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Sample records for cell-mediated cardiac allograft

  1. 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

  2. Risk factors of cardiac allograft vasculopathy

    PubMed Central

    Szczurek, Wioletta; Gąsior, Mariusz; Zembala, Marian

    2015-01-01

    Despite advances in prevention and treatment of heart transplant rejection, development of cardiac allograft vasculopathy (CAV) remains the leading factor limiting long-term survival of the graft. Cardiac allograft vasculopathy etiopathogenesis is not fully understood, but a significant role is attributed to endothelial cell damage, caused by immunological and non-immunological mechanisms. Immunological factors include the differences between the recipient's and the donor's HLA systems, the presence of alloreactive antibodies and episodes of acute rejection. Among the non-immunological factors the most important are the age of the donor, ischemia-reperfusion injury and cytomegalovirus infection. The classical cardiovascular risk factors (diabetes, hypertension, obesity and hyperlipidemia) are also important. This study presents an up-to-date overview of current knowledge on the vasculopathy etiopathogenesis and the role played by endothelium and inflammatory processes in CAV, and it also investigates the factors which may serve as risk markers of cardiac allograft vasculopathy. PMID:26855649

  3. Cutting edge: membrane lymphotoxin regulates CD8(+) T cell-mediated intestinal allograft rejection.

    PubMed

    Guo, Z; Wang, J; Meng, L; Wu, Q; Kim, O; Hart, J; He, G; Zhou, P; Thistlethwaite, J R; Alegre, M L; Fu, Y X; Newell, K A

    2001-11-01

    Blocking the CD28/B7 and/or CD154/CD40 costimulatory pathways promotes long-term allograft survival in many transplant models where CD4(+) T cells are necessary for rejection. When CD8(+) T cells are sufficient to mediate rejection, these approaches fail, resulting in costimulation blockade-resistant rejection. To address this problem we examined the role of lymphotoxin-related molecules in CD8(+) T cell-mediated rejection of murine intestinal allografts. Targeting membrane lymphotoxin by means of a fusion protein, mAb, or genetic mutation inhibited rejection of intestinal allografts by CD8(+) T cells. This effect was associated with decreased monokine induced by IFN-gamma (Mig) and secondary lymphoid chemokine (SLC) gene expression within allografts and spleens respectively. Blocking membrane lymphotoxin did not inhibit rejection mediated by CD4(+) T cells. Combining disruption of membrane lymphotoxin and treatment with CTLA4-Ig inhibited rejection in wild-type mice. These data demonstrate that membrane lymphotoxin is an important regulatory molecule for CD8(+) T cells mediating rejection and suggest a strategy to avoid costimulation blockade-resistant rejection. PMID:11673481

  4. Predicting the development of cardiac allograft vasculopathy.

    PubMed

    Seki, Atsuko; Fishbein, Michael C

    2014-01-01

    Cardiac transplantation is a lifesaving therapy for patients with end-stage cardiovascular disease. There has been remarkable progress in controlling acute rejection, and the early survival rate after the heart transplantation has significantly improved. Cardiac allograft vasculopathy (CAV) is one of the common causes of death and a major limiting factor for long-term graft survival years after heart transplantation. CAV is a progressive occlusion of arteries and veins of the transplanted heart. CAV is often clinically silent because of the denervation of the transplanted heart. CAV tends to be found at an advanced stage of disease, including myocardial infarction (MI), congestive heart failure, arrhythmia, and/or sudden cardiac death. Because of the serious sequelae of CAV, risk factors, prevention, and prediction of CAV have been investigated. Despite the effort by many researchers, the pathogenesis is not yet completely understood. There are a number of both immune and nonimmune factors in the donor and recipient that are related to the development of CAV. In addition, several biomarkers in blood and tissue are found to correlate with the presence of CAV, and that may be able to predict CAV. Here, we review the pathology, pathogenesis, risk factors, diagnosis, and the potential for prediction of CAV. PMID:24972526

  5. Disruption of Murine Cardiac Allograft Acceptance by Latent Cytomegalovirus

    PubMed Central

    Cook, Charles H.; Bickerstaff, Alice A.; Wang, Jiao-Jing; Zimmerman, Peter D.; Forster, Meghan R.; Nadasdy, Tibor; Colvin, Robert B.; Hadley, Gregg A.; Orosz, Charles G.

    2008-01-01

    Cytomegalovirus (CMV) reactivation is a well described complication of solid organ transplantation. These studies were performed to 1.) determine if cardiac allograft transplantation of latently infected recipients results in reactivation of CMV, and 2.) determine what impact CMV might have on development of graft acceptance/tolerance. BALB/c cardiac allografts were transplanted into C57BL/6 mice with/without latent murine CMV (MCMV). Recipients were treated with gallium nitrate induction and monitored for graft survival, viral immunity, and donor reactive DTH responses. Latently infected allograft recipients had ∼80% graft loss by 100 days after transplant, compared with ∼8% graft loss in naïve recipients. PCR evaluation demonstrated that MCMV was transmitted to cardiac grafts in all latently infected recipients, and 4/8 allografts had active viral transcription compared to 0/6 isografts. Latently infected allograft recipients showed intragraft IFN-α expression consistent with MCMV reactivation, but MCMV did not appear to negatively influence regulatory gene expression. Infected allograft recipients had disruption of splenocyte DTH regulation, but recipient splenocytes remained unresponsive to donor antigen even after allograft losses. These data suggest that transplantation in an environment of latent CMV infection may reactivate virus, and that intragraft responses disrupt development of allograft acceptance. PMID:18976295

  6. Recipient-derived EDA fibronectin promotes cardiac allograft fibrosis.

    PubMed

    Booth, Adam J; Wood, Sherri C; Cornett, Ashley M; Dreffs, Alyssa A; Lu, Guanyi; Muro, Andrés F; White, Eric S; Bishop, D Keith

    2012-03-01

    Advances in donor matching and immunosuppressive therapies have decreased the prevalence of acute rejection of cardiac grafts; however, chronic rejection remains a significant obstacle for long-term allograft survival. While initiating elements of anti-allograft immune responses have been identified, the linkage between these factors and the ultimate development of cardiac fibrosis is not well understood. Tissue fibrosis resembles an exaggerated wound healing response, in which extracellular matrix (ECM) molecules are central. One such ECM molecule is an alternatively spliced isoform of the ubiquitous glycoprotein fibronectin (FN), termed extra domain A-containing cellular fibronectin (EDA cFN). EDA cFN is instrumental in fibrogenesis; thus, we hypothesized that it might also regulate fibrotic remodelling associated with chronic rejection. We compared the development of acute and chronic cardiac allograft rejection in EDA cFN-deficient (EDA(-/-)) and wild-type (WT) mice. While EDA(-/-) mice developed acute cardiac rejection in a manner indistinguishable from WT controls, cardiac allografts in EDA(-/-) mice were protected from fibrosis associated with chronic rejection. Decreased fibrosis was not associated with differences in cardiomyocyte hypertrophy or intra-graft expression of pro-fibrotic mediators. Further, we examined expression of EDA cFN and total FN by whole splenocytes under conditions promoting various T-helper lineages. Conditions supporting regulatory T-cell (Treg) development were characterized by greatest production of total FN and EDA cFN, though EDA cFN to total FN ratios were highest in Th1 cultures. These findings indicate that recipient-derived EDA cFN is dispensable for acute allograft rejection responses but that it promotes the development of fibrosis associated with chronic rejection. Further, conditions favouring the development of regulatory T cells, widely considered graft-protective, may drive production of ECM molecules which enhance

