivity to experience higher levels of jealousy, and subsequently have a greater propensity for aggression, than individuals with low rejection sensitivity. Future research that substantiates a link between hypersensitivity to rejection, jealousy, and aggression may provide an avenue for prevention, education, or intervention in reducing aggression within interpersonal relationships.

  5. WILLIAM SEAL REJECTING AN INCOMPLETE OR IMPROPERLY SET BEARDSLEY AND ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    WILLIAM SEAL REJECTING AN INCOMPLETE OR IMPROPERLY SET BEARDSLEY AND PIPER ROTOMOLD CORMATIC CORE. - Southern Ductile Casting Company, Core Making, 2217 Carolina Avenue, Bessemer, Jefferson County, AL

  6. Acquired thrombotic thrombocytopenic purpura due to antibody-mediated ADAMTS13 deficiency precipitated by a localized Castleman's disease: a case report.

    PubMed

    Benevides, Thais Celi Lopes; Orsi, Fernanda Andrade; Colella, Marina Pereira; Percout, Priscila de Oliveira; Moura, Muriel Silva; Dias, Maria Almeida; Lins, Betina Diniz; Paula, Erich Vinicius de; Vassallo, Jose; Annichino-Bizzachi, Joyce

    2015-01-01

    Acquired ADAMTS13 inhibitor causing thrombotic thrombocytopenic purpura (TTP) may be precipitated by some infections, inflammatory diseases or neoplasia. We reported a case of refractory TTP precipitated by a newly diagnosed localized Castleman's disease (CD). TTP was initially treated with plasma exchange and immunosuppressive therapy with corticosteroids; however the treatment failed to promote sustained response. During hospitalization, an abdominal tumor was diagnosed and resected; the histological analysis revealed a CD of hyaline-vascular variant rich stroma. After tumor removal, the patient achieved a long-lasting clinical remission and normalized ADAMTS13 activity. This clinical case describes a novel association of acquired ADAMTS13 inhibitor and CD. The antibody to ADAMTS13 developed along with the systemic manifestation of CD and promptly disappeared after the resection of the tumor. There are reports of neoplasia-associated thrombotic microangiopathy however direct evidence of CD-dependent ADAMTS13 inhibitor had not yet been reported.

  7. Partial characterization of n-butanol-solubilized rejection-type antigens of syngeneic murine colon tumors.

    PubMed

    Sato, N; Kikuchi, K

    1985-04-01

    Previous investigation of the transplantation immunity of 2 cultured murine colon lines of BALB/c origin, C-C36 and C-C26, showed these tumor lines to be immunogenic against individual tumors and to have possibly cross-reactive, tumor-rejection-type antigens. For characterization of the molecular features of tumor-rejection antigens expressed on the colon tumor cells, n-butanol was used for the extraction of rejection-type antigens from tumor cells and immunogenic molecules were analyzed on transplantation immunity. The data demonstrated that extraction of the rejection-type antigens from C-C36 and C-C26 surface membrane without cellular lysis was possible with n-butanol treatment of these cells, and immunogenic activities of these extracts from C-C36 and C-C26 cells were more potent than those of nonionic detergent Nonidet P40 extracts in the tumor-rejection assays. The extracts were partially characterized by chromatographic separation on Sephadex G-200 gel filtration and lectin-affinity chromatography. It was suggested that the C-C36 antigens responsible for tumor-rejection activity against the same tumor cells had a molecular weight range of approximately 150,000 to 250,000 (fraction II) in the presence of 5 mM EDTA and had been eluted into unbound fractions to lens culinaris lectin on affinity chromatography. Moreover, immunization of mice with antigens from the same fractions (fraction II) of n-butanol extracts of C-C26 tumor on the gel filtration could induce the resistance against challenged C-C36 as well as against challenged C-C26 tumor growth. These results may indicate that solubilized tumor-rejection-type antigens found in C-C36 and C-C26 colon tumors have a size similar to that of the molecules and that cross-reacting, rejection-type antigens between these cells are the products of the same gene clusters or somatic derivatives of a single gene.

  8. 75 FR 32490 - Issues in the Development of Medical Products for the Prophylaxis and/or Treatment of Acute...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-08

    ... Prophylaxis and/or Treatment of Acute Antibody Mediated Rejection in Kidney Transplant Recipients; Public... prophylaxis and/or treatment of acute antibody mediated rejection (AMR) in kidney transplant recipients....

  9. Designing a HER2/neu promoter to drive α1,3galactosyltransferase expression for targeted anti-αGal antibody-mediated tumor cell killing

    PubMed Central

    Lanteri, Marion; Ollier, Laurence; Giordanengo, Valérie; Lefebvre, Jean-Claude

    2005-01-01

    Introduction Our goal was to specifically render tumor cells susceptible to natural cytolytic anti-αGal antibodies by using a murine α1,3galactosyltransferase (mαGalT) transgene driven by a designed form of HER2/neu promoter (pNeu), the transcription of which is frequently observed to be above basal in breast tumors. Indeed, the αGalT activity that promotes Galα1,3Galβ1,4GlcNAc-R (αGal) epitope expression has been mutationally disrupted during the course of evolution, starting from Old World primates, and this has led to the counter-production of large amounts of cytotoxic anti-αGal antibodies in recent primates, including man. Method Expression of the endogenous c-erbB-2 gene was investigated in various cell lines by northern blotting. A mαGalT cDNA was constructed into pcDNA3 vector downstream of the original CMV promoter (pCMV/mαGalT) and various forms of pNeu were prepared by PCR amplification and inserted in the pCMV/mαGalT construct upstream of the mαGalT cDNA, in the place of the CMV promoter. These constructs were transferred into HEK-293 control and breast tumor cell lines. Stably transfected cells were analyzed by northern blotting for their expression of αGalT and c-erbB-2, and by flow cytometry for their binding with fluorescein isothiocyanate-conjugated Griffonia simplicifolia/isolectin B4. Results We show that expression of the mαGalT was up- or down-modulated according to the level of endogenous pNeu activity and the particular form of constructed pNeu. Among several constructs, two particular forms of the promoter, pNeu250 containing the CCAAT box and the PEA3 motif adjacent to the TATAA box, and pNeu664, which has three additional PEA3 motifs upstream of the CCAAT box, were found to promote differential αGalT expression. Conclusion Our results strengthen current concepts about the crucial role played by the proximal PEA3 motif of pNeu, and may represent a novel therapeutic approach for the development of targeted transgene expression

  10. Noninvasive detection of rejection of transplanted hearts with indium-111-labeled lymphocytes

    SciTech Connect

    Eisen, H.J.; Eisenberg, S.B.; Saffitz, J.E.; Bolman, R.M. 3d.; Sobel, B.E.; Bergmann, S.R.

    1987-04-01

    To determine whether cardiac transplant rejection can be detected noninvasively with indium-111 (/sup 111/In)-labeled lymphocytes, we studied 11 dogs with thoracic heterotopic cardiac transplants without immunosuppression and five dogs with transplants treated with cyclosporine (10 mg/kg/day) and prednisone (1 mg/kg/day). All were evaluated sequentially with gamma scintigraphy after administration of 150 to 350 muCi of autologous /sup 111/In-lymphocytes. Technetium-99m-labeled red blood cells (1 to 3 mCi) were used for correction of radioactivity in the blood pool attributable to circulating labeled lymphocytes. Lymphocyte infiltration was quantified as the ratio of indium in the myocardium of the transplant or native heart compared with that in blood (indium excess, IE). Results were correlated with mechanical and electrical activity of allografts and with histologic findings in sequential biopsy specimens. In untreated dogs (n = 11), IE was 15.5 +/- 7.0 (SD) in transplanted hearts undergoing rejection and 0.4 +/- 1.1 in native hearts on the day before animals were killed. In dogs treated with cyclosporine and prednisone (n = 5), IE was minimal in allografts during the course of immunosuppression (0.8 +/- 0.4) and increased to 22.9 +/- 11.1 after immunosuppression was stopped. Scintigraphic criteria of rejection (IE greater than 2 SD above that in native hearts) correlated with results of biopsies indicative of rejection and appeared before electrophysiologic or mechanical manifestations of dysfunction. Thus infiltration of labeled lymphocytes in allografts, indicative of rejection, is detectable noninvasively by gamma scintigraphy and provides a sensitive approach potentially applicable to clinical monitoring for early detection of rejection and guidance for titration of immunosuppressive measures.

  11. Inhibition of αvβ6 promotes acute renal allograft rejection in nonhuman primates.

    PubMed

    Lo, D J; Farris, A B; Song, M; Leopardi, F; Anderson, D J; Strobert, E A; Ramakrishnan, S; Turgeon, N A; Mehta, A K; Turnbull, B; Maroni, B; Violette, S M; Kirk, A D

    2013-12-01

    The integrin αvβ6 activates latent transforming growth factor-β (TGF-β) within the kidney and may be a target for the prevention of chronic allograft fibrosis after kidney transplantation. However, TGF-β also has known immunosuppressive properties that are exploited by calcineurin inhibitors (CNIs); thus, the net benefit of αvβ6 inhibition remains undetermined. To assess the acute impact of interference with αvβ6 on acute rejection, we tested a humanized αvβ6-specific monoclonal antibody (STX-100) in a randomized, double-blinded, placebo-controlled nonhuman primate renal transplantation study to evaluate whether αvβ6 blockade alters the risk of acute rejection during CNI-based immunosuppression. Rhesus monkeys underwent renal allotransplantation under standard CNI-based maintenance immunosuppression; 10 biopsy-confirmed rejection-free animals were randomized to receive weekly STX-100 or placebo. Animals treated with STX-100 experienced significantly decreased rejection-free survival compared to placebo animals (p = 0.049). Immunohistochemical analysis confirmed αvβ6 ligand presence, and αvβ6 staining intensity was lower in STX-100-treated animals (p = 0.055), indicating an apparent blockade effect of STX-100. LAP, LTBP-1 and TGF-β were all decreased in animals that rejected on STX-100 compared to those that rejected on standard immunosuppression alone, suggesting a relevant effect of αvβ6 blockade on local TGF-β. These data caution against the use of αvβ6 blockade to achieve TGF-β inhibition in kidney transplantation.

  12. Development of rituximab-resistant B-NHL clones: an in vitro model for studying tumor resistance to monoclonal antibody-mediated immunotherapy.

    PubMed

    Jazirehi, Ali R; Bonavida, Benjamin

    2011-01-01

    Therapeutic strategies for cancer include chemotherapy, immunotherapy, and radiation. Such therapies result in significant short-term clinical responses; however, relapses and recurrences occur with no treatments. Targeted therapies using monoclonal antibodies have improved responses with minimal toxicities. For instance, Rituximab (chimeric anti-CD20 monoclonal antibody) was the first FDA-approved monoclonal antibody for the treatment of patients with non-Hodgkin's lymphoma (NHL). The clinical response was significantly improved when used in combination with chemotherapy. However, a subset of patients does not respond or becomes resistant to further treatment. Rituximab-resistant (RR) clones were used as a model to address the potential mechanisms of resistance. In this chapter, we discuss the underlying molecular mechanisms by which rituximab signals the cells and modifies several intracellular survival/antiapoptotic pathways, leading to its chemo/immunosensitizing activities. RR clones were developed to mimic in vivo resistance observed in patients. In comparison with the sensitive parental cells, the RR clones are refractory to rituximab-mediated cell signaling and chemosensitization. Noteworthy, interference with the hyperactivated survival/antiapoptotic pathways in the RR clones with various pharmacological inhibitors mimicked rituximab effects in the parental cells. The development of RR clones provides a paradigm for studying resistance by other anticancer monoclonal antibodies in various tumor models.

  13. Permeability studies on taeniid metacestodes: II. Antibody-mediated effects on membrane permeability in larvae of Taenia taeniaeformis and Taenia crassiceps.

    PubMed

    Hustead, S T; Williams, J F

    1977-04-01

    Incubation in immune rat serum (IRS) was shown to increase the rate of absorption of 125I RNase-A but not 125I BSA by larvae of Taenia taeniaeformis and T. crassiceps. This effect required a heat labile factor in serum, and partial activity could be restored in heat-treated IRS by adding normal rat serum (NRS) as a source of complement. In addition, the effectiveness of IRS in altering permeability was shown to be dependent on the concentration of functional complement. Both live and dead larvae incubated in NRS rapidly depleted hemolytic complement levels in the surrounding medium. Immunoglobulin fractions from IRS separated by anion exchange chromatography and and gel filtration were tested in the presence of excess complement for their ability to affect uptake of 125I RNase-A. Enhanced permeability was observed in larvae incubated in each fraction. The results show that antibodies in conjunction with complement are capable of disrupting larval permeability control in vitro. The observation that larvae were able to restore normal control as complement levels declined suggests that the parasites may overcome this immunologic effector mechanism by interfering with complement function.

  14. Antibody-Mediated and Cellular Immune Responses Induced in Naive Volunteers by Vaccination with Long Synthetic Peptides Derived from the Plasmodium vivax Circumsporozoite Protein

    PubMed Central

    Arévalo-Herrera, Myriam; Soto, Liliana; Perlaza, Blanca Liliana; Céspedes, Nora; Vera, Omaira; Lenis, Ana Milena; Bonelo, Anilza; Corradin, Giampietro; Herrera, Sócrates

    2011-01-01

    Plasmodium vivax circumsporozoite (CS) protein is a leading malaria vaccine candidate. We describe the characterization of specific immune responses induced in 21 malaria-naive volunteers vaccinated with long synthetic peptides derived from the CS protein formulated in Montanide ISA 720. Both antibody- and cell-mediated immune responses were analyzed. Antibodies were predominantly of IgG1 and IgG3 isotypes, recognized parasite proteins on the immunofluorescent antibody test, and partially blocked sporozoite invasion of hepatoma cell lines in vitro. Peripheral blood mononuclear cells from most volunteers (94%) showed IFN-γ production in vitro upon stimulation with both long signal peptide and short peptides containing CD8+ T-cell epitopes. The relatively limited sample size did not allow conclusions about HLA associations with the immune responses observed. In summary, the inherent safety and tolerability together with strong antibody responses, invasion blocking activity, and the IFN-γ production induced by these vaccine candidates warrants further testing in a phase II clinical trial. PMID:21292876

  15. Changing Paradigms in the Management of Rejection in Kidney Transplantation

    PubMed Central

    Maier, Mirela; Takano, Tomoko; Sapir-Pichhadze, Ruth

    2017-01-01

    Purpose of review: P4 medicine denotes an evolving field of medicine encompassing predictive, preventive, personalized, and participatory medicine. Using the example of kidney allograft rejection because of donor-recipient incompatibility in human leukocyte antigens, this review outlines P4 medicine’s relevance to the various stages of the kidney transplant cycle. Sources of information: A search for English articles was conducted in Medline via OvidSP (up to August 18, 2016) using a combination of subject headings (MeSH) and free text in titles, abstracts, and author keywords for the concepts kidney transplantation and P4 medicine. The electronic database search was expanded further on particular subject headings. Findings: Available histocompatibility methods exemplify current applications of the predictive and preventive domains of P4 medicine in kidney transplant recipients’ care. Pharmacogenomics are discussed as means to facilitate personalized immunosuppression regimens and promotion of active patient participation as a means to improve adherence. Limitations: For simplicity, this review focuses on rejection. P4 medicine, however, should more broadly address health concerns in kidney transplant recipients, including competing outcomes such as infections, malignancies, and cardiovascular disease. This review highlights how biomarkers to evaluate these competing outcomes warrant validation and standardization prior to their incorporation into clinical practice. Implications: Consideration of all 4 domains of the P4 medicine framework when caring for and/or studying kidney transplant recipients has the potential of increasing therapeutic efficiency, minimizing adverse effects, decreasing health care costs, and maximizing wellness. Technologies to gauge immune competency, immunosuppression requirements, and early/reversible immune-mediated injuries are required to optimize kidney transplant care. PMID:28270929

  16. Rejection Sensitivity in Late Adolescence: Social and Emotional Sequelae

    ERIC Educational Resources Information Center

    Marston, Emily G.; Hare, Amanda; Allen, Joseph P.

    2010-01-01

    This study used longitudinal, multireporter data, in a community sample, to examine the role of rejection sensitivity in late adolescents' social and emotional development. Rejection sensitivity was linked to a relative increase in adolescent depressive and anxiety symptoms over a 3-year period, even after accounting for teens' baseline level of…

  17. 25 CFR 163.18 - Acceptance and rejection of bids.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 25 Indians 1 2013-04-01 2013-04-01 false Acceptance and rejection of bids. 163.18 Section 163.18 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER GENERAL FORESTRY REGULATIONS Forest Management and Operations § 163.18 Acceptance and rejection of bids. (a) The high bid received...

  18. 25 CFR 163.18 - Acceptance and rejection of bids.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 25 Indians 1 2014-04-01 2014-04-01 false Acceptance and rejection of bids. 163.18 Section 163.18 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER GENERAL FORESTRY REGULATIONS Forest Management and Operations § 163.18 Acceptance and rejection of bids. (a) The high bid received...

  19. 25 CFR 163.18 - Acceptance and rejection of bids.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false Acceptance and rejection of bids. 163.18 Section 163.18 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER GENERAL FORESTRY REGULATIONS Forest Management and Operations § 163.18 Acceptance and rejection of bids. (a) The high bid received...

  20. 25 CFR 163.18 - Acceptance and rejection of bids.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 25 Indians 1 2011-04-01 2011-04-01 false Acceptance and rejection of bids. 163.18 Section 163.18 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER GENERAL FORESTRY REGULATIONS Forest Management and Operations § 163.18 Acceptance and rejection of bids. (a) The high bid received...

  1. 25 CFR 163.18 - Acceptance and rejection of bids.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 25 Indians 1 2012-04-01 2011-04-01 true Acceptance and rejection of bids. 163.18 Section 163.18 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER GENERAL FORESTRY REGULATIONS Forest Management and Operations § 163.18 Acceptance and rejection of bids. (a) The high bid received...

  2. 48 CFR 314.404 - Rejection of bids.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 4 2010-10-01 2010-10-01 false Rejection of bids. 314.404 Section 314.404 Federal Acquisition Regulations System HEALTH AND HUMAN SERVICES CONTRACTING METHODS AND CONTRACT TYPES SEALED BIDDING Opening of Bids and Award of Contract 314.404 Rejection of bids....

  3. Peer Rejection in Preschool: Foregrounding Children’s Voices

    ERIC Educational Resources Information Center

    Tay-Lim, Joanna; Gan, Linda

    2013-01-01

    Existing studies on peer rejection are predominantly quantitative in nature and do not adequately engage children’s voices and provide a comprehensive view of the peer rejection phenomenon. There are also limited studies at the preschool level, especially in the Singapore context. This study addresses these limitations by presenting insights into…

  4. 48 CFR 1419.505 - Rejecting Small Business Administration recommendations.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... Administration recommendations. 1419.505 Section 1419.505 Federal Acquisition Regulations System DEPARTMENT OF... Rejecting Small Business Administration recommendations. (a) A written justification in support of the CO's decision to reject the set-aside recommendation shall be approved by the HCA. It shall then be...

  5. 48 CFR 2919.505 - Rejecting Small Business Administration recommendations.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... Administration recommendations. 2919.505 Section 2919.505 Federal Acquisition Regulations System DEPARTMENT OF... Small Business 2919.505 Rejecting Small Business Administration recommendations. When the SBA Procurement Center Representative appeals a “rejection of an SBA recommendation” as referenced in FAR...

  6. 48 CFR 219.505 - Rejecting Small Business Administration recommendations.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 3 2013-10-01 2013-10-01 false Rejecting Small Business Administration recommendations. 219.505 Section 219.505 Federal Acquisition Regulations System DEFENSE...-Asides for Small Business 219.505 Rejecting Small Business Administration recommendations. (b)...

  7. 48 CFR 2919.505 - Rejecting Small Business Administration recommendations.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... Administration recommendations. 2919.505 Section 2919.505 Federal Acquisition Regulations System DEPARTMENT OF... Small Business 2919.505 Rejecting Small Business Administration recommendations. When the SBA Procurement Center Representative appeals a “rejection of an SBA recommendation” as referenced in FAR...

  8. 48 CFR 219.505 - Rejecting Small Business Administration recommendations.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 3 2014-10-01 2014-10-01 false Rejecting Small Business Administration recommendations. 219.505 Section 219.505 Federal Acquisition Regulations System DEFENSE...-Asides for Small Business 219.505 Rejecting Small Business Administration recommendations. (b)...

  9. 48 CFR 2919.505 - Rejecting Small Business Administration recommendations.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... Administration recommendations. 2919.505 Section 2919.505 Federal Acquisition Regulations System DEPARTMENT OF... Small Business 2919.505 Rejecting Small Business Administration recommendations. When the SBA Procurement Center Representative appeals a “rejection of an SBA recommendation” as referenced in FAR...

  10. 48 CFR 1419.505 - Rejecting Small Business Administration recommendations.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... Administration recommendations. 1419.505 Section 1419.505 Federal Acquisition Regulations System DEPARTMENT OF... Rejecting Small Business Administration recommendations. (a) A written justification in support of the CO's decision to reject the set-aside recommendation shall be approved by the HCA. It shall then be...

  11. 48 CFR 1419.505 - Rejecting Small Business Administration recommendations.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... Administration recommendations. 1419.505 Section 1419.505 Federal Acquisition Regulations System DEPARTMENT OF... Rejecting Small Business Administration recommendations. (a) A written justification in support of the CO's decision to reject the set-aside recommendation shall be approved by the HCA. It shall then be...

  12. 48 CFR 219.505 - Rejecting Small Business Administration recommendations.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 3 2012-10-01 2012-10-01 false Rejecting Small Business Administration recommendations. 219.505 Section 219.505 Federal Acquisition Regulations System DEFENSE...-Asides for Small Business 219.505 Rejecting Small Business Administration recommendations. (b)...

  13. 48 CFR 1419.505 - Rejecting Small Business Administration recommendations.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... Administration recommendations. 1419.505 Section 1419.505 Federal Acquisition Regulations System DEPARTMENT OF... Rejecting Small Business Administration recommendations. (a) A written justification in support of the CO's decision to reject the set-aside recommendation shall be approved by the HCA. It shall then be...

  14. 48 CFR 219.505 - Rejecting Small Business Administration recommendations.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 3 2011-10-01 2011-10-01 false Rejecting Small Business Administration recommendations. 219.505 Section 219.505 Federal Acquisition Regulations System DEFENSE...-Asides for Small Business 219.505 Rejecting Small Business Administration recommendations. (b)...

  15. 48 CFR 2919.505 - Rejecting Small Business Administration recommendations.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... Administration recommendations. 2919.505 Section 2919.505 Federal Acquisition Regulations System DEPARTMENT OF... Small Business 2919.505 Rejecting Small Business Administration recommendations. When the SBA Procurement Center Representative appeals a “rejection of an SBA recommendation” as referenced in FAR...

  16. Process Demands of Rejection Mechanisms of Recognition Memory

    ERIC Educational Resources Information Center

    Odegard, Timothy N.; Koen, Joshua D.; Gama, Jorge M.

    2008-01-01

    A surge of research has been conducted to examine memory editing mechanisms that help distinguish accurate from inaccurate memories. In the present experiment, the authors examined the ability of participants to use novelty detection, recollection rejection, and plausibility judgments to reject lures presented on a recognition memory test.…

  17. 32 CFR 274.8 - Bids-revocations-rejections-postponements.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 false Bids-revocations-rejections-postponements. 274.8 Section 274.8 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE... EXPORT LOAN AGREEMENTS § 274.8 Bids-revocations-rejections-postponements. The Secretary of Defense or...

  18. Peer victimization and peer rejection during early childhood

    PubMed Central

    Godleski, Stephanie A.; Kamper, Kimberly E.; Ostrov, Jamie M.; Hart, Emily J.; Blakely-McClure, Sarah J.

    2014-01-01

    Objective The development and course of the subtypes of peer victimization is a relatively understudied topic despite the association of victimization with important developmental and clinical outcomes. Moreover, understanding potential predictors, such as peer rejection and emotion regulation, in early childhood may be especially important to elucidate possible bi-directional pathways between relational and physical victimization and rejection. The current study (N = 97) was designed to explore several gaps and limitations in the peer victimization and peer rejection literature. In particular, the prospective associations between relational and physical victimization and peer rejection over the course of 3.5 months during early childhood (i.e., 3- to 5- years-old) were investigated in an integrated model. Method The study consisted of 97 (42 girls) preschool children recruited from four early childhood schools in the northeast of the US. Using observations, research assistant report and teacher report, relational and physical aggression, relational and physical victimization, peer rejection, and emotion regulation were measured in a short-term longitudinal study. Path analyses were conducted to test the overall hypothesized model. Results Peer rejection was found to predict increases in relational victimization. In addition, emotion regulation was found to predict decreases in peer rejection and physical victimization. Conclusions Implications for research and practice are discussed, including teaching coping strategies for peer rejection and emotional distress. PMID:25133659

  19. 48 CFR 219.505 - Rejecting Small Business Administration recommendations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 3 2010-10-01 2010-10-01 false Rejecting Small Business Administration recommendations. 219.505 Section 219.505 Federal Acquisition Regulations System DEFENSE...-Asides for Small Business 219.505 Rejecting Small Business Administration recommendations. (b)...

  20. 48 CFR 1419.505 - Rejecting Small Business Administration recommendations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Administration recommendations. 1419.505 Section 1419.505 Federal Acquisition Regulations System DEPARTMENT OF... Rejecting Small Business Administration recommendations. (a) A written justification in support of the CO's decision to reject the set-aside recommendation shall be approved by the HCA. It shall then be...

  1. 48 CFR 2919.505 - Rejecting Small Business Administration recommendations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Administration recommendations. 2919.505 Section 2919.505 Federal Acquisition Regulations System DEPARTMENT OF... Small Business 2919.505 Rejecting Small Business Administration recommendations. When the SBA Procurement Center Representative appeals a “rejection of an SBA recommendation” as referenced in FAR...

  2. Social Rejection and ADHD in Young Adults: An Analogue Experiment

    ERIC Educational Resources Information Center

    Paulson, James F.; Buermeyer, Curt; Nelson-Gray, Rosemery O.

    2005-01-01

    Poor outcomes in ADHD may be related to problematic social functioning and consequences of social rejection. This study examines how ADHD symptom expression affects mood and social rejection. Working from findings in depression that describe maintenance through negative interpersonal interactions, the authors seek to examine this theory's…

  3. 48 CFR 914.404 - Rejection of bids.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 5 2014-10-01 2014-10-01 false Rejection of bids. 914.404 Section 914.404 Federal Acquisition Regulations System DEPARTMENT OF ENERGY CONTRACTING METHODS AND CONTRACT TYPES SEALED BIDDING Opening of Bids and Award of Contract 914.404 Rejection of bids....