  7. Recipient–derived EDA fibronectin promotes cardiac allograft fibrosis

    PubMed Central

    Booth, Adam J; Wood, Sherri C; Cornett, Ashley M; Dreffs, Alyssa A; Lu, Guanyi; Muro, Andrés F; White, Eric S; Bishop, D Keith

    2014-01-01

    Advances in donor matching and immunosuppressive therapies have decreased the prevalence of acute rejection of cardiac grafts; however, chronic rejection remains a significant obstacle for long-term allograft survival. While initiating elements of anti-allograft immune responses have been identified, the linkage between these factors and the ultimate development of cardiac fibrosis is not well understood. Tissue fibrosis resembles an exaggerated wound healing response, in which extracellular matrix (ECM) molecules are central. One such ECM molecule is an alternatively spliced isoform of the ubiquitous glycoprotein fibronectin (FN), termed extra domain A-containing cellular fibronectin (EDA cFN). EDA cFN is instrumental in fibrogenesis; thus, we hypothesized that it might also regulate fibrotic remodelling associated with chronic rejection. We compared the development of acute and chronic cardiac allograft rejection in EDA cFN-deficient (EDA−/−) and wild-type (WT) mice. While EDA−/− mice developed acute cardiac rejection in a manner indistinguishable from WT controls, cardiac allografts in EDA−/− mice were protected from fibrosis associated with chronic rejection. Decreased fibrosis was not associated with differences in cardiomyocyte hypertrophy or intra-graft expression of pro-fibrotic mediators. Further, we examined expression of EDA cFN and total FN by whole splenocytes under conditions promoting various T-helper lineages. Conditions supporting regulatory T-cell (Treg) development were characterized by greatest production of total FN and EDA cFN, though EDA cFN to total FN ratios were highest in Th1 cultures. These findings indicate that recipient-derived EDA cFN is dispensable for acute allograft rejection responses but that it promotes the development of fibrosis associated with chronic rejection. Further, conditions favouring the development of regulatory T cells, widely considered graft-protective, may drive production of ECM molecules which

  8. 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.

  9. 21 CFR 862.1163 - Cardiac allograft gene expression profiling test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1163 Cardiac allograft gene expression profiling test system....

  10. 21 CFR 862.1163 - Cardiac allograft gene expression profiling test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1163 Cardiac allograft gene expression profiling test system....

  11. 21 CFR 862.1163 - Cardiac allograft gene expression profiling test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1163 Cardiac allograft gene expression profiling test system....

  12. 21 CFR 862.1163 - Cardiac allograft gene expression profiling test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1163 Cardiac allograft gene expression profiling test system....

  13. 21 CFR 862.1163 - Cardiac allograft gene expression profiling test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1163 Cardiac allograft gene expression profiling test system....

  14. Histopathology of cell mediated immune reaction in mouse colon--allograft rejection.

    PubMed Central

    Holden, R J; Ferguson, A

    1976-01-01

    Grafts of mouse fetal colon, implanted beneath the renal capsule of adult hosts, have been used to study the growth and development of colonic isografts and the rejection of colonic allografts. Isografts grew normally and maintained a structure similar to normal colon. Grafts between strains with H2 histocompatibility differences were rejected by 13 days after transplantation. Early progressive infiltration of the grafts by lymphoid cells was followed by increasing damage to, and subsequent loss of, the epithelial cell layer and destruction of the underlying muscle, changes which parallel those seen in rejection of skin and small bowel. The increase in survival time which is seen in allografts between strains with H2 identity was longer in the colon than has been seen in the skin or small bowel; none of the allografts of colon were completely rejected before 30 days, and some remained viable at 50 days. Comparison of the appearances of rejection in the colon with those of ulcerative colitis and colonic Crohn's disease does not show the striking similarity which is seen between small bowel rejection and coeliac disease. Many of the individual features of these diseases are, however, present in the course of colonic rejection. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 PMID:976806

  15. Medication management of cardiac allograft vasculopathy after heart transplantation.

    PubMed

    Hollis, Ian B; Reed, Brent N; Moranville, Michael P

    2015-05-01

    Cardiac allograft vasculopathy (CAV) is a common complication following heart transplantation (HT), resulting in diminished graft survival. The preferred strategy for preventing CAV is optimal medical management; however, for patients who develop CAV, delaying disease progression through effective medication management is equally important. A review of the literature regarding medication management of CAV was conducted via a search of the MEDLINE database. Studies were included if they were published in English, conducted in humans ≥ 18 years of age or older, and used noninvestigational medications. Immunosuppressive medications such as the antiproliferative mycophenolate, the calcineurin inhibitor tacrolimus, and the proliferation signal inhibitors sirolimus and everolimus have been shown to prevent the development of CAV. Certain cardiovascular medications, such as HMG-CoA reductase inhibitors (statins), gemfibrozil, calcium channel blockers, and angiotensin-converting enzyme inhibitors, have also demonstrated efficacy in preventing this disease process. Prevention of CAV has also been observed with prophylaxis against cytomegalovirus infection and antioxidant medications. Despite being commonly used in HT patients, neither antiplatelet agents nor glycemic control have proved effective at preventing CAV. Only sirolimus has been shown to arrest the progress of existing CAV. PMID:26011142

  16. Imaging of cardiac allograft rejection in dogs using indium-111 monoclonal antimyosin Fab

    SciTech Connect

    Addonizio, L.J.; Michler, R.E.; Marboe, C.; Esser, P.E.; Johnson, L.L.; Seldin, D.W.; Gersony, W.M.; Alderson, P.O.; Rose, E.A.; Cannon, P.J.