  4. 48 CFR 914.404 - Rejection of bids.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 5 2012-10-01 2012-10-01 false Rejection of bids. 914.404 Section 914.404 Federal Acquisition Regulations System DEPARTMENT OF ENERGY CONTRACTING METHODS AND CONTRACT TYPES SEALED BIDDING Opening of Bids and Award of Contract 914.404 Rejection of bids....

  5. 48 CFR 914.404 - Rejection of bids.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 5 2013-10-01 2013-10-01 false Rejection of bids. 914.404 Section 914.404 Federal Acquisition Regulations System DEPARTMENT OF ENERGY CONTRACTING METHODS AND CONTRACT TYPES SEALED BIDDING Opening of Bids and Award of Contract 914.404 Rejection of bids....

  6. 48 CFR 914.404 - Rejection of bids.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Rejection of bids. 914.404 Section 914.404 Federal Acquisition Regulations System DEPARTMENT OF ENERGY CONTRACTING METHODS AND CONTRACT TYPES SEALED BIDDING Opening of Bids and Award of Contract 914.404 Rejection of bids....

  7. 48 CFR 914.404 - Rejection of bids.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 5 2011-10-01 2011-10-01 false Rejection of bids. 914.404 Section 914.404 Federal Acquisition Regulations System DEPARTMENT OF ENERGY CONTRACTING METHODS AND CONTRACT TYPES SEALED BIDDING Opening of Bids and Award of Contract 914.404 Rejection of bids....

  8. Preadolescent Friendship and Peer Rejection as Predictors of Adult Adjustment.

    ERIC Educational Resources Information Center

    Bagwell, Catherine L.; Newcomb, Andrew F.; Bukowski, William M.

    1998-01-01

    Compared adjustment of 30 young adults who had a stable, reciprocal best friend in fifth grade and 30 who did not. Found that lower peer rejection uniquely predicted overall life status adjustment. Friended preadolescents had higher general self-worth in adulthood, even after controlling for perceived preadolescence competence. Peer rejection and…

  9. Rheumatoid course of humoral (vascular) rejection after heart allotransplantation.

    PubMed

    Beletskaya, L V; Kupriyanova, A G; Kormer, A Ya; Mironkov, B L; Kazakov, E N; Shumakov, V I

    2006-09-01

    Analysis of planned endomyocardial biopsy specimens of heart allotransplants from 22 recipients revealed signs of humoral type rejection (slight, medium, and severe) presenting as fixation of IgG, IgM, and complement components (C3, C4d) in 61 of 63 sections. Permanent presence of rejection signs attests to rheumatoid course of this process.

  10. Heterosexual Rejection and Mate Choice: A Sociometer Perspective

    PubMed Central

    Zhang, Lin; Liu, Shen; Li, Yue; Ruan, Lu-Jun

    2015-01-01

    Previous studies about the effects of social rejection on individuals' social behaviors have produced mixed results and tend to study mating behaviors from a static point of view. However, mate selection in essence is a dynamic process, and therefore sociometer theory opens up a new perspective for studying mating and its underlying practices. Based on this theory and using self-perceived mate value in the relationship between heterosexual rejection and mate choice as a mediating role, this current study examined the effects of heterosexual rejection on mate choice in two experiments. Results showed that heterosexual rejection significantly reduced self-perceived mate value, expectation, and behavioral tendencies, while heterosexual acceptance indistinctively increased these measures. Self-perceived mate value did not serve as a mediator in the relationship between heterosexual rejection and mate expectation, but it mediated the relationship between heterosexual rejection and mating behavior tendencies toward potential objects. Moreover, individuals evaded both rejection and irrelevant people when suffering from rejection. PMID:26648898

  11. Peer victimization and peer rejection during early childhood.

    PubMed

    Godleski, Stephanie A; Kamper, Kimberly E; Ostrov, Jamie M; Hart, Emily J; Blakely-McClure, Sarah J

    2015-01-01

    The development and course of the subtypes of peer victimization is a relatively understudied topic despite the association of victimization with important developmental and clinical outcomes. Moreover, understanding potential predictors, such as peer rejection and emotion regulation, in early childhood may be especially important to elucidate possible bidirectional pathways between relational and physical victimization and rejection. The current study (N = 97) was designed to explore several gaps and limitations in the peer victimization and peer rejection literature. In particular, the prospective associations between relational and physical victimization and peer rejection over the course of 3.5 months during early childhood (i.e., 3 to 5 years old) were investigated in an integrated model. The study consisted of 97 (42 girls) preschool children recruited from four early childhood schools in the northeast of the United States. Using observations, research assistant report, and teacher report, relational and physical aggression, relational and physical victimization, peer rejection, and emotion regulation were measured in a short-term longitudinal study. Path analyses were conducted to test the overall hypothesized model. Peer rejection was found to predict increases in relational victimization. In addition, emotion regulation was found to predict decreases in peer rejection and physical victimization. Implications for research and practice are discussed, including teaching coping strategies for peer rejection and emotional distress.

  12. Neutralization Takes Precedence Over IgG or IgA Isotype-related Functions in Mucosal HIV-1 Antibody-mediated Protection.

    PubMed

    Astronomo, Rena D; Santra, Sampa; Ballweber-Fleming, Lamar; Westerberg, Katharine G; Mach, Linh; Hensley-McBain, Tiffany; Sutherland, Laura; Mildenberg, Benjamin; Morton, Georgeanna; Yates, Nicole L; Mize, Gregory J; Pollara, Justin; Hladik, Florian; Ochsenbauer, Christina; Denny, Thomas N; Warrier, Ranjit; Rerks-Ngarm, Supachai; Pitisuttithum, Punnee; Nitayapan, Sorachai; Kaewkungwal, Jaranit; Ferrari, Guido; Shaw, George M; Xia, Shi-Mao; Liao, Hua-Xin; Montefiori, David C; Tomaras, Georgia D; Haynes, Barton F; McElrath, Juliana M

    2016-12-01

    HIV-1 infection occurs primarily through mucosal transmission. Application of biologically relevant mucosal models can advance understanding of the functional properties of antibodies that mediate HIV protection, thereby guiding antibody-based vaccine development. Here, we employed a human ex vivo vaginal HIV-1 infection model and a rhesus macaque in vivo intrarectal SHIV challenge model to probe the protective capacity of monoclonal broadly-neutralizing (bnAb) and non-neutralizing Abs (nnAbs) that were functionally modified by isotype switching. For human vaginal explants, we developed a replication-competent, secreted NanoLuc reporter virus system and showed that CD4 binding site bnAbs b12 IgG1 and CH31 IgG1 and IgA2 isoforms potently blocked HIV-1JR-CSF and HIV-1Bal26 infection. However, IgG1 and IgA nnAbs, either alone or together, did not inhibit infection despite the presence of FcR-expressing effector cells in the tissue. In macaques, the CH31 IgG1 and IgA2 isoforms infused before high-dose SHIV challenge were completely to partially protective, respectively, while nnAbs (CH54 IgG1 and CH38 mIgA2) were non-protective. Importantly, in both mucosal models IgG1 isotype bnAbs were more protective than the IgA2 isotypes, attributable in part to greater neutralization activity of the IgG1 variants. These findings underscore the importance of potent bnAb induction as a primary goal of HIV-1 vaccine development.

  13. Imaging-based diagnosis of acute renal allograft rejection

    PubMed Central

    Thölking, Gerold; Schuette-Nuetgen, Katharina; Kentrup, Dominik; Pawelski, Helga; Reuter, Stefan

    2016-01-01

    Kidney transplantation is the best available treatment for patients with end stage renal disease. Despite the introduction of effective immunosuppressant drugs, episodes of acute allograft rejection still endanger graft survival. Since efficient treatment of acute rejection is available, rapid diagnosis of this reversible graft injury is essential. For diagnosis of rejection, invasive core needle biopsy of the graft is the “gold-standard”. However, biopsy carries the risk of significant graft injury and is not immediately feasible in patients taking anticoagulants. Therefore, a non-invasive tool assessing the whole organ for specific and fast detection of acute allograft rejection is desirable. We herein review current imaging-based state of the art approaches for non-invasive diagnostics of acute renal transplant rejection. We especially focus on new positron emission tomography-based as well as targeted ultrasound-based methods. PMID:27011915

  14. Uptake of myocardial imaging agents by rejected hearts

    SciTech Connect

    Bergsland, J.; Carr, E.A.; Carroll, M.; Wright, J.W.; Feldman, M.J.; Massucci, J.; Bhayana, J.N.; Gona, J.M.

    1985-09-01

    Technetium 99 m pyrophosphate, Gallium 67 and Thallium 201 uptakes were measured in heterotopically transplanted rat hearts. Five days after transplantation, Technetium 99 m pyrophosphate, and Gallium 67 uptakes were significantly higher in allogeneic grafts than in syngeneic grafts. At an early stage of rejection (three days after transplantation), only Technetium 99 m pyrophosphate uptake in the left ventricle of allogeneic grafts showed a significant difference (p less than 0.04). At five days, Thallium 201 uptake was significantly lower in allo- than syngeneic grafts. There was a positive correlation between radionuclide uptake and histologic degree of rejection for Technetium 99 m pyrophosphate and Gallium 67 while Thallium 201 uptake correlated negatively. Analysis of variance revealed that hearts with no or minimal rejection had statistically different uptakes than hearts with mild to moderate rejection. These results suggest that uptake of imaging agents might be useful in the diagnosis of rejection of the transplanted heart.

  15. Solar dynamic heat rejection technology. Task 1: System concept development

    NASA Technical Reports Server (NTRS)

    Gustafson, Eric; Carlson, Albert W.

    1987-01-01

    The results are presented of a concept development study of heat rejection systems for Space Station solar dynamic power systems. The heat rejection concepts are based on recent developments in high thermal transport capacity heat pipe radiators. The thermal performance and weights of each of the heat rejection subsystems is addressed in detail, and critical technologies which require development tests and evaluation for successful demonstration are assessed and identified. Baseline and several alternate heat rejection system configurations and optimum designs are developed for both Brayton and Rankine cycles. The thermal performance, mass properties, assembly requirements, reliability, maintenance requirements and life cycle cost are determined for each configuration. A specific design was then selected for each configuration which represents an optimum design for that configuration. The final recommendations of heat rejection system configuration for either the Brayton or Rankine cycles depend on the priorities established for the evaluation criteria.

  16. Emotional Self-Regulation, Peer Rejection, and Antisocial Behavior: Developmental Associations from Early Childhood to Early Adolescence

    PubMed Central

    Trentacosta, Christopher J.; Shaw, Daniel S.

    2009-01-01

    This study examined relations among emotional self-regulation, peer rejection, and antisocial behavior in a sample of 122 boys from low-income families who participated in a summer camp and were followed longitudinally from early childhood to early adolescence. Emotional self- regulation strategies were coded in early childhood from a waiting task, measures of peer rejection were collected during middle childhood at the summer camp, and reports of antisocial behavior were obtained during early adolescence. Structural equation modeling was utilized to examine longitudinal relations among these constructs, with results supporting a negative association between use of active distraction and peer rejection and a positive association between peer rejection and antisocial behavior. Furthermore, an indirect effect of active distraction on antisocial behavior was found through peer rejection. Thus, adaptive self-regulation strategy use in early childhood demonstrated direct longitudinal relations with peer rejection and an indirect association with antisocial behavior in early adolescence. Results have implications for early prevention and intervention efforts to foster adaptive self-regulation of emotion and reduce risk for later social problems and delinquency. PMID:20161105

  17. Impact of ambient conditions on SMP elimination and rejection in MBRs.

    PubMed

    Drews, Anja; Mante, Jan; Iversen, Vera; Vocks, Martin; Lesjean, Boris; Kraume, Matthias

    2007-09-01

    The widespread application of the membrane-assisted activated sludge process is restricted by membrane fouling, which increases investment and operating costs. Soluble microbial products (SMPs) are currently considered as the major cause of membrane fouling in membrane bioreactors (MBRs). This study aims at elucidating and quantifying the effects of varying environmental conditions on SMP elimination and rejection based on findings in a pilot MBR and in well-defined lab trials. Several factors are thought to influence the concentration of SMP and their fouling propensity in one way or the other, but findings are often inconsistent or even contradictory. Here, SMP loading rate was found to have the greatest effect on SMP elimination and thus on concentration in the MBR. The degree of elimination decreased at very low DO and low nitrate concentrations. On average, 75% of influent SMP were eliminated in both pilot and lab trials, with the elimination of polysaccharides (PS) mostly above 80%. Rejection of SMP components by the used membrane (PAN, 37nm) ranged mainly from 20% to 70% for proteins and from 75% to 100% for PS. Especially protein rejection decreased at higher temperatures and higher nitrification activity. The increased fouling rates at lower temperatures might therefore partly be explained by this increased rejection. Apparently, mainly the nitrite-oxidising community is responsible for the formation for smaller SMP molecules that can pass the membrane.

  18. How rejection of essences expresses despair.

    PubMed

    Tougas, C T

    1999-07-01

    The Self and the ego in Jung's psychology are an instance of what Edmund Husserl called a 'double intentionality': one tending toward meaning is distinct from another tending toward meaning, yet they are reciprocally inseparable from each other. As perception in a present moment and memory of a past are impossible without each other, so an intending of ego and that of Self are impossible without each other. Accompanying the ego (mostly in the background) during each moment of time is a tending towards a particular Idea or essence. This reciprocity is expressed in a unique way over a lifetime and is like the relation of mother and child, and so it is important for all of us born of women to retain a sense of essences and the fullness of Self. 'Constructivism', however, is a current belief held by some feminists, and it influences both theorizing and practice in analytical psychology. It involves a rejection of essences, a revision of Jung's Idea of Self, and an attempt to conduct analysis without reference to an intentional subjective Self. Such constructivist revision expresses a despair both about essences as Ideas and about Self as intentional and subjective. It is despair over Self in a Kierkegaardian sense.

  19. Alpha Background Rejection in Bolometer Detectors

    NASA Astrophysics Data System (ADS)

    Deporzio, Nicholas

    2016-03-01

    This study presents the modification of bolometer detectors used in particle searches to veto or otherwise reject alpha radiation background and the statistical advantages of doing so. Several techniques are presented in detail - plastic film scintillator vetoes, metallic film ionization vetoes, and scintillating bolometer vetoes. Plastic scintillator films are cooled to bolometer temperatures and bombarded with 1.4MeV to 6.0MeV alpha particles representative of documented detector background. Photomultipliers detect this scintillation light and produce a veto signal. Layered metallic films of a primary metal, dielectric, and secondary metal, such as gold-polyethylene-gold films, are cooled to milli-kelvin temperatures and biased to produce a current signal veto when incident 1.4MeV to 6.0MeV alpha particles ionize conduction paths through the film. Modified Zinc Molybdate Bolometers are used to produce scintillation light when stimulated by alpha background. Calibration of veto signal to background energy is presented. Results are used to quantify the statistical impact of such modifications on bolometer searches.

  20. Alpha Background Rejection in Bolometer Detectors

    NASA Astrophysics Data System (ADS)

    Deporzio, Nicholas; Cuore Collaboration

    This study presents the modification of bolometer detectors used in particle searches to veto or otherwise reject alpha radiation background and the statistical advantages of doing so. Several techniques are presented in detail - plastic film scintillator vetoes, metallic film ionization vetoes, and Cherenkov radiation vetoes. Plastic scintillator films are cooled to bolometer temperatures and bombarded with 1.4MeV to 6.0MeV alpha particles representative of documented detector background. Quantum dot based liquid scintillator is similarly bombarded to produce a background induced scintillation light. Photomultipliers detect this scintillation light and produce a veto signal. Layered metallic films of a primary metal, dielectric, and secondary metal, such as gold-polyethylene-gold films, are cooled to milli-kelvin temperatures and biased to produce a current signal veto when incident 1.4MeV to 6.0MeV alpha particles ionize conduction paths through the film. Calibration of veto signal to background energy is presented. These findings are extrapolated to quantify the statistical impact of such modifications to bolometer searches. Effects of these techniques on experiment duration and signal-background ratio are discussed.

  1. South African court rejects country's new constitution.

    PubMed

    1996-09-20

    Fundamental principles designed to ensure that South Africa's new constitution upholds a wide range of individual rights and freedoms and establishes a responsive government with a balanced separation of powers, including recognition of the role of traditional tribal leadership, were adopted into the current interim constitution shortly before the 1994 free elections which brought Nelson Mandela and the African National Congress to power. In a judgement issued on September 6, 1996, South Africa's Constitutional Court rejected the country's new draft constitution, arguing that it failed to meet the standards of nine of the 34 principles established at the Kempton Park negotiations. The Constitutional Assembly is comprised of a joint meeting of the National Assembly and Senate. One of the court's major objections to the constitution concerned the proposed structure of rule, which was seen to give inadequate power to South Africa's nine provinces as compared with the national government. However, the bill of rights was almost entirely upheld. The bill would create a favorable environment for legalized abortion and guarantee a universal right of access to health care, including reproductive health services

  2. Specimen rejection in laboratory medicine: Necessary for patient safety?

    PubMed Central

    Dikmen, Zeliha Gunnur; Pinar, Asli; Akbiyik, Filiz

    2015-01-01

    Introduction The emergency laboratory in Hacettepe University Hospitals receives specimens from emergency departments (EDs), inpatient services and intensive care units (ICUs). The samples are accepted according to the rejection criteria of the laboratory. In this study, we aimed to evaluate the sample rejection ratios according to the types of pre-preanalytical errors and collection areas. Materials and methods The samples sent to the emergency laboratory were recorded during 12 months between January to December, 2013 in which 453,171 samples were received and 27,067 specimens were rejected. Results Rejection ratios was 2.5% for biochemistry tests, 3.2% for complete blood count (CBC), 9.8% for blood gases, 9.2% for urine analysis, 13.3% for coagulation tests, 12.8% for therapeutic drug monitoring, 3.5% for cardiac markers and 12% for hormone tests. The most frequent rejection reasons were fibrin clots (28%) and inadequate volume (9%) for biochemical tests. Clotted samples (35%) and inadequate volume (13%) were the major causes for coagulation tests, blood gas analyses and CBC. The ratio of rejected specimens was higher in the EDs (40%) compared to ICUs (30%) and inpatient services (28%). The highest rejection ratio was observed in neurology ICU (14%) among the ICUs and internal medicine inpatient service (10%) within inpatient clinics. Conclusions We detected an overall specimen rejection rate of 6% in emergency laboratory. By documentation of rejected samples and periodic training of healthcare personnel, we expect to decrease sample rejection ratios below 2%, improve total quality management of the emergency laboratory and promote patient safety. PMID:26527231

  3. Rejection of micropollutants by clean and fouled forward osmosis membrane.

    PubMed

    Valladares Linares, Rodrigo; Yangali-Quintanilla, Victor; Li, Zhenyu; Amy, Gary

    2011-12-15

    As forward osmosis (FO) gains attention as an efficient technology to improve wastewater reclamation processes, it is fundamental to determine the influence of fouling in the rejection of emerging contaminants (micropollutants). This study focuses on the rejection of 13 selected micropollutants, spiked in a secondary wastewater effluent, by a FO membrane, using Red Sea water as draw solution (DS), differentiating the effects on the rejection caused by a clean and fouled membrane. The resulting effluent was then desalinated at low pressure with a reverse osmosis (RO) membrane, to produce a high quality permeate and determine the rejection with a coupled forward osmosis - low pressure reverse osmosis (FO-LPRO) system. When considering only FO with a clean membrane, the rejection of the hydrophilic neutral compounds was between 48.6% and 84.7%, for the hydrophobic neutrals the rejection ranged from 40.0% to 87.5%, and for the ionic compounds the rejections were between 92.9% and 96.5%. With a fouled membrane, the rejections were between 44.6% and 95.2%, 48.7%-91.5% and 96.9%-98.6%, respectively. These results suggest that, except for the hydrophilic neutral compounds, the rejection of the micropollutants is increased by the presence of a fouling layer, possibly due to the higher hydrophilicity of the FO fouled membrane compared to the clean one, the increased adsorption capacity of hydrophilic compounds and reduced mass transport capacity, membrane swelling, and the higher negative charge of the membrane surface, related to the foulants composition, mainly NOM acids (carboxylic radicals) and polysaccharides or polysaccharide-like substances. However, when coupled with RO, the rejections in both cases increased above 96%. The coupled FO-LPRO system was an effective double barrier against the selected micropollutants.

  4. Trait rejection sensitivity is associated with vigilance and defensive response rather than detection of social rejection cues

    PubMed Central

    Kawamoto, Taishi; Nittono, Hiroshi; Ura, Mitsuhiro

    2015-01-01

    Prior studies suggest that psychological difficulties arise from higher trait Rejection Sensitivity (RS)—heightened vigilance and differential detection of social rejection cues and defensive response to. On the other hand, from an evolutionary perspective, rapid and efficient detection of social rejection cues can be considered beneficial. We conducted a survey and an electrophysiological experiment to reconcile this seeming contradiction. We compared the effects of RS and Rejection Detection Capability (RDC) on perceived interpersonal experiences (Study 1) and on neurocognitive processes in response to cues of social rejection (disgusted faces; Study 2). We found that RS and RDC were not significantly related, although RS was positively related to perceived social rejection experiences and RDC was positively related to perceived social inclusion experiences. Event-related brain potentials (ERPs) revealed that higher RS was related to cognitive avoidance (i.e., P1) and heightened motivated attention (i.e., late positive potential: LPP), but not to facial expression encoding (i.e., N170) toward disgusted faces. On the other hand, higher RDC was related to heightened N170 amplitude, but not to P1 and LPP amplitudes. These findings imply that sensitivity to rejection is apparently distinct from the ability to detect social rejection cues and instead reflects intense vigilance and defensive response to those cues. We discussed an alternative explanation of the relationship between RS and RDC from a signal detection perspective. PMID:26483750

  5. Rejected by peers-attracted to antisocial media content: rejection-based anger impairs moral judgment among adolescents.

    PubMed

    Plaisier, Xanthe S; Konijn, Elly A

    2013-06-01

    Adolescence is an important developmental stage during which both peers and the media have a strong influence. Both peer rejection and the use of morally adverse media are associated with negative developmental outcomes. This study examines processes by which peer rejection might drive adolescents to select antisocial media content by tying together developmental research on peer rejection and research on media effects. Assumed underlying mechanisms are rejection-based anger and frustration and the adolescent's moral judgment. A between-participants experimental design manipulated peer rejection versus acceptance in adolescents (Mage = 13.88 years; N = 74) and young adults (Mage = 21.37 years; N = 75), applying the Cyberball paradigm. Measures included the State Anger Inventory (STAXI) to assess feelings of rejection and the newly devised Media, Morals, and Youth Questionnaire (MMaYQue) to assess media preferences and moral judgment of media content. Using bootstrapping analyses, a double mediation was established: Higher levels of state anger in peer-rejected adolescents induced more tolerable moral judgments of antisocial media content, subsequently instigating a preference for antisocial media content. In contrast, the young adult sample showed no relations between peer rejection and antisocial media preference. Results are discussed within a downward spiral framework of combined peer and media influences.

  6. 21 CFR 111.170 - What requirements apply to rejected components, packaging, and labels, and to rejected products...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 2 2011-04-01 2011-04-01 false What requirements apply to rejected components, packaging, and labels, and to rejected products that are received for packaging or labeling as a dietary supplement? 111.170 Section 111.170 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH...

  7. 21 CFR 111.170 - What requirements apply to rejected components, packaging, and labels, and to rejected products...

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 2 2013-04-01 2013-04-01 false What requirements apply to rejected components, packaging, and labels, and to rejected products that are received for packaging or labeling as a dietary supplement? 111.170 Section 111.170 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH...

  8. 21 CFR 111.170 - What requirements apply to rejected components, packaging, and labels, and to rejected products...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 2 2010-04-01 2010-04-01 false What requirements apply to rejected components, packaging, and labels, and to rejected products that are received for packaging or labeling as a dietary supplement? 111.170 Section 111.170 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH...

  9. 21 CFR 111.170 - What requirements apply to rejected components, packaging, and labels, and to rejected products...

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 2 2014-04-01 2014-04-01 false What requirements apply to rejected components, packaging, and labels, and to rejected products that are received for packaging or labeling as a dietary supplement? 111.170 Section 111.170 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH...

  10. 21 CFR 111.170 - What requirements apply to rejected components, packaging, and labels, and to rejected products...

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 2 2012-04-01 2012-04-01 false What requirements apply to rejected components, packaging, and labels, and to rejected products that are received for packaging or labeling as a dietary supplement? 111.170 Section 111.170 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH...

  11. Rejected by Peers--Attracted to Antisocial Media Content: Rejection-Based Anger Impairs Moral Judgment among Adolescents

    ERIC Educational Resources Information Center

    Plaisier, Xanthe S.; Konijn, Elly A.

    2013-01-01

    Adolescence is an important developmental stage during which both peers and the media have a strong influence. Both peer rejection and the use of morally adverse media are associated with negative developmental outcomes. This study examines processes by which peer rejection might drive adolescents to select antisocial media content by tying…

  12. Rejection versus escape: the tumor MHC dilemma.

    PubMed

    Garrido, Federico; Ruiz-Cabello, Francisco; Aptsiauri, Natalia

    2017-02-01

    Most tumor cells derive from MHC-I-positive normal counterparts and remain positive at early stages of tumor development. T lymphocytes can infiltrate tumor tissue, recognize and destroy MHC class I (MHC-I)-positive cancer cells ("permissive" phase I). Later, MHC-I-negative tumor cell variants resistant to T-cell killing emerge. During this process, tumors first acquire a heterogeneous MHC-I expression pattern and finally become uniformly MHC-I-negative. This stage (phase II) represents a "non-permissive" encapsulated structure with tumor nodes surrounded by fibrous tissue containing different elements including leukocytes, macrophages, fibroblasts, etc. Molecular mechanisms responsible for total or partial MHC-I downregulation play a crucial role in determining and predicting the antigen-presenting capacity of cancer cells. MHC-I downregulation caused by reversible ("soft") lesions can be upregulated by TH1-type cytokines released into the tumor microenvironment in response to different types of immunotherapy. In contrast, when the molecular mechanism of the tumor MHC-I loss is irreversible ("hard") due to a genetic defect in the gene/s coding for MHC-I heavy chains (chromosome 6) or beta-2-microglobulin (B2M) (chromosome 15), malignant cells are unable to upregulate MHC-I, remain undetectable by cytotoxic T-cells, and continue to grow and metastasize. Based on the tumor MHC-I molecular analysis, it might be possible to define MHC-I phenotypes present in cancer patients in order to distinguish between non-responders, partial/short-term responders, and likely durable responders. This highlights the need for designing strategies to enhance tumor MHC-I expression that would allow CTL-mediated tumor rejection.