    1987-03-01

    The acute rejection of cardiac allografts is currently diagnosed by the presence of myocyte necrosis on endomyocardial biopsy. We evaluated the efficacy of noninvasive scintigraphic imaging with indium-111-labeled anticardiac myosin Fab fragments (indium-111 antimyosin) to detect and quantify cardiac allograft rejection. Six dogs that had intrathoracic heterotopic cardiac allograft transplantation were injected with indium-111 antimyosin and planar and single photon emission computed tomographic (SPECT) images were obtained in various stages of acute and subacute rejection. Four dogs had an allograft older than 8 months and had been on long-term immunosuppressive therapy; two dogs had an allograft less than 2 weeks old and were not on immunosuppressive therapy. Count ratios comparing heterotopic with native hearts were calculated from both SPECT images and in vitro scans of excised and sectioned hearts and were compared with the degree of rejection scored by an independent histopathologic review. Indium-111 antimyosin uptake was not visible in planar or SPECT images of native hearts. Faint diffuse uptake was apparent in cardiac allografts during long-term immunosuppression and intense radioactivity was present in hearts with electrocardiographic evidence of rejection. The heterotopic to native heart count ratios in SPECT images correlated significantly with the count ratios in the excised hearts (r = 0.93) and with the histopathologic rejection score (r = 0.97). The distribution of indium-111 antimyosin activity in right and left ventricles corresponded to areas of histopathologic abnormalities.

  17. International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy-2010.

    PubMed

    Mehra, Mandeep R; Crespo-Leiro, Maria G; Dipchand, Anne; Ensminger, Stephan M; Hiemann, Nicola E; Kobashigawa, Jon A; Madsen, Joren; Parameshwar, Jayan; Starling, Randall C; Uber, Patricia A

    2010-07-01

    The development of cardiac allograft vasculopathy remains the Achilles heel of cardiac transplantation. Unfortunately, the definitions of cardiac allograft vasculopathy are diverse, and there are no uniform international standards for the nomenclature of this entity. This consensus document, commissioned by the International Society of Heart and Lung Transplantation Board, is based on best evidence and clinical consensus derived from critical analysis of available information pertaining to angiography, intravascular ultrasound imaging, microvascular function, cardiac allograft histology, circulating immune markers, non-invasive imaging tests, and gene-based and protein-based biomarkers. This document represents a working formulation for an international nomenclature of cardiac allograft vasculopathy, similar to the development of the system for adjudication of cardiac allograft rejection by histology. PMID:20620917

  18. Induction of "infectious" tolerance to MHC-incompatible cardiac allografts in CD4 monoclonal antibody-treated sensitized rat recipients.

    PubMed

    Onodera, K; Lehmann, M; Akalin, E; Volk, H D; Sayegh, M H; Kupiec-Weglinski, J W

    1996-09-01

    LBNF1 heart grafts are rejected in an accelerated manner within 36 h by LEW rats that have been sensitized with Brown Norway rat skin grafts on day -7. Treatment with RIB-5/2, a CD4-nondepleting mAb (10 doses of 5 mg/rat/day, i.v., from day -7 to day +21) abrogated rejection at <36 h and produced indefinite (>200 days) cardiac allograft survival. Transplantation tolerance in this model developed within several weeks, and during the maintenance phase (>100 days) it was associated with diminished host circulating allo-Ab responses and induction of peripheral allospecific T cell unresponsiveness both in vitro and in vivo. Tolerant cells in mAb-treated hosts could disable naive or alloimmune cells, so that they failed to trigger graft rejection. Moreover, donor-specific and organ-nonspecific tolerance could be adoptively transferred by spleen cells alone into new sets of primary (100%) and secondary (>40%) test recipients. CD4+ T cells were instrumental for the induction of such readily transferable tolerance. The first and second generation suppressive regulatory cells were also critical for the inhibition of allograft recognition by normal or even alloimmune cells. Hence, the features of an "infectious" tolerance pathway to minor histocompatibility-mismatched skin grafts, originally described in thymectomized mice, may be applied to the euthymic primed rats rendered tolerant to fully MHC-incompatible vascularized organ allografts. Such reprogramming of host cell-mediated regulatory mechanisms following CD4-targeted therapy adds to our appreciation of the potential utility and applicability of infectious tolerance in transplant recipients treated with a perioperative course of CD4-targeted monotherapy. PMID:8757313

  19. Trichinella spiralis infection changes immune response in mice performed abdominal heterotopic cardiac transplantation and prolongs cardiac allograft survival time.

    PubMed

    Deng, Gengguo; Deng, Ronghai; Yao, Jianping; Liao, Bing; Chen, Yinghua; Wu, Zhongdao; Hu, Hongxing; Zhou, Xingwang; Ma, Yi

    2016-01-01

    Allograft rejection has been an obstacle for long-term survival of patients for many years. Current strategies for transplant rejection are not as optimal as we expected, especially for long-term treatments. Trichinella spiralis, a nematode parasitized in mammalian muscle and as an invader, maintains harmonious with host in the long term by evading host immune attack. To determine whether T. spiralis infection impacts on allograft rejection, we performed mice cardiac allograft transplantation model by using BALB/c (H-2(b)) mice as donors and C57BL/6 (H-2(b)) mice orally infected with 300 muscle larvae for 28 days as recipients. Graft survival was monitored by daily palpation of the abdomen; histologic change was observed by H&E stain; and CD4(+), CD8(+), CD4(+)IFN-γ(+), and CD4(+)IL-17(+) T cells and regulatory T cells were examined with the use of flow cytometry. Serum cytokine levels were measured by Luminex. Finally, we found that mean survival time of cardiac allografts in T. spiralis group was 23.40 ± 1.99 days, while the vehicle control group was 10.60 ± 0.75 days. Furthermore, we observed alleviated histological changes in the heart allograft, decreased corresponding CD8(+) T cells, suppressed Th1 and Th17 responses, and increased regulatory T cell frequency in a murine cardiac transplantation model at day 7 post-transplantation in experimental group. These data suggest that T. spiralis infection resulted in prolonged allograft survival following murine cardiac transplantation, with suppressed Th1/Th17 responses and augmented regulatory T cells. PMID:26481486

  20. CD8+IL-17+ T Cells Mediate Neutrophilic Airway Obliteration in T-bet–Deficient Mouse Lung Allograft Recipients

    PubMed Central

    Dodd-o, Jeffrey M.; Coon, Tiffany A.; Miller, Hannah L.; Ganguly, Sudipto; Popescu, Iulia; O'Donnell, Christopher P.; Cardenes, Nayra; Levine, Melanie; Rojas, Mauricio; Weathington, Nathaniel M.; Zhao, Jing; Zhao, Yutong; McDyer, John F.

    2015-01-01

    Acute cellular rejection is a known risk factor for the development of obliterative bronchiolitis, which limits the long-term survival of lung transplant recipients. However, the T cell effector mechanisms in both of these processes remain incompletely understood. Using the mouse orthotopic lung transplant model, we investigated whether C57BL/6 T-bet−/− recipients of major histocompatibility complex (MHC)-mismatched BALB/c lung grafts develop rejection pathology and allospecific cytokine responses that differ from wild-type mice. T-bet−/− recipients demonstrated vigorous allograft rejection at 10 days, characterized by neutrophilic inflammation and predominantly CD8+ T cells producing allospecific IL-17 and/or IFN-γ, in contrast to IFN-γ–dominant responses in WT mice. CD4+ T cells produced IL-17 but not IFN-γ responses in T-bet−/− recipients, in contrast to WT controls. Costimulation blockade using anti-CD154 Ab significantly reduced allospecific CD8+IFN-γ+ responses in both T-bet−/− and WT mice but had no attenuating effect on lung rejection pathology in T-bet−/− recipients or on the development of obliterative airway inflammation that occurred only in T-bet−/− recipients. However, neutralization of IL-17A significantly attenuated costimulation blockade–resistant rejection pathology and airway inflammation in T-bet−/− recipients. In addition, CXCL1 (neutrophil chemokine) was increased in T-bet−/− allografts, and IL-17 induced CXCL1 from mouse lung epithelial cells in vitro. Taken together, our data show that T-bet–deficient recipients of complete MHC-mismatched lung allografts develop costimulation blockade–resistant rejection characterized by neutrophilia and obliterative airway inflammation that is predominantly mediated by CD8+IL-17+ T cells. Our data support T-bet–deficient mouse recipients of lung allografts as a viable animal model to study the immunopathogenesis of small airway injury in lung transplantation

  1. Ischemia-Reperfusion Injury Enhances Lymphatic Endothelial VEGFR3 and Rejection in Cardiac Allografts.

    PubMed

    Dashkevich, A; Raissadati, A; Syrjälä, S O; Zarkada, G; Keränen, M A I; Tuuminen, R; Krebs, R; Anisimov, A; Jeltsch, M; Leppänen, V-M; Alitalo, K; Nykänen, A I; Lemström, K B

    2016-04-01

    Organ damage and innate immunity during heart transplantation may evoke adaptive immunity with serious consequences. Because lymphatic vessels bridge innate and adaptive immunity, they are critical in immune surveillance; however, their role in ischemia-reperfusion injury (IRI) in allotransplantation remains unknown. We investigated whether the lymphangiogenic VEGF-C/VEGFR3 pathway during cardiac allograft IRI regulates organ damage and subsequent interplay between innate and adaptive immunity. We found that cardiac allograft IRI, within hours, increased graft VEGF-C expression and lymphatic vessel activation in the form of increased lymphatic VEGFR3 and adhesion protein expression. Pharmacological VEGF-C/VEGFR3 stimulation resulted in early lymphatic activation and later increase in allograft inflammation. In contrast, pharmacological VEGF-C/VEGFR3 inhibition during cardiac allograft IRI decreased early lymphatic vessel activation with subsequent dampening of acute and chronic rejection. Genetic deletion of VEGFR3 specifically in the lymphatics of the transplanted heart recapitulated the survival effect achieved by pharmacological VEGF-C/VEGFR3 inhibition. Our results suggest that tissue damage rapidly changes lymphatic vessel phenotype, which, in turn, may shape the interplay of innate and adaptive immunity. Importantly, VEGF-C/VEGFR3 inhibition during solid organ transplant IRI could be used as lymphatic-targeted immunomodulatory therapy to prevent acute and chronic rejection. PMID:26689983

  2. 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.

  3. Induction of tolerance to cardiac allografts in lethally irradiated rats reconstituted with syngeneic bone marrow

    SciTech Connect

    Hartnett, L.C.

    1983-01-01

    Generally, organ grafts from one individual animal to another are rejected in one-two weeks. However, if the recipients are given Total Body Irradiation (TBI) just prior to grafting, followed by reconstitution of hemopoietic function with syngeneic (recipient-type) bone marrow cells, then vascularized organ grafts are permanently accepted. Initially after irradiation, it is possible to induce tolerance to many strain combinations in rats. This thesis examines the system of TBI as applied to the induction of tolerance in LEW recipients of WF cardiac allografts. These two rat strains are mismatched across the entire major histocompatibility complex. When the LEW recipient are given 860 rads, a WF cardiac allograft and LEW bone marrow on the same day, 60% of the grafts are accepted. Methods employed to improve the rate of graft acceptance include: treating either donor or recipient with small amounts of methotrexate, or waiting until two days after irradiation to repopulate with bone marrow. It seems from these investigations of some of the early events in the induction of tolerance to allografts following TBI and syngeneic marrow reconstitution that an immature cell population in the bone marrow interacts with a radioresistant cell population in the spleen to produce tolerance to completely MHC-mismatched allografts.

  4. Early allograft dysfunction in liver transplantation with donation after cardiac death donors results in inferior survival.

    PubMed

    Lee, David D; Singh, Amandeep; Burns, Justin M; Perry, Dana K; Nguyen, Justin H; Taner, C Burcin

    2014-12-01

    Donation after cardiac death (DCD) liver allografts have been associated with increased morbidity from primary nonfunction, biliary complications, early allograft failure, cost, and mortality. Early allograft dysfunction (EAD) after liver transplantation has been found to be associated with inferior patient and graft survival. In a cohort of 205 consecutive liver-only transplant patients with allografts from DCD donors at a single center, the incidence of EAD was found to be 39.5%. The patient survival rates for those with no EAD and those with EAD at 1, 3, and 5 years were 97% and 89%, 79% and 79%, and 61% and 54%, respectively (P = 0.009). Allograft survival rates for recipients with no EAD and those with EAD at 1, 3, and 5 years were 90% and 75%, 72% and 64%, and 53% and 43%, respectively (P = 0.003). A multivariate analysis demonstrated a significant association between the development of EAD and the cold ischemia time [odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.01-1.56, P = 0.037] and hepatocellular cancer as a secondary diagnosis in recipients (OR = 2.26, 95% CI = 1.11-4.58, P = 0.025). There was no correlation between EAD and the development of ischemic cholangiopathy. In conclusion, EAD results in inferior patient and graft survival in recipients of DCD liver allografts. Understanding the events that cause EAD and developing preventive or early therapeutic approaches should be the focus of future investigations. PMID:25179581

  5. 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.

  6. Prospective coronary angioscopy assessment of allograft coronary artery disease in human cardiac transplant recipients

    NASA Astrophysics Data System (ADS)

    Jain, Ashit; Ventura, Hector O.; Collins, Tyrone J.; Ramee, Stephen R.; White, Christopher J.

    1993-09-01

    Annual angiographic assessment to determine the presence or progression of allograft coronary artery disease (CAD) has been unable to modify the natural history of this disease. Coronary angioscopy is a sensitive method to detect the early presence of coronary artery disease and in a retrospective analysis severity of CAD by angioscopy correlated with the time since transplantation. The purpose of this study was to prospectively evaluate progression of coronary artery disease over a one year period in 40 cardiac transplant recipients. The progression of coronary artery disease as assessed by angioscopy is directly related to time after transplantation and therefore angioscopy may be the method of choice for detection and evaluation of therapeutic regimens to control allograft coronary artery disease.