  13. Antibody-mediated cofactor-driven reactions

    DOEpatents

    Schultz, Peter G.

    1993-01-01

    Chemical reactions capable of being rate-enhanced by auxiliary species which interact with the reactants but do not become chemically bound to them in the formation of the final product are performed in the presence of antibodies which promote the reactions. The antibodies contain regions within their antigen binding sites which recognize the auxiliary species in a conformation which promotes the reaction. The antigen binding site frequently recognizes a particular transition state complex or other high energy complex along the reaction coordinate, thereby promoting the progress of the reaction along the desired route as opposed to other less favorable routes. Various classes of reaction together with appropriate antigen binding site specificities tailored for each are disclosed.

  14. Antibody-mediated Hsp70 protein therapy.

    PubMed

    Hansen, James E; Sohn, William; Kim, Charles; Chang, Sophia S; Huang, Natalie C; Santos, Donaldson G; Chan, Grace; Weisbart, Richard H; Nishimura, Robert N

    2006-05-09

    Intracellular Hsp70 provides cytoprotection against a variety of stressful stimuli, and an effective means of increasing intracellular Hsp70 levels could prove beneficial in the prevention and treatment of a variety of human diseases. A novel protein transduction domain consisting of the single chain Fv fragment of an anti-DNA antibody known to penetrate into living cells and tissues, mAb 3E10, has recently been used to deliver functional proteins to cells. The ability of the single chain Fv fragment to deliver Hsp70 into living cells was tested by generating an Fv-Hsp70 fusion protein. Fv-Hsp70 was produced as a secreted protein in both COS-7 cells and the methylotropic yeast strain Pichia pastoris and was shown capable of penetrating into COS-7 cells and primary rat cortical neurons. Pre-treatment with Fv-Hsp70 protected both COS-7 cells and primary rat cortical neurons against subsequent exposure to hydrogen peroxide. These results provide the first evidence that the Fv fragment of mAb 3E10 is capable of delivering proteins to neurons and indicate its potential in the development of Hsp70 protein therapy.

  15. Organ transplant tissue rejection: detection and staging by fluorescence spectroscopy

    NASA Astrophysics Data System (ADS)

    MacAulay, Calum E.; Whitehead, Peter D.; McManus, Bruce; Zeng, Haishan; Wilson-McManus, Janet; MacKinnon, Nick; Morgan, David C.; Dong, Chunming; Gerla, Paul; Kenyon, Jennifer

    1998-07-01

    Patients receiving heart or other organ transplants usually require some level of anti-rejection drug therapy, most commonly cyclosporine. The rejection status of the organ must be monitored to determine the optimal anti-rejection drug therapy. The current method for monitoring post-transplant rejection status of heart transplant patients consists of taking biopsies from the right ventricle. In this work we have developed a system employing optical and signal-processing techniques that will allow a cardiologist to measure spectral changes associated with tissue rejection using an optical catheter probe. The system employs time gated illumination and detection systems to deal with the dynamic signal acquisition problems associated with in vivo measurements of a beating heart. Spectral data processing software evaluates and processes the data to produce a simple numerical score. Results of measurements made on 100 excised transplanted isograft and allograft rat hearts have demonstrated the ability of the system to detect the presence of rejection and to accurately correlate the spectroscopic results with the ISHLT (International Society for Heart and Lung Transplantation) stage of rejection determined by histopathology. In vivo measurements using a pig transplant model are now in process.

  16. Novel Multivariate Methods for Integration of Genomics and Proteomics Data: Applications in a Kidney Transplant Rejection Study

    PubMed Central

    Günther, Oliver P.; Shin, Heesun; Ng, Raymond T.; McMaster, W. Robert; McManus, Bruce M.; Keown, Paul A.; Tebbutt, Scott. J.

    2014-01-01

    Abstract Multi-omics research is a key ingredient of data-intensive life sciences research, permitting measurement of biological molecules at different functional levels in the same individual. For a complete picture at the biological systems level, appropriate statistical techniques must however be developed to integrate different ‘omics’ data sets (e.g., genomics and proteomics). We report here multivariate projection-based analyses approaches to genomics and proteomics data sets, using the case study of and applications to observations in kidney transplant patients who experienced an acute rejection event (n=20) versus non-rejecting controls (n=20). In this data sets, we show how these novel methodologies might serve as promising tools for dimension reduction and selection of relevant features for different analytical frameworks. Unsupervised analyses highlighted the importance of post transplant time-of-rejection, while supervised analyses identified gene and protein signatures that together predicted rejection status with little time effect. The selected genes are part of biological pathways that are representative of immune responses. Gene enrichment profiles revealed increases in innate immune responses and neutrophil activities and a depletion of T lymphocyte related processes in rejection samples as compared to controls. In all, this article offers candidate biomarkers for future detection and monitoring of acute kidney transplant rejection, as well as ways forward for methodological advances to better harness multi-omics data sets. PMID:25387159

  17. Developmental influences on the neural bases of responses to social rejection: implications of social neuroscience for education.

    PubMed

    Sebastian, Catherine L; Tan, Geoffrey C Y; Roiser, Jonathan P; Viding, Essi; Dumontheil, Iroise; Blakemore, Sarah-Jayne

    2011-08-01

    Relational aggression such as social rejection is common within school peer groups. Converging evidence suggests that adolescent females are particularly sensitive to social rejection. We used a novel fMRI adaptation of the Cyberball social rejection paradigm to investigate the neural response to social rejection in 19 mid-adolescent (aged 14-16) and 16 adult female participants. Across all participants, social exclusion (relative to inclusion) elicited a response in bilateral medial prefrontal cortex (mPFC) extending into ventral and subgenual anterior cingulate cortex and medial orbitofrontal cortex; and the left ventrolateral PFC (vlPFC); regions that have been associated in previous studies with social evaluation, negative affective processing, and affect regulation respectively. However, the exclusion-related response in right vlPFC, a region associated in previous studies with the regulation of rejection-related distress, was attenuated in adolescents. Within mPFC, greater activation during exclusion vs. inclusion was associated with greater self-reported susceptibility to peer influence in adolescents but not in adults. This suggests that the brain's response to experimentally-induced social rejection relates to adolescent behaviour in real-world social interactions. We speculate about the potential implications of these findings for educational settings. In particular, functional development of affective circuitry during adolescence may influence social interaction within the school peer group.

  18. Perceptions of Intragroup Rejection and Coping Strategies: Malleable Factors Affecting Hispanic Adolescents’ Emotional and Academic Outcomes

    PubMed Central

    Warren, Michael T.; Crano, William D.; Unger, Jennifer B.

    2015-01-01

    Understanding psychosocial factors that affect the academic achievement of Hispanic adolescents remains a nationwide priority in the United States. Extending previous studies of the stressful effects of perceived discrimination, this year-long longitudinal study examined the correlates of perceived ethnic in-group rejection, coping strategies and fatalistic beliefs, on depressive symptoms, grades, and college aspirations of 2,214 Hispanic adolescents (54 % female) in Southern California. Based on the transactional model of stress and coping and on self-perception theory, structural equation models revealed that high perceived intragroup rejection (10th grade) and low levels of active coping (11th grade) were associated with depressive symptoms in 11th grade. Also, depressive symptoms partially mediated the link between intragroup rejection and both academic outcomes. Avoidant coping strategies (e.g., watching TV) also predicted depressive symptoms and were positively related to fatalism. In addition, fatalism was negatively related to grades and aspiration to attend college. The findings suggest the need to help adolescents find adequate outlets for communication and to create awareness about the potential effects of intragroup rejection. PMID:24234042

  19. Bioremediation of reject water from anaerobically digested waste water sludge with macroalgae (Ulva lactuca, Chlorophyta).

    PubMed

    Sode, Sidsel; Bruhn, Annette; Balsby, Thorsten J S; Larsen, Martin Mørk; Gotfredsen, Annemarie; Rasmussen, Michael Bo

    2013-10-01

    Phosphorus and biologically active nitrogen are valuable nutrient resources. Bioremediation with macroalgae is a potential means for recovering nutrients from waste streams. In this study, reject water from anaerobically digested sewage sludge was successfully tested as nutrient source for cultivation of the green macroalgae Ulva lactuca. Maximal growth rates of 54.57±2.16% FW d(-1) were achieved at reject water concentrations equivalent to 50 μM NH4(+). Based on the results, the growth and nutrient removal was parameterised as function of NH4(+) concentration a tool for optimisation of any similar phycoremediation system. Maximal nutrient removal rates of 22.7 mg N g DW(-1) d(-1) and 2.7 mg P g DW(-1) d(-1) were achieved at reject water concentrations equivalent to 80 and 89 μM NH4(+), respectively. A combined and integrated use of the produced biomass in a biorefinery is thought to improve the feasibility of using Ulva for bioremediation of reject water.

  20. T-cell immune response cDNA 7 in allograft rejection and inflammation.

    PubMed

    Utku, Nalân; Heinemann, Thomas; Milford, Edgar L

    2007-05-01

    The membrane protein T-cell immune response cDNA 7 (TIRC7) is transiently expressed in subsets of lymphocytes following antigen stimulation. The importance of TIRC7 in immune activation is demonstrated by the effect of antibodies directed against extracellular domains of TIRC7. In vitro targeting of TIRC7 inhibits proliferation and cytokine expression in human, mouse and rat lymphocytes, and these inhibitory effects have been associated with induction of cytotoxic T-lymphocyte antigen 4 mRNA and protein in the presence of TIRC7 antibodies. In vivo, anti-TIRC7 antibodies prevent kidney transplant rejection in rats and heart allograft rejection in mice. Treatment with an anti-TIRC7 antibody as monotherapy or in combination with TNFalpha blockade inhibits disease progression in collagen-induced arthritis. TIRC7 expression decreases in the peripheral blood of humans who have undergone cardiac transplant prior to clinical rejection, and is therefore a promising noninvasive tool for the prediction of rejection. Thus, targeting of TIRC7 may lead to the development of specific and effective therapeutic and diagnostic approaches by unifying relevant cellular and molecular responses in T- and B-cell subsets, and represents a promising new pathway for immune regulation in transplantation and autoimmune disease.

  1. Gene-based bio-signature patterns and cardiac allograft rejection.

    PubMed

    Mehra, Mandeep R; Uber, Patricia A; Benitez, Roberto M

    2010-01-01

    Clinicians have long awaited an alternative to invasive endomyocardial biopsy for surveillance of cardiac transplant rejection. Transcriptional signals in peripheral blood mononuclear cells allow for the development of multigene-based panels that can inform on the presence or absence of immunologic quiescence. The informative genes represent several biologic pathways, including T-cell activation (PDCD1), T-cell migration (ITGA4), and mobilization of hematopoietic precursors (WDR40A and microRNA gene family cMIR), and steroid-responsive genes such as IL1R2, the decoy receptor for interleukin 2. The greatest value may include the ability to inform on the potential of future proclivity for rejection, allowing patients to be stratified into low, intermediate, or high risk subsets for future rejection. In these individuals, this knowledge may allow clinicians to use tailored approaches to immunosuppression, thereby avoiding adverse pharmacologic effects in low-risk patients while improving rejection outcomes in those at high risk for future allograft compromise. Despite these advances, clinical entrenchment of gene-based pharmacotherapy in cardiac transplantation will require independent replication and validation of investigational findings.

  2. Rejection is less common in children undergoing liver transplantation for hepatoblastoma.

    PubMed

    Ruth, N D; Kelly, D; Sharif, K; Morland, B; Lloyd, C; McKiernan, P J

    2014-02-01

    To compare the incidence of acute histologically proven rejection in children who have had a liver transplant for hepatoblastoma with a control group of children transplanted for biliary atresia (EHBA). A retrospective case notes based study was performed. Twenty patients were identified with hepatoblastoma who were transplanted at a single unit between 1991 and 2008. These were matched as closely as possible for age, gender, year of transplant and type of immunosuppression used to the control group transplanted for biliary atresia (n = 60). There was a significant decrease in rate of acute rejection as assessed by the rejection activity index (RAI) in the hepatoblastoma group (75% vs. 50%, respectively, p < 0.04). Chronic rejection was rare in both groups, but twice as common in the biliary atresia group. Equal levels of immunosuppression were achieved in both groups. Renal function was noted to be reduced one yr post-transplant in both groups, as previously reported. A modified immunosuppression regimen could be considered in children with hepatoblastoma undergoing liver transplantation.

  3. Reduction of Acute Rejection by Bone Marrow Mesenchymal Stem Cells during Rat Small Bowel Transplantation

    PubMed Central

    Zhang, Wen; Wu, Ben-Juan; Fu, Nan-Nan; Zheng, Wei-Ping; Don, Chong; Shen, Zhong-Yang

    2014-01-01

    Background Bone marrow mesenchymal stem cells (BMMSCs) have shown immunosuppressive activity in transplantation. This study was designed to determine whether BMMSCs could improve outcomes of small bowel transplantation in rats. Methods Heterotopic small bowel transplantation was performed from Brown Norway to Lewis rats, followed by infusion of BMMSCs through the superficial dorsal veins of the penis. Controls included rats infused with normal saline (allogeneic control), isogeneically transplanted rats (BN-BN) and nontransplanted animals. The animals were sacrificed after 1, 5, 7 or 10 days. Small bowel histology and apoptosis, cytokine concentrations in serum and intestinal grafts, and numbers of T regulatory (Treg) cells were assessed at each time point. Results Acute cellular rejection occurred soon after transplantation and became aggravated over time in the allogeneic control rats, with increase in apoptosis, inflammatory response, and T helper (Th)1/Th2 and Th17/Treg-related cytokines. BMMSCs significantly attenuated acute cellular rejection, reduced apoptosis and suppressed the concentrations of interleukin (IL)-2, IL-6, IL-17, IL-23, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ while upregulating IL-10 and transforming growth factor (TGF)-β expression and increasing Treg levels. Conclusion BMMSCs improve the outcomes of allogeneic small bowel transplantation by attenuating the inflammatory response and acute cellular rejection. Treatment with BMMSCs may overcome acute cellular rejection in small bowel transplantation. PMID:25500836

  4. Immune Responses to Tissue-Restricted Nonmajor Histocompatibility Complex Antigens in Allograft Rejection

    PubMed Central

    Bharat, Ankit

    2017-01-01

    Chronic diseases that result in end-stage organ damage cause inflammation, which can reveal sequestered self-antigens (SAgs) in that organ and trigger autoimmunity. The thymus gland deletes self-reactive T-cells against ubiquitously expressed SAgs, while regulatory mechanisms in the periphery control immune responses to tissue-restricted SAgs. It is now established that T-cells reactive to SAgs present in certain organs (e.g., lungs, pancreas, and intestine) are incompletely eliminated, and the dysregulation of peripheral immuneregulation can generate immune responses to SAgs. Therefore, chronic diseases can activate self-reactive lymphocytes, inducing tissue-restricted autoimmunity. During organ transplantation, donor lymphocytes are tested against recipient serum (i.e., cross-matching) to detect antibodies (Abs) against donor human leukocyte antigens, which has been shown to reduce Ab-mediated hyperacute rejection. However, primary allograft dysfunction and rejection still occur frequently. Because donor lymphocytes do not express tissue-restricted SAgs, preexisting Abs against SAgs are undetectable during conventional cross-matching. Preexisting and de novo immune responses to tissue-restricted SAgs (i.e., autoimmunity) play a major role in rejection. In this review, we discuss the evidence that supports autoimmunity as a contributor to rejection. Testing for preexisting and de novo immune responses to tissue-restricted SAgs and treatment based on immune responses after organ transplantation may improve short- and long-term outcomes after transplantation. PMID:28164137

  5. [Rapamycin: a new immunosuppressive agent capable of inhibiting chronic rejection?].

    PubMed

    Viklický, O; Matl, I

    2001-01-19

    Chronic rejection represents the most common cause of transplanted graft loss in the long term. Rapamycin (sirolimus), and it's derivate RAD, are new and potent, immunosuppressive drugs. They inhibit cell proliferation driven by various growth factors. These drugs were successfully tested in some experimental models of the chronic rejection. Results of the first clinical trials have defined rapamycin pharmacokinetics and proved immunosuppressive efficacy. Rapamycin acts synergistically with cyclosporin A. The side effects are a dose-dependent thrombocytopenia and leukopenia but the most frequent is hyperlipidemia. The question, if rapamycin and RAD inhibit development of chronic rejection in man, will be solved by the prospective clinical trials over years.

  6. Liquid droplet radiators for heat rejection in space

    NASA Technical Reports Server (NTRS)

    Mattick, A. T.; Hertzberg, A.

    1980-01-01

    A radiator for heat rejection in space is described which utilizes a stream of liquid droplets to radiate waste heat. The large surface area per mass makes the liquid droplet radiator at least an order of magnitude lighter than tube and fin radiators. Generation and collection of the droplets, as well as heat transfer to the liquid, can be achieved with modest extensions of conventional technology. Low vapor pressure liquids are available which cover a radiating temperature range 250-1000 K with negligible evaporation losses. The droplet radiator may be employed for a wide range of heat rejection applications in space. Three applications - heat rejection for a high temperature Rankine cycle, cooling of photovoltaic cells, and low temperature heat rejection for refrigeration in space illustrate the versatility of the radiator.

  7. Reliability and construct validity for scale of rejection of Christianity.

    PubMed

    Robbins, Mandy; Francis, Leslie J; Bradford, Amanda

    2003-02-01

    A sample of 16 male and 30 female undergraduates completed the Greer and Francis Scale of Rejection of Christianity. The data support the internal consistency reliability and construct validity of the scale for this sample.

  8. 48 CFR 14.404-2 - Rejection of individual bids.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... total price of the bid, but the prices for individual line items as well. (g) Any bid may be rejected if the prices for any line items or subline items are materially unbalanced (see 15.404-1(g)). (h)...

  9. 48 CFR 19.505 - Rejecting Small Business Administration recommendations.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... Administration recommendations. 19.505 Section 19.505 Federal Acquisition Regulations System FEDERAL ACQUISITION... Small Business Administration recommendations. (a) If the contracting officer rejects a recommendation... the recommendation. (b) The SBA procurement center representative (or, if a procurement...

  10. 48 CFR 19.505 - Rejecting Small Business Administration recommendations.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... Administration recommendations. 19.505 Section 19.505 Federal Acquisition Regulations System FEDERAL ACQUISITION... Small Business Administration recommendations. (a) If the contracting officer rejects a recommendation... the recommendation. (b) The SBA procurement center representative (or, if a procurement...

  11. 48 CFR 19.505 - Rejecting Small Business Administration recommendations.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... Administration recommendations. 19.505 Section 19.505 Federal Acquisition Regulations System FEDERAL ACQUISITION... Small Business Administration recommendations. (a) If the contracting officer rejects a recommendation... the recommendation. (b) The SBA procurement center representative (or, if a procurement...

  12. 48 CFR 19.505 - Rejecting Small Business Administration recommendations.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... Administration recommendations. 19.505 Section 19.505 Federal Acquisition Regulations System FEDERAL ACQUISITION... Small Business Administration recommendations. (a) If the contracting officer rejects a recommendation... the recommendation. (b) The SBA procurement center representative (or, if a procurement...

  13. The Effect of Circumstantial Rejection on Infant Behavior

    ERIC Educational Resources Information Center

    Tait, Perla

    1972-01-01

    Intentional or unintentional rejection of a blind infant by the mother is shown to be conducive to the child's unwillingness to explore his environment, which in turn can have negative effects on the child's development. (CB)

  14. Children's Use of Memory Editing Strategies to Reject Source Misinformation.

    PubMed

    Moore, Kara N; Lampinen, James M; Gallo, David A; Adams, Eryn J; Bridges, Ana J

    2017-02-15

    This is the first reported study of children's use of two metacognitive strategies, recollection rejection and diagnostic monitoring, to reject misinformation. Recollection rejection involves the retrieval of details that disqualify an event, whereas diagnostic monitoring involves the failure to retrieve expected details. First (n = 56, age 7 years) and third graders (n = 52, age 9 years) witnessed a staged classroom interaction involving common and bizarre accidents, were presented with misinformation about the source of these events, and took a memory test. Both age groups used recollection rejection, but third graders were more effective. There was little evidence that diagnostic monitoring influenced responses for bizarre events, potentially because these events were not sufficiently bizarre in the context of the stereotype induction.

  15. 48 CFR 19.505 - Rejecting Small Business Administration recommendations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Administration recommendations. 19.505 Section 19.505 Federal Acquisition Regulations System FEDERAL ACQUISITION... Small Business Administration recommendations. (a) If the contracting officer rejects a recommendation... the recommendation. (b) The SBA procurement center representative (or, if a procurement...

  16. Rotating reverse osmosis: a dynamic model for flux and rejection

    NASA Technical Reports Server (NTRS)

    Lee, S.; Lueptow, R. M.

    2001-01-01

    Reverse osmosis (RO) is a compact process for the removal of ionic and organic pollutants from contaminated water. However, flux decline and rejection deterioration due to concentration polarization and membrane fouling hinders the application of RO technology. In this study, a rotating cylindrical RO membrane is theoretically investigated as a novel method to reduce polarization and fouling. A dynamic model based on RO membrane transport incorporating concentration polarization is used to predict the performance of rotating RO system. Operating parameters such as rotational speed and transmembrane pressure play an important role in determining the flux and rejection in rotating RO. For a given geometry, a rotational speed sufficient to generate Taylor vortices in the annulus is essential to maintain high flux as well as high rejection. The flux and rejection were calculated for wide range of operating pressures and rotational speeds. c 2001 Elsevier Science B.V. All rights reserved.

  17. Pain Processing after Social Exclusion and Its Relation to Rejection Sensitivity in Borderline Personality Disorder

    PubMed Central

    Bungert, Melanie; Koppe, Georgia; Niedtfeld, Inga; Vollstädt-Klein, Sabine; Schmahl, Christian

    2015-01-01

    Objective There is a general agreement that physical pain serves as an alarm signal for the prevention of and reaction to physical harm. It has recently been hypothesized that “social pain,” as induced by social rejection or abandonment, may rely on comparable, phylogenetically old brain structures. As plausible as this theory may sound, scientific evidence for this idea is sparse. This study therefore attempts to link both types of pain directly. We studied patients with borderline personality disorder (BPD) because BPD is characterized by opposing alterations in physical and social pain; hyposensitivity to physical pain is associated with hypersensitivity to social pain, as indicated by an enhanced rejection sensitivity. Method Twenty unmedicated female BPD patients and 20 healthy participants (HC, matched for age and education) played a virtual ball-tossing game (cyberball), with the conditions for exclusion, inclusion, and a control condition with predefined game rules. Each cyberball block was followed by a temperature stimulus (with a subjective pain intensity of 60% in half the cases). The cerebral responses were measured by functional magnetic resonance imaging. The Adult Rejection Sensitivity Questionnaire was used to assess rejection sensitivity. Results Higher temperature heat stimuli had to be applied to BPD patients relative to HCs to reach a comparable subjective experience of painfulness in both groups, which suggested a general hyposensitivity to pain in BPD patients. Social exclusion led to a subjectively reported hypersensitivity to physical pain in both groups that was accompanied by an enhanced activation in the anterior insula and the thalamus. In BPD, physical pain processing after exclusion was additionally linked to enhanced posterior insula activation. After inclusion, BPD patients showed reduced amygdala activation during pain in comparison with HC. In BPD patients, higher rejection sensitivity was associated with lower activation

  18. Two strategies for phosphorus removal from reject water of municipal wastewater treatment plant using alum sludge.

    PubMed

    Yang, Y; Zhao, Y Q; Babatunde, A O; Kearney, P

    2009-01-01

    In view of the well recognized need of reject water treatment in MWWTP (municipal wastewater treatment plant), this paper outlines two strategies for P removal from reject water using alum sludge, which is produced as by-product in drinking water treatment plant when aluminium sulphate is used for flocculating raw waters. One strategy is the use of the alum sludge in liquid form for co-conditioning and dewatering with the anaerobically digested activated sludge in MWWTP. The other strategy involves the use of the dewatered alum sludge cakes in a fixed bed for P immobilization from the reject water that refers to the mixture of the supernatant of the sludge thickening process and the supernatant of the anaerobically digested sludge. Experimental trials have demonstrated that the alum sludge can efficiently reduce P level in reject water. The co-conditioning strategy could reduce P from 597-675 mg P/L to 0.14-3.20 mg P/L in the supernatant of the sewage sludge while the organic polymer dosage for the conditioning of the mixed sludges would also be significantly reduced. The second strategy of reject water filtration with alum sludge bed has shown a good performance of P reduction. The alum sludge has P-adsorption capacity of 31 mg-P/g-sludge, which was tested under filtration velocity of 1.0 m/h. The two strategies highlight the beneficial utilization of alum sludge in wastewater treatment process in MWWTP, thus converting the alum sludge as a useful material, rather than a waste for landfill.

  19. Virus Rejection by the Reverse Osmosis - Ultrafiltration Processes

    DTIC Science & Technology

    Rejection of viruses by commercial grade asymmetrical cellulose acetate membranes commonly used in the ultrafiltration and reverse osmosis processes...penetration of viruses may be attributable to the presence of random areas of imperfect crosslinkage of the cellulose acetate in the dense layer of...the membrane. Despite limited virus penetration, all of the cellulose acetate membranes used in this study rejected an extremely high percentage of the viruses and provided a product water of excellent quality.

  20. Eosinophils orchestrate cancer rejection by normalizing tumor vessels and enhancing infiltration of CD8(+) T cells.

    PubMed

    Carretero, Rafael; Sektioglu, Ibrahim M; Garbi, Natalio; Salgado, Oscar C; Beckhove, Philipp; Hämmerling, Günter J

    2015-06-01

    Tumor-associated eosinophilia is frequently observed in cancer. However, despite numerous studies of patients with cancer and mouse models of cancer, it has remained uncertain if eosinophils contribute to tumor immunity or are mere bystander cells. Here we report that activated eosinophils were essential for tumor rejection in the presence of tumor-specific CD8(+) T cells. Tumor-homing eosinophils secreted chemoattractants that guided T cells into the tumor, which resulted in tumor eradication and survival. Activated eosinophils initiated substantial changes in the tumor microenvironment, including macrophage polarization and normalization of the tumor vasculature, which are known to promote tumor rejection. Thus, our study presents a new concept for eosinophils in cancer that may lead to novel therapeutic strategies.