  7. Use of [18F]FDG PET to Monitor The Development of Cardiac Allograft Rejection

    PubMed Central

    Daly, Kevin P.; Dearling, Jason L. J.; Seto, Tatsuichiro; Dunning, Patricia; Fahey, Frederic; Packard, Alan B.; Briscoe, David M.

    2014-01-01

    Background Positron Emission Tomography (PET) has the potential to be a specific, sensitive and quantitative diagnostic test for transplant rejection. To test this hypothesis, we evaluated 18F-labeled fluorodeoxyglucose ([18F]FDG) and 13N-labeled ammonia ([13N]NH3) small animal PET imaging in a well-established murine cardiac rejection model. Methods Heterotopic transplants were performed using minor MHC mismatched B6.C-H2bm12 donor hearts in C57BL/6(H-2b) recipients. C57BL/6 donor hearts into C57BL/6 recipients served as isograft controls. [18F]FDG PET imaging was performed weekly between post-transplant days 7 and 42 and the percent injected dose was computed for each graft. [13N]NH3 imaging was performed to evaluate myocardial perfusion. Results There was a significant increase in [18F]FDG uptake in allografts from day 14 to day 21 (1.6% to 5.2%; P<0.001) and uptake in allografts was significantly increased on post-transplant days 21 (5.2% vs. 0.9%; P=0.005) and 28 (4.8% vs. 0.9%; P=0.006) compared to isograft controls. Furthermore, [18F]FDG uptake correlated with an increase in rejection within allografts between days 14 and 28 post-transplant. Finally, the uptake of [13N]NH3 was significantly lower relative to the native heart in allografts with chronic vasculopathy compared to isograft controls on day 28 (P=0.01). Conclusions PET imaging with [18F]FDG can be used following transplantation to monitor the evolution of rejection. In addition, decreased uptake of [13N]NH3 in rejecting allografts may be reflective of decreased myocardial blood flow. These data suggest that combined [18F]FDG and [13N]NH3 PET imaging could be used as a non-invasive, quantitative technique for serial monitoring of allograft rejection and has potential application in human transplant recipients. PMID:25675207

  8. Nitric oxide formation in acutely rejecting cardiac allografts correlates with GTP cyclohydrolase I activity

    PubMed Central

    2005-01-01

    Inducible nitric oxide synthase (iNOS) is a prominent component of the complex array of mediators in acute graft rejection. While NO production is determined by iNOS expression, BH4 (tetrahydrobiopterin), a cofactor of iNOS synthesized by GTP cyclohydrolase I, has been considered critical in sustaining NO production. In the present study, we examined time-dependent changes in iNOS and GTP cyclohydrolase I in rat cardiac allografts. The increase in iNOS protein and mRNA in allografts was similar at POD4 (post-operative day 4) and POD6. However, the peak increase in intragraft NO level at POD4 was not sustained at POD6. This disparity could not be explained by any decrease in iNOS enzyme activity measured ex vivo with optimal amounts of substrate and cofactors. Lower iNOS activity could be explained by changes in total biopterin levels in allografts at POD4 that was decreased to baseline at POD6. Changes in biopterin production correlated with lower GTP cyclohydrolase I protein levels but not by any change in GTP cyclohydrolase I mRNA. Functionally, allografts displayed bradycardia and distended diastolic and systolic dimensions at POD6 but not at POD4. Likewise, histological rejection scores were increased at POD4 but with a secondary increased stage at POD6. It is hypothesized that the dissimilar amounts of NO at early and later stages of rejection is due to uncoupling of iNOS arising from disproportionate synthesis of BH4. These findings provide insight into a potential pathway regulating NO bioactivity in graft rejection. Such knowledge may potentially assist in the design of newer strategies to prevent acute graft rejection. PMID:16000090

  9. Arsenic trioxide attenuated the rejection of major histocompatibility complex fully-mismatched cardiac allografts in mice.

    PubMed

    Yan, S; Zhang, Q Y; Zhou, B; Xue, L; Chen, H; Wang, Y; Zheng, S S

    2009-06-01

    We investigated the effects of arsenic trioxide (As(2)O(3)) on allogeneic immune response using a mouse heart transplantation model. Mice were randomly divided into 4 groups of 6 animals each. The control group received phosphate-buffered saline (PBS); the As(2)O(3)-treated group, intraperitoneal (IP) injection of As(2)O(3) (1 mg/kg) from days -3 to 10 after heart transplantation. The cyclosporine (CsA)-treated group was given a subtherapeutic dose of CsA (10 mg/kg) IP, and the As(2)O(3) plus CsA-treated group, a combined protocol of As(2)O(3) and CsA. Six days after transplantation, cardiac allografts were harvested for immunohistology and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. The survival of the allografts was significantly improved among the As(2)O(3)-treated group compared with the control group (17.2 +/- 1.9 vs 8.0 +/- 0.9 days; P < .05). A marked prolongation (28.6 +/- 6.0 days) of graft survival was achieved by the combined protocol compared with the CsA-treated group (9.6 +/- 3.0 days; P < .05) or the As(2)O(3)-treated group. Allografts of As(2)O(3)-treated and As(2)O(3) plus CsA-treated mice showed a changing pattern of Th1/Th2 cytokine mRNA expression. Allograft rejection was apparently alleviated by low-dose As(2)O(3), and particularly when combined with a subtherapeutic CsA dose. PMID:19545743

  10. Rejection of cardiac allografts by T cells expressing a restricted repertoire of T-cell receptor V beta genes.

    PubMed Central

    Shirwan, H; Barwari, L; Cramer, D V

    1997-01-01

    We have recently shown that T cells infiltrating cardiac allografts early in graft rejection use a limited T-cell receptor (TCR) V beta repertoire. In this study we tested whether this limited repertoire of V beta genes is important for graft rejection. A cell line, AL2-L3, was established from LEW lymphocytes infiltrating ACI heart allografts 2 days after transplantation. This cell line is composed of CD4+ T cells that primarily recognize the class II RTI.B major histocompatibility complex (MHC) molecule expressed by the donor graft. This cell line precipitated acute rejection of donor hearts with a median survival time (MST) of 10.5 days following adoptive transfer to sublethally irradiated LEW recipients. This rate of graft rejection was significantly (P < 0.0007) accelerated when compared with a MST of 60 days for allografts in irradiated control recipients. The AL2-L3-mediated acceleration of graft rejection was donor specific as WF third-party heart allografts were rejected with a delayed tempo (MST = 28.5 days). The V beta repertoire of this cell line was primarily restricted to the expression of V beta 4, 15 and 19 genes. The nucleotide sequence analysis of the beta-chain cDNAs from this cell line demonstrated that the restricted use of the V gene repertoire was not shared with the N, D and J regions. A wide variety of CDR3 loops and J beta genes were used in association with selected V beta genes. These data provide evidence for the role a restricted repertoire of V beta genes plays in cardiac allograft rejection in this model. The restricted usage of the V beta repertoire in an early T-cell response to allografts may provide the opportunity to therapeutically disrupt the rejection reaction by targeting selected T-cell populations for elimination at the time of organ transplantation. Images Figure 2 PMID:9176111

  11. 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. PMID:19945064

  12. Effect of anti-interleukin 2 monoclonal antibody treatment on the survival of rat cardiac allograft

    SciTech Connect

    Sakagami, K.; Ohsaki, T.; Ohnishi, T.; Saito, S.; Matsuoka, J.; Orita, K.