  1. Active disturbance rejection control: methodology and theoretical analysis.

    PubMed

    Huang, Yi; Xue, Wenchao

    2014-07-01

    The methodology of ADRC and the progress of its theoretical analysis are reviewed in the paper. Several breakthroughs for control of nonlinear uncertain systems, made possible by ADRC, are discussed. The key in employing ADRC, which is to accurately determine the "total disturbance" that affects the output of the system, is illuminated. The latest results in theoretical analysis of the ADRC-based control systems are introduced.

  2. Lysis of pig endothelium by IL-2 activated human natural killer cells is inhibited by swine and human major histocompatibility complex (MHC) class I gene products.

    PubMed

    Itescu, S; Artrip, J H; Kwiatkowski, P A; Wang, S F; Minanov, O P; Morgenthau, A S; Michler, R E

    1997-01-01

    We have previously described a form of xenograft rejection, mediated by natural killer (NK) cells, occurring in pig-to-primate organ transplants beyond the period of antibody-mediated hyperacute rejection. In this study, two distinct NK activation pathways were identified as mechanisms of pig aortic endotheliual cell (PAEC) lysis by human NK cells. Using an antibody-dependent cellular cytotoxicity (ADCC) assay, a progressive increase in human NK lysis of PAEC was observed following incubation with human IgG at increasing serum titer. In the absence of IgG, a second mechanism of PAEC lysis by human NK cells was observed following activation with IL-2. IL-2 activation of human NK cells increased lysis of PAEC by over 3-fold compared with ADCC. These results indicate that IL-2 activation of human NK cells induces significantly higher levels of lytic activity than does conventional ADCC involving IgG and FcRIII. We next investigated the role of MHC class I molecules in the regulation of NK lysis following IL-2 activation. PAEC expression of SLA class I molecules was increased by up to 75% by treatment with human TNFa. Following treatment with TNFa at 1 u/ml, IL-2 activated human NK lysis of PAEC was inhibited at every effector:target (E:T) ratio tested. Maximal effect occurred at an E:T ratio of 10:1, with TNFa inhibiting specific lysis by 59% (p < 0.01). Incubation with an anti-SLA class I Mab, but not IgG isotype control, abrogated the protective effects of TNFa on NK lysis of PAEC, suggesting direct inhibitory effects of SLA class I molecules on human NK function. To investigate whether human MHC class I molecules might have similar effects on human NK lysis of PAEC, further experiments were performed using a soluble peptide derived from the alpha-helical region of HLA-B7. Incubation with the HLA-B7 derived peptide significantly reduced the IL-2 activated NK lytic activity against PAEC in a dose-dependent fashion. Maximal effect occurred at a concentration of 10 mg

  3. Lunar Portable Life Support System Heat Rejection Study

    NASA Technical Reports Server (NTRS)

    Conger, Bruce; Sompayrac,Robert G.; Trevino, Luis A.; Bue, Grant C.

    2009-01-01

    Performing extravehicular activity (EVA) at various locations of the lunar surface presents thermal challenges that exceed those experienced in space flight to date. The lunar Portable Life Support System (PLSS) cooling unit must maintain thermal conditions within the space suit and reject heat loads generated by the crewmember and the PLSS equipment. The amount of cooling required varies based on the lunar location and terrain due to the heat transferred between the suit and its surroundings. A study has been completed which investigated the resources required to provide cooling under various lunar conditions, assuming three different thermal technology categories: 1. Spacesuit Water Membrane Evaporator (SWME) 2. Subcooled Phase Change Material (SPCM) 3. Radiators with and without heat pumps Results from the study are presented that show mass and power impacts on the cooling system as a function of the location and terrain on the lunar surface. Resources (cooling equipment mass and consumables) are greater at the equator and inside sunlit craters due to the additional heat loads on the cooling system. While radiator and SPCM technologies require minimal consumables, they come with carry-weight penalties and have limitations. A wider investigation is recommended to determine if these penalties and limitations are offset by the savings in consumables.

  4. Effect of deoxyspergualin on vascular rejection in canine kidney transplantation.

    PubMed

    Tanabe, K; Takahashi, K; Nemoto, K; Okada, M; Yasuo, M; Hayasaka, Y; Toma, H; Ota, K

    1994-08-01

    Deoxyspergualin (DSG), an analogue of spergualin produced by Bacillus laterosporus, has a strong immunosuppressive effect in various transplantation models. In this study, we investigated the effect of DSG on vascular rejection in canine kidney transplantation. To enhance vascular rejection, donor-specific blood transfusion (DST) was carried out on days 28, 21 and 14 preceding kidney transplantation. After DST, the donor kidney was transplanted to the recipient iliac fossa. The recipient animals were divided into five groups: namely, Group 1 (n = 7), no treatment; Group 2 (n = 6), DST only; Group 3 (n = 5), DSG only (treated with DSG intravenously at 1.2 mg./kg./day for the first 3 days after transplantation, 1.0 mg./kg./day for the following 3 days and 0.8 mg./kg./day for the following 8 days); Group 4 (n = 6), DST and DSG treatment (same protocol as Group 3); and Group 5 (n = 5), DST and cyclosporine (CsA) (treated with CsA orally at 10 mg./kg./day for 14 days after transplantation). In Group 2, DST treatment significantly reduced kidney graft survival time (8.6 +/- 2.2 days) compared with Group 1 (14.1 +/- 5.5 days). Despite DST, DSG treatment (Group 4) significantly prolonged graft survival time (29.5 +/- 2.6 days), whereas treatment with CsA (Group 5) did not prolong survival time (14.1 +/- 5.5 days) (Group 4 versus 5, p < 0.01). The onset of rejection was significantly delayed in Group 4 (22.1 +/- 2.7 days) compared with Groups 2 (5.7 +/- 2.4 days) and 5 (13.0 +/- 5.7 days) (p < 0.01). In contrast, the interval between rejection onset and animal death was significantly reduced in Groups 2 (3.0 +/- 0.6 days) and 5 (2.4 +/- 1.0 days) compared with Group 4 (7.3 +/- 1.7 days) (p < 0.01). These findings suggest that DSG successfully prevented humoral-type (accelerated acute-type) rejections. Histologically, nonDST groups (Groups 1 and 3) showed minimum vascular rejection. In contrast, all recipients in Group 2 showed severe vascular rejection, as did 80% of Cs

  5. CD47 is required for suppression of allograft rejection by donor-specific transfusion.

    PubMed

    Wang, Hui; Wu, Xiaojian; Wang, Yuantao; Oldenborg, Per-Arne; Yang, Yong-Guang

    2010-04-01

    CD47 is a ligand of the inhibitory receptor, signal regulatory protein (SIRP)alpha, and its interaction with SIRPalpha on macrophages prevents phagocytosis of autologous hematopoietic cells. CD47-SIRPalpha signaling also regulates dendritic cell (DC) endocytosis, activation, and maturation. In this study, we show that CD47 expression on donor cells plays an important role in suppression of allograft rejection by donor-specific transfusion (DST). DST was performed by i.v. injection of splenocytes from C57BL/6 donors into MHC class I-disparate bm1 mice 7 d prior to donor skin grafting. Administration of wild-type (WT) C57BL/6 donor splenocytes markedly prolonged donor skin survival in bm1 mouse recipients. In contrast, bm1 mice receiving DST from CD47 knockout (KO) donors showed no inhibition or even acceleration of donor skin graft rejection compared with non-DST control (naive) bm1 mice. T cells from bm1 mice receiving CD47 KO, but not WT, DST exhibited strong anti-donor responses. The ability of DST to suppress alloresponses was positively correlated with the density of CD47 molecules on donor cells, as CD47(+/-) DST was able to prolonged donor skin survival, but to a significantly less extent than WT DST. Furthermore, DCs from CD47 KO, but not WT, DST recipients showed rapid activation and contributed to donor skin rejection. These results show for the first time that CD47 on donor cells is required to repress recipient DC activation and suppress allograft rejection after DST, and suggest CD47 as a potential target for facilitating the induction of transplant tolerance.

  6. Why don't you like me? Midfrontal theta power in response to unexpected peer rejection feedback.

    PubMed

    van der Molen, M J W; Dekkers, L M S; Westenberg, P M; van der Veen, F M; van der Molen, M W

    2017-02-01

    Social connectedness theory posits that the brain processes social rejection as a threat to survival. Recent electrophysiological evidence suggests that midfrontal theta (4-8Hz) oscillations in the EEG provide a window on the processing of social rejection. Here we examined midfrontal theta dynamics (power and inter-trial phase synchrony) during the processing of social evaluative feedback. We employed the Social Judgment paradigm in which 56 undergraduate women (mean age=19.67 years) were asked to communicate their expectancies about being liked vs. disliked by unknown peers. Expectancies were followed by feedback indicating social acceptance vs. rejection. Results revealed a significant increase in EEG theta power to unexpected social rejection feedback. This EEG theta response could be source-localized to brain regions typically reported during activation of the saliency network (i.e., dorsal anterior cingulate cortex, insula, inferior frontal gyrus, frontal pole, and the supplementary motor area). Theta phase dynamics mimicked the behavior of the time-domain averaged feedback-related negativity (FRN) by showing stronger phase synchrony for feedback that was unexpected vs. expected. Theta phase, however, differed from the FRN by also displaying stronger phase synchrony in response to rejection vs. acceptance feedback. Together, this study highlights distinct roles for midfrontal theta power and phase synchrony in response to social evaluative feedback. Our findings contribute to the literature by showing that midfrontal theta oscillatory power is sensitive to social rejection but only when peer rejection is unexpected, and this theta response is governed by a widely distributed neural network implicated in saliency detection and conflict monitoring.

  7. Variation in the mu-opioid receptor gene (OPRM1) is associated with dispositional and neural sensitivity to social rejection.

    PubMed

    Way, Baldwin M; Taylor, Shelley E; Eisenberger, Naomi I

    2009-09-01

    Scientific understanding of social pain--the hurt feelings resulting from social rejection, separation, or loss--has been facilitated by the hypothesis that such feelings arise, in part, from some of the same neural and neurochemical systems that generate the unpleasant feelings resulting from physical pain. Accordingly, in animals, the painkiller morphine not only alleviates the distress of physical pain, but also the distress of social separation. Because morphine acts on the mu-opioid receptor, we examined whether variation in the mu-opioid receptor gene (OPRM1), as measured by the functional A118G polymorphism, was associated with individual differences in rejection sensitivity. Participants (n = 122) completed a self-report inventory of dispositional sensitivity to social rejection and a subsample (n = 31) completed a functional MRI session in which they were rejected from an online ball-tossing game played with two supposed others. The A118G polymorphism was associated with dispositional sensitivity to rejection in the entire sample and in the fMRI subsample. Consistent with these results, G allele carriers showed greater reactivity to social rejection in neural regions previously shown to be involved in processing social pain as well as the unpleasantness of physical pain, particularly the dorsal anterior cingulate cortex (dACC) and anterior insula. Furthermore, dACC activity mediated the relationship between the A118G polymorphism and dispositional sensitivity to rejection, suggesting that this is a critical site for mu-opioid-related influence on social pain. Taken together, these data suggest that the A118G polymorphism specifically, and the mu-opioid receptor more generally, are involved in social pain in addition to physical pain.

  8. Motion artifact cancellation and outlier rejection for clip-type ppg-based heart rate sensor.

    PubMed

    Shimazaki, Takunori; Hara, Shinsuke; Okuhata, Hiroyuki; Nakamura, Hajime; Kawabata, Takashi

    2015-01-01

    Heart rate sensing can be used to not only understand exercise intensity but also detect life-critical condition during sports activities. To reduce stress during exercise and attach heart rate sensor easily, we developed a clip-type photoplethysmography (PPG)-based heart rate sensor. The sensor can be attached just by hanging it to the waist part of undershorts, and furthermore, it employs the motion artifact (MA) cancellation technique. However, due to its low contact pressure, sudden jumps and drops, which are called "outliers," are often observed in the sensed heart rate, so we also developed a simple outlier rejection technique. By an experiment using five male subjects (4 sets per subject), we confirmed the MA cancellation and outlier rejection capabilities.

  9. Recent Advances in Power Conversion and Heat Rejection Technology for Fission Surface Power

    NASA Technical Reports Server (NTRS)

    Mason, Lee

    2010-01-01

    Under the Exploration Technology Development Program, the National Aeronautics and Space Administration (NASA) and the Department of Energy (DOE) are jointly developing Fission Surface Power (FSP) technology for possible use in human missions to the Moon and Mars. A preliminary reference concept was generated to guide FSP technology development. The concept consists of a liquid-metal-cooled reactor, Stirling power conversion, and water heat rejection, with Brayton power conversion as a backup option. The FSP project has begun risk reduction activities on some key components with the eventual goal of conducting an end-to-end, non-nuclear, integrated system test. Several power conversion and heat rejection hardware prototypes have been built and tested. These include multi-kilowatt Stirling and Brayton power conversion units, titanium-water heat pipes, and composite radiator panels.