    1989-03-01

    The effect of anti-interleukin 2 monoclonal antibody (anti-IL2 MoAb) and the accumulation of intravenously administered /sup 125/I-labeled anti-IL2 MoAb were examined in heterotopic rat cardiac allografts. Mouse anti-human recombinant IL2 MoAb was obtained by the hybridoma technique. The anti-IL2 MoAb, termed 8H-10, was an IgG2a which inhibited IL2-driven (/sup 3/H)TdR incorporation in cytolytic T lymphocyte line cells at a dilution of 2(6). 8H-10 was injected iv at a dose of 200 micrograms/day for 8 consecutive days, beginning on the day of transplantation. Hearts from F344 rats (RT11v1) were transplanted into ACI recipient rats (RT1av1). The mean survival time was 7.6 +/- 0.8 days in untreated controls, 9.0 +/- 1.2 days in additional controls treated with mouse anti-sheep red blood cell monoclonal antibody, and 25.3 +/- 18.4 days in the anti-IL2 MoAb (8H-10)-treated group (P less than 0.05). Furthermore, the accumulation of intravenously administered 125I-labeled anti-IL2 MoAb (8H-10) was specifically seen in the grafted heart. In conclusion, these results suggest that IL2 may play an important role in allograft rejection and that anti-IL2 MoAb may serve as a useful immunosuppressive agent in clinical transplantation.

  13. Statin therapy in cardiac allograft vasculopathy progression in heart transplant patients: Does potency matter?

    PubMed

    Sieg, Adam; Weeks, Phillip; Krustchinsky, Lori; Rajapreyar, Indranee

    2016-07-01

    Cardiac allograft vasculopathy (CAV) is a unique multi-factorial pathologic process encountered following heart transplantation. Several risk factors have been identified including a combination of immunologic and non-immunologic processes. Significant research has been conducted to elucidate the driving forces of CAV as well as improved identification, prevention and treatment strategies. Statin therapy following transplant remains the standard of care to help prevent the progression of CAV. The benefits of statin therapy following transplantation correspond to cholesterol control, anti-inflammatory and immunomodulatory mechanisms as well as potentially unknown mechanisms. Despite known drug interactions with calcineurin inhibitors, the use of statins is highly recommended in the current International Society for Heart and Lung Transplantation guidelines. Limited research has been conducted on the impact of higher intensity statin therapy following heart transplant and the relative risks and benefits are unknown. This review focuses on risk factors and pathophysiology of CAV, the role of statin therapy in heart transplantation, and the potential added benefit of more intense statin therapy to limit the progression of this graft-limiting complication. PMID:27079752

  14. Host-Derived Smooth Muscle Cells Accumulate in Cardiac Allografts: Role of Inflammation and Monocyte Chemoattractant Protein 1

    PubMed Central

    Bojakowski, Krzysztof; Soin, Joanna; Nozynski, Jerzy; Zakliczynski, Michal; Gaciong, Zbigniew; Zembala, Marian; Söderberg-Nauclér, Cecilia

    2009-01-01

    Transplant arteriosclerosis is characterized by inflammation and intimal thickening caused by accumulation of smooth muscle cells (SMCs) both from donor and recipient. We assessed the relationship between clinical factors and the presence of host-derived SMCs in 124 myocardial biopsies from 26 consecutive patients who received hearts from opposite-sex donors. Clinical and demographic information was obtained from the patients' medical records. Host-derived SMCs accounted for 3.35±2.3% of cells in arterioles (range, 0.08–12.51%). As shown by linear regression analysis, an increased number of SMCs was associated with rejection grade (mean, 1.41±1.03, p = 0.034) and the number of leukocytes (19.1±12.7 per 20 high-power fields, p = 0.01). The accumulation of host-derived SMCs was associated with an increased number of leukocytes in the allografts. In vitro, monocyte chemoattractant protein 1 (MCP-1) released from leukocytes was crucial for SMC migration. After heart allotransplantion, mice treated with MCP-1-specific antibodies had significantly fewer host-derived SMCs in the grafts than mice treated with isotypic antibody controls. We conclude that the number of host-derived SMCs in human cardiac allografts is associated with the rejection grade and that MCP-1 may play pivotal role in recruiting host-derived SMCs into cardiac allografts. PMID:19142231

  15. Donor Heart Treatment With COMP-Ang1 Limits Ischemia-Reperfusion Injury and Rejection of Cardiac Allografts.

    PubMed

    Syrjälä, S O; Nykänen, A I; Tuuminen, R; Raissadati, A; Keränen, M A I; Arnaudova, R; Krebs, R; Koh, G Y; Alitalo, K; Lemström, K B

    2015-08-01

    The major cause of death during the first year after heart transplantation is primary graft dysfunction due to preservation and ischemia-reperfusion injury (IRI). Angiopoietin-1 is a Tie2 receptor-binding paracrine growth factor with anti-inflammatory properties and indispensable roles in vascular development and stability. We used a stable variant of angiopoietin-1 (COMP-Ang1) to test whether ex vivo intracoronary treatment with a single dose of COMP-Ang1 in donor Dark Agouti rat heart subjected to 4-h cold ischemia would prevent microvascular dysfunction and inflammatory responses in the fully allogeneic recipient Wistar Furth rat. COMP-Ang1 reduced endothelial cell-cell junction disruption of the donor heart in transmission electron microscopy during 4-h cold ischemia, improved myocardial reflow, and reduced microvascular leakage and cardiomyocyte injury of transplanted allografts during IRI. Concurrently, the treatment reduced expression of danger signals, dendritic cell maturation markers, endothelial cell adhesion molecule VCAM-1 and RhoA/Rho-associated protein kinase activation and the influx of macrophages and neutrophils. Furthermore, COMP-Ang1 treatment provided sustained anti-inflammatory effects during acute rejection and prevented the development of cardiac fibrosis and allograft vasculopathy. These results suggest donor heart treatment with COMP-Ang1 having important clinical implications in the prevention of primary and subsequent long-term injury and dysfunction in cardiac allografts. PMID:25932532