  10. Spleen tyrosine kinase contributes to acute renal allograft rejection in the rat

    PubMed Central

    Ramessur Chandran, Sharmila; Tesch, Greg H; Han, Yingjie; Woodman, Naomi; Mulley, William R; Kanellis, John; Blease, Kate; Ma, Frank Y; Nikolic-Paterson, David J

    2015-01-01

    Kidney allografts induce strong T-cell and antibody responses which mediate acute rejection. Spleen tyrosine kinase (Syk) is expressed by most leucocytes, except mature T cells, and is involved in intracellular signalling following activation of the Fcγ-receptor, B-cell receptor and some integrins. A role for Syk signalling has been established in antibody-dependent native kidney disease, but little is known of Syk in acute renal allograft rejection. Sprague–Dawley rats underwent bilateral nephrectomy and received an orthotopic Wistar renal allograft. Recipient rats were treated with a Syk inhibitor (CC0482417, 30 mg/kg/bid), or vehicle, from 1 h before surgery until being killed 5 days later. Vehicle-treated recipients developed severe allograft failure with marked histologic damage in association with dense leucocyte infiltration (T cells, macrophages, neutrophils and NK cells) and deposition of IgM, IgG and C3. Immunostaining identified Syk expression by many infiltrating leucocytes. CC0482417 treatment significantly improved allograft function and reduced histologic damage, although allograft injury was still clearly evident. CC0482417 failed to prevent T-cell infiltration and activation within the allograft. However, CC0482417 significantly attenuated acute tubular necrosis, infiltration of macrophages and neutrophils and thrombosis of peritubular capillaries. In conclusion, this study identifies a role for Syk in acute renal allograft rejection. Syk inhibition may be a useful addition to T-cell-based immunotherapy in renal transplantation. PMID:25529862

  11. An fMRI investigation of responses to peer rejection in adolescents with autism spectrum disorders.

    PubMed

    Masten, Carrie L; Colich, Natalie L; Rudie, Jeffrey D; Bookheimer, Susan Y; Eisenberger, Naomi I; Dapretto, Mirella

    2011-07-01

    Peer rejection is particularly pervasive among adolescents with autism spectrum disorders (ASD). However, how adolescents with ASD differ from typically developing adolescents in their responses to peer rejection is poorly understood. The goal of the current investigation was to examine neural responses to peer exclusion among adolescents with ASD compared to typically developing adolescents. Nineteen adolescents with ASD and 17 typically developing controls underwent fMRI as they were ostensibly excluded by peers during an online game called Cyberball. Afterwards, participants reported their distress about the exclusion. Compared to typically developing adolescents, those with ASD displayed less activity in regions previously linked with the distressing aspect of peer exclusion, including the subgenual anterior cingulate and anterior insula, as well as less activity in regions previously linked with the regulation of distress responses during peer exclusion, including the ventrolateral prefrontal cortex and ventral striatum. Interestingly, however, both groups self-reported equivalent levels of distress. This suggests that adolescents with ASD may engage in differential processing of social experiences at the neural level, but be equally aware of, and concerned about, peer rejection. Overall, these findings contribute new insights about how this population may differentially experience negative social events in their daily lives.

  12. Amino acid rejection behaviour as a function of concentration.

    PubMed

    Shirley, Jason; Mandale, Stephen; Williams, Paul M

    2011-05-11

    The solute rejection versus concentration behaviour of five different amino acids has been investigated using a Nitto Denko NTR7450 nanofiltration membrane. The experimental data for amino acid rejection was also compared against a combined steric and charge rejection model. At its isoelectric point, lysine was effectively neutral and its behaviour was well described by the model incorporating a steric function only. For phenylalanine, the combined model was found to fit the data well. In contrast there was poor agreement between the model and rejection data for glutamine, glutamic acid and glycine whose rejection values at first increased with concentration. This result implied that another governing process was in operation. Dimerisation as an explanation for the observed phenomena was also investigated. Size analysis of amino acid molecules as a function of the prevailing concentration using dynamic light scattering was limited but showed no evidence of dimerisation. This data was supported by osmotic pressure measurements which demonstrated no evidence of non-linearity in the relation between osmotic pressure and concentration.

  13. Relational Victimization and Rejection Sensitivity: The Long-Term Impact of Social Hurt

    ERIC Educational Resources Information Center

    Mellin, Elizabeth A.

    2012-01-01

    The Rejection Sensitivity Model is used to examine the social antecedents to expectations of rejection among adults. College students (N = 314) completed measures of relational victimization and rejection sensitivity. Results indicate that relational victimization is significantly related to rejection sensitivity for women. Implications for…

  14. Immunosuppression in cardiac graft rejection: A human in vitro model to study the potential use of new immunomodulatory drugs

    SciTech Connect

    Crescioli, Clara Squecco, Roberta; Cosmi, Lorenzo; Sottili, Mariangela; Gelmini, Stefania; Borgogni, Elisa; Sarchielli, Erica; Scolletta, Sabino; Francini, Fabio; Annunziato, Francesco; Vannelli, Gabriella Barbara; Serio, Mario

    2008-04-01

    CXCL10-CXCR3 axis plays a pivotal role in cardiac allograft rejection, so that targeting CXCL10 without inducing generalized immunosuppression may be of therapeutic significance in allotransplantation. Since the role of resident cells in cardiac rejection is still unclear, we aimed to establish reliable human cardiomyocyte cultures to investigate Th1 cytokine-mediated response in allograft rejection. We used human fetal cardiomyocytes (Hfcm) isolated from fetal hearts, obtained after legal abortions. Hfcm expressed specific cardiac lineage markers, specific cardiac structural proteins, typical cardiac currents and generated ventricular action potentials. Thus, Hfcm represent a reliable in vitro tool for allograft rejection research, since they resemble the features of mature cells. Hfcm secreted CXCL10 in response to IFN{gamma} and TNF{alpha}{alpha}; this effect was magnified by cytokine combination. Cytokine synergy was associated to a significant TNF{alpha}-induced up-regulation of IFN{gamma}R. The response of Hfcm to some currently used immunosuppressive drugs compared to rosiglitazone, a peroxisome proliferator-activated receptor {gamma} agonist and Th1-mediated response inhibitor, was also evaluated. Only micophenolic acid and rosiglitazone halved CXCL10 secretion by Hfcm. Given the pivotal role of IFN{gamma}-induced chemokines in Th1-mediated allograft rejection, these preliminary results suggest that the combined effects of immunosuppressive agents and rosiglitazone could be potentially beneficial to patients receiving heart transplants.

  15. Chronic cardiac allograft rejection: critical role of ED-A(+) fibronectin and implications for targeted therapy strategies.

    PubMed

    Franz, Marcus; Neri, Dario; Berndt, Alexander

    2012-03-01

    Chronic cardiac allograft rejection is characterized by cardiac allograft vasculopathy (CAV) and cardiac interstitial fibrosis (CIF) causing severe long-term complications after heart transplantation and determining allograft function and patients' prognosis. Until now, there have been no sufficient preventive or therapeutic strategies. CAV and CIF are accompanied by changes in the extracellular matrix, including re-expression of the fetal fibronectin splice variant known as ED-A(+) fibronectin. This molecule has been shown to be crucial for the development of myofibroblasts (MyoFbs) as the main cell type in CIF and for the activation of vascular smooth muscle cells (VSMCs) as the main cell type in CAV. Relevant re-expression and protein deposition of ED-A(+) fibronectin has been demonstrated in animal models of chronic rejection, with spatial association to CAV and CIF, and a quantitative correlation to the rejection grade. The paper by Booth et al published in this issue of The Journal of Pathology could prove for the first time the functional importance of ED-A(+) fibronectin for the development of CIF as a main component of chronic cardiac rejection. Thus, promising conclusions for the development of new diagnostic, preventive, and therapeutic strategies for chronic cardiac rejection focusing on ED-A(+) fibronectin can be suggested.

  16. Self-contained heat rejection module for future spacecraft

    NASA Technical Reports Server (NTRS)

    Fleming, M. L.; Williams, J. L.; Baskett, J. D.; Leach, J. W.

    1975-01-01

    This paper discusses development of a Self-Contained Heat Rejection Module (SHRM) which can be used on a wide variety of future spacecraft launched by the space shuttle orbiter. The SHRM contains radiators which are deployed by a scissor-mechanism and the flow equipment including pumps, accumulator, by-pass valves, and controllers necessary to reject heat from those radiators. Heat transfer between SHRM and the parent vehicle is effected by a contact heat exchanger. This device provides heat transfer between two separate flow loops through a mechanical connection. This approach reduces the time required to attach the SHRM to the payload, and increases the reliability of the SHRM flow loop since breaking into the fluid system in the field is not required. The SHRM concept also includes a refrigeration system to increase heat rejection capacity in adverse environments, or to provide for a lower return temperature, down to -23 C.

  17. Data augmentation for models based on rejection sampling

    PubMed Central

    Rao, Vinayak; Lin, Lizhen; Dunson, David B.

    2016-01-01

    We present a data augmentation scheme to perform Markov chain Monte Carlo inference for models where data generation involves a rejection sampling algorithm. Our idea is a simple scheme to instantiate the rejected proposals preceding each data point. The resulting joint probability over observed and rejected variables can be much simpler than the marginal distribution over the observed variables, which often involves intractable integrals. We consider three problems: modelling flow-cytometry measurements subject to truncation; the Bayesian analysis of the matrix Langevin distribution on the Stiefel manifold; and Bayesian inference for a nonparametric Gaussian process density model. The latter two are instances of doubly-intractable Markov chain Monte Carlo problems, where evaluating the likelihood is intractable. Our experiments demonstrate superior performance over state-of-the-art sampling algorithms for such problems. PMID:27279660

  18. Graft rejection by cytolytic T cells. Specificity of the effector mechanism in the rejection of allogeneic marrow

    SciTech Connect

    Nakamura, H.; Gress, R.E. )

    1990-02-01

    Cellular effector mechanisms of allograft rejection remain incompletely described. Characterizing the rejection of foreign-marrow allografts rather than solid-organ grafts has the advantage that the cellular composition of the marrow graft, as a single cell suspension, can be altered to include cellular components with differing antigen expression. Rejection of marrow grafts is sensitive to lethal doses of radiation in the mouse but resistant to sublethal levels of radiation. In an effort to identify cells mediating host resistance, lymphocytes were isolated and cloned from spleens of mice 7 days after sublethal TBI (650 cGy) and inoculation with allogeneic marrow. All clones isolated were cytolytic with specificity for MHC encoded gene products of the allogeneic marrow donor. When cloned cells were transferred in vivo into lethally irradiated (1025 cGy) recipients unable to reject allogeneic marrow, results utilizing splenic 125IUdR uptake indicated that these MHC-specific cytotoxic clones could suppress marrow proliferation. In order to characterize the effector mechanism and the ability of the clones to affect final engraftment, double donor chimeras were constructed so that 2 target cell populations differing at the MHC from each other and from the host were present in the same marrow allograft. Results directly demonstrated an ability of CTL of host MHC type to mediate graft rejection and characterized the effector mechanism as one with specificity for MHC gene products.

  19. Autoantibodies to Vimentin Cause Accelerated Rejection of Cardiac Allografts

    PubMed Central

    Mahesh, Balakrishnan; Leong, Hon-Sing; McCormack, Ann; Sarathchandra, Padmini; Holder, Angela; Rose, Marlene L.

    2007-01-01

    Autoimmune responses to vimentin occur after solid organ transplantation, but their pathogenic effects are unclear. The aim of these studies was to investigate the effects of vimentin preimmunization on allogeneic and isografted hearts in a murine transplant model. Immunization of C57BL/6 mice with murine vimentin in complete Freund’s adjuvant resulted in anti-vimentin antibodies and vimentin-reactive Th-1 cells. Transplantation of 129/sv hearts into vimentin-immunized C57BL/6 recipients resulted in accelerated rejection (8.4 ± 1.5 days; n = 18), compared with hen egg lysozyme-immunized C57BL/6 (13.3 ± 2.2 days; n = 10; P < 0.0001, log-rank test). In contrast, isografts continued to beat beyond 90 days. Immunohistochemical analysis of allografts from vimentin/complete Freund’s adjuvant mice demonstrated increased numbers of T cells and enhanced microvascular deposition of C3d, CD41, and P-selectin compared with controls. Antibodies were necessary for accelerated rejection, shown by the fact that vimentin-immunized B-cell-deficient IgH6 mice did not show accelerated rejection of 129/sv allografts, but rejection was restored by adoptive transfer of serum containing anti-vimentin antibodies. Eluates from donor hearts placed in vimentin/complete Freund’s adjuvant recipients contained anti-vimentin antibodies, shown by Western blotting. Confocal imaging of rejected hearts demonstrated presence of vimentin and C3d on apoptosed leukocytes, endothelial cells, and platelet/leukocyte conjugates. These results demonstrate that autoantibodies to vimentin, in conjunction with the alloimmune response, have a pathogenic role in allograft rejection. PMID:17392180

  20. Method and apparatus for analog pulse pile-up rejection

    DOEpatents

    De Geronimo, Gianluigi

    2013-12-31

    A method and apparatus for pulse pile-up rejection are disclosed. The apparatus comprises a delay value application constituent configured to receive a threshold-crossing time value, and provide an adjustable value according to a delay value and the threshold-crossing time value; and a comparison constituent configured to receive a peak-occurrence time value and the adjustable value, compare the peak-occurrence time value with the adjustable value, indicate pulse acceptance if the peak-occurrence time value is less than or equal to the adjustable value, and indicate pulse rejection if the peak-occurrence time value is greater than the adjustable value.