  16. Targeting Sirtuin-1 prolongs murine renal allograft survival and function.

    PubMed

    Levine, Matthew H; Wang, Zhonglin; Xiao, Haiyan; Jiao, Jing; Wang, Liqing; Bhatti, Tricia R; Hancock, Wayne W; Beier, Ulf H

    2016-05-01

    Current immunosuppressive medications used after transplantation have significant toxicities. Foxp3(+) T-regulatory cells can prevent allograft rejection without compromising protective host immunity. Interestingly, inhibiting the class III histone/protein deacetylase Sirtuin-1 can augment Foxp3(+) T-regulatory suppressive function through increasing Foxp3 acetylation. Here we determined whether Sirtuin-1 targeting can stabilize biological allograft function. BALB/c kidney allografts were transplanted into C57BL/6 recipients with a CD4-conditional deletion of Sirtuin-1 (Sirt1(fl/fl)CD4(cre)) or mice treated with a Sirtuin-1-specific inhibitor (EX-527), and the native kidneys removed. Blood chemistries and hematocrit were followed weekly. Sirt1(fl/fl)CD4(cre) recipients showed markedly longer survival and improved kidney function. Sirt1(fl/fl)CD4(cre) recipients exhibited donor-specific tolerance, accepted BALB/c, but rejected third-party C3H cardiac allografts. C57BL/6 recipients of BALB/c renal allografts that were treated with EX-527 showed improved survival and renal function at 1, but not 10 mg/kg/day. Pharmacologic inhibition of Sirtuin-1 also improved renal allograft survival and function with dosing effects having relevance to outcome. Thus, inhibiting Sirtuin-1 can be a useful asset in controlling T-cell-mediated rejection. However, effects on non-T cells that could adversely affect allograft survival and function merit consideration. PMID:27083279

  17. Noninvasive cardiac risk stratification of diabetic and nondiabetic uremic renal allograft candidates using dipyridamole-thallium-201 imaging and radionuclide ventriculography

    SciTech Connect

    Brown, K.A.; Rimmer, J.; Haisch, C. )

    1989-11-01

    The ability of noninvasive risk stratification using dipyridamole-thallium-201 (Tl-201) imaging and radionuclide ventriculography to predict perioperative and long-term cardiac events (myocardial infarction or cardiac death) was evaluated in 36 uremic diabetic and 29 nondiabetic candidates for renal allograft surgery. Of the 35 patients who underwent renal allograft surgery 8 +/- 7 months after the study, none had transient Tl-201 defects (although 13 had depressed left ventricular ejection fraction) and none developed perioperative cardiac events. During a mean follow-up of 23 +/- 11 months, 6 (9%) patients developed cardiac events. Logistic regression analysis was used to compare the predictive value of clinical data (including age, sex, diabetes, chest pain history, allograft recipient) and radionuclide data. Presence of transient Tl-201 defect and left ventricular ejection fraction were the only significant predictors of future cardiac events (p less than 0.01). No other patient variables, including diabetes or receiving a renal allograft, had either univariate or multivariate predictive value. All 3 patients with transient Tl-201 defects had cardiac events compared with only 3 of 62 (5%) patients without transient Tl-201 defect (p less than 0.0001). Mean left ventricular ejection fraction was lower in patients with cardiac events (44 +/- 13%) compared with patients without cardiac events (57 +/- 9%, p less than 0.005). Overall, 5 of 6 patients with cardiac events had either transient Tl-201 defects or depressed left ventricular ejection fraction. Dipyridamole-Tl-201 imaging and radionuclide ventriculography may be helpful in identifying uremic candidates for renal allograft surgery who are at low risk for perioperative and long-term cardiac events.

  18. In vitro analysis of T cell-mediated cytotoxicity displayed by rat heart allograft recipients rendered unresponsive by total-lymphoid irradiation and extracted donor antigen

    SciTech Connect

    Florence, L.S.; Jiang, G.L.; Ang, K.K.; Stepkowski, S.M.; Kahan, B.D. )

    1990-02-01

    The addition of 3M KCl-extracted donor antigen (HAg) to immunosuppressive therapy with 16 Gy total lymphoid irradiation produces a significantly higher fraction of Wistar-Furth (WFu) recipients displaying indefinite survival of heterotopic buffalo (BUF) heart allografts, namely 80 versus 20%. The experiments presented herein analyzed the direct activity as well as estimated the potential precursor numbers at 1 and 3 months in treated recipients. At 1 month post-TLI/HAg therapy, recipients showed reduced proliferative responses in mixed lymphocyte reactions (MLR) in a specific pattern toward donor but not third-party stimulators. Both TLI/Graft and TLI/HAg/Graft groups showed a higher frequency of BUF antigen-directed T-cytotoxic cells (fTc) than TLI-treated, but nontransplanted, WFu hosts. In addition, the TLI/HAg group alone displayed alloantigen-specific suppressor cells that suppressed the MLR proliferative responses of normal spleen T cells against donor, but not third-party, alloantigens. At 3 months postirradition, both TLI/Graft and TLI/HAg/Graft groups displayed variable MLR proliferative responses toward donor and third-party alloantigens. Whereas nontransplanted, TLI-treated WFu rats recovered their fTc to normal levels at 3 months, the TLI and TLI/HAg treated recipients bearing functional heart allografts demonstrated significantly decreased splenic fTc. These results show that reduced numbers of cytotoxic cell precursors may afford more reliable indices of prolonged heart allograft survival than MLR responses. The observations suggest that TLI/HAg transplant hosts display both reduced cytotoxic precursors and activated suppressor elements.

  19. Reduced Progression of Cardiac Allograft Vasculopathy with Routine Use of Induction Therapy with Basiliximab

    PubMed Central

    Wang, Ricardo; Moura, Lidia Ana Zytynski; Lopes, Sergio Veiga; da Costa, Francisco Diniz Affonso; Souza Filho, Newton Fernando Stadler; Fernandes, Tiago Luiz; Salvatti, Natália Boing; Faria Neto, José Rocha

    2015-01-01

    Background Cardiac allograft vasculopathy (CAV) is a major limitation for long-term survival of patients undergoing heart transplantation (HT). Some immunosuppressants can reduce the risk of CAV. Objectives The primary objective was to evaluate the variation in the volumetric growth of the intimal layer measured by intracoronary ultrasound (IVUS) after 1 year in patients who received basiliximab compared with that in a control group. Methods Thirteen patients treated at a single center between 2007 and 2009 were analyzed retrospectively. Evaluations were performed with IVUS, measuring the volume of a coronary segment within the first 30 days and 1 year after HT. Vasculopathy was characterized by the volume of the intima of the vessel. Results Thirteen patients included (7 in the basiliximab group and 6 in the control group). On IVUS assessment, the control group was found to have greater vessel volume (120–185.43 mm3 vs. 127.77–131.32 mm3; p = 0.051). Intimal layer growth (i.e., CAV) was also higher in the control group (27.30–49.15 mm3 [∆80%] vs. 20.23–26.69 mm3 [∆33%]; p = 0.015). Univariate regression analysis revealed that plaque volume and prior atherosclerosis of the donor were not related to intima growth (r = 0.15, p = 0.96), whereas positive remodeling was directly proportional to the volumetric growth of the intima (r = 0.85, p < 0.001). Conclusion Routine induction therapy with basiliximab was associated with reduced growth of the intima of the vessel during the first year after HT. PMID:26107815

  20. Music exposure induced prolongation of cardiac allograft survival and generated regulatory CD4⁺ cells in mice.

    PubMed

    Uchiyama, M; Jin, X; Zhang, Q; Amano, A; Watanabe, T; Niimi, M

    2012-05-01

    In clinical practice, music has been used to decrease stress, heart rate, and blood pressure and to provide a distraction from disease symptoms. We investigated sound effects on alloimmune responses in murine heart transplantation. Naïve and eardrum-ruptured CBA/N (CBA, H2(K)) underwent transplantation of a C57BL/6 (B6, H2(b)) heart and were exposed to 1 of 3 types of music-opera (La Traviata), classical (Mozart), and New Age (Enya)-or 1 of 6 different single sound frequencies for 7 days. An adoptive transfer study was performed to determine whether regulatory cells were generated in allograft recipients. Cell-proliferation, cytokine, and flow cytometry assessments were also performed. CBA recipients of a B6 graft exposed to opera and classical music had significantly prolonged allograft survival (median survival times [MSTs], 26.5 and 20 days, respectively), whereas those exposed to 6 single sound frequencies and New Age did not (MSTs, 7, 8, 9, 8, 8, 8, and 11 days, respectively). Untreated and eardrum-ruptured CBA rejected B6 grafts acutely (MSTs, 7 and 8.5 days, respectively). Adoptive transfer of whole splenocytes, CD4(+) cells, and CD4(+)CD25(+) cells from opera-exposed primary recipients resulted in significantly prolonged allograft survival in naive secondary recipients (MSTs, 36, 68, and >50 days, respectively). Cell-proliferation, interleukin (IL)-2 and interferon-γ were suppressed in opera-exposed mice, whereas IL-4 and IL-10 from opera-exposed recipients were up-regulated. Flow cytometry studies showed an increased CD4(+)CD25(+)Foxp3(+) cell population in splenocytes from opera-exposed mice. In conclusion, exposure to some types of music may induce prolonged survival of fully allogeneic cardiac allografts and generate CD4(+)CD25(+)Foxp3(+) regulatory cells. PMID:22564629

  1. Diagnostic Performance of Echocardiography for the Detection of Acute Cardiac Allograft Rejection: A Systematic Review and Meta-Analysis

    PubMed Central

    Pan, Xudong; Sun, Lizhong

    2015-01-01

    Objective Many studies have addressed the diagnostic performance of echocardiography to evaluate acute cardiac allograft rejection compared with endomyocardial biopsy. But the existence of heterogeneity limited its clinical application. Thus, we conducted a comprehensive, systematic literature review and meta-analysis for the purpose. Methods Studies prior to September 1, 2014 identified by Medline/PubMed, EMBASE and Cochrance were examined by two independent reviews. We conducted meta-analysis by using Meta-DiSc 1.4 software. An assessment tool of QUADAS-2 was applied to evaluate the risk of bias and applicability of the studies. Results Thirty studies met the inclusion criteria of meta-analysis. The four parameters of pressure half time, isovolumic relaxation time, index of myocardial performance and late diastolic mitral annular motion velocity were included in the meta-analysis, with a pooled diagnostic odds ratio of 10.43, 6.89, 15.95 and 5.68 respectively, and the area under the summary receiver operating characteristic curves value of 0.829, 0.599, 0.871 and 0.685 respectively. Conclusion The meta-analysis and systematic review demonstrate that no single parameter of echocardiography showed a reliable diagnostic performance for acute cardiac allograft rejection. A result of echocardiography for ACAR should be comprehensively considered by physicians in the context of clinical presentations and imaging feature. PMID:25822627

  2. Sirt1-Positive Lymphocytes in Acute Cellular Cardiac Allograft Rejection: Contributor to Pathogenesis and a Therapeutic Target.

    PubMed

    Welsh, Kerry J; Zhao, Bihong; Buja, L Maximilian; Brown, Robert E

    2016-01-01

    Cardiac allograft rejection remains a problem, despite advances with immunosuppressants. Understanding the mechanisms behind rejection is essential for developing targeted therapies. The goal of this investigation is to explore Sirtuin 1 (Sirt1) as a therapeutic target for cardiac allograft rejection. Thirteen endomyocardial biopsy specimens with acute cellular rejection (grade 2R or 3R) were selected. CD3, CD4, CD8, CD20, CD68, T-cell intracytoplasmic antigen (TIA-1), and Sirt1 expressions were determined by immunohistochemical stains. Comparison of Sirt1 expression was made with 10 cases of grade 0R and grade 1R. Quantitative image analysis was performed. There were 2 cases of grade 3R and 11 cases of grade 2R acute cellular rejection. Sirtuin 1 expression was present in the majority of mononuclear cells (median percentage, 73.5; interquartile range, 51.2-100%); staining was also observed in cardiomyocytes. Twelve of the 13 cases (92.3%) had an elevated CD8/FoxP3 ratio, coinciding with acute cellular rejection. Sirtuin 1 expression in the nuclei of FoxP3+ cells can lead to deacetylation and inactivation of FoxP3 rendering the T-suppressor cells inactive and promoting acute cellular rejection. The use of a Sirt1 inhibitor may be a therapeutic option in expanding the functionality of the FoxP3+ T-suppressor cells and moderating the severity of such rejection. PMID:26771391

  3. Induction of tolerance to cardiac allografts using donor splenocytes engineered to display on their surface an exogenous fas ligand protein.

    PubMed

    Yolcu, Esma S; Gu, Xiao; Lacelle, Chantale; Zhao, Hong; Bandura-Morgan, Laura; Askenasy, Nadir; Shirwan, Haval

    2008-07-15

    The critical role played by Fas ligand (FasL) in immune homeostasis renders this molecule an attractive target for immunomodulation to achieve tolerance to auto- and transplantation Ags. Immunomodulation with genetically modified cells expressing FasL was shown to induce tolerance to alloantigens. However, genetic modification of primary cells in a rapid, efficient, and clinically applicable manner proved challenging. Therefore, we tested the efficacy of donor splenocytes rapidly and efficiently engineered to display on their surface a chimeric form of FasL protein (SA-FasL) for tolerance induction to cardiac allografts. The i.p. injection of ACI rats with Wistar-Furth rat splenocytes displaying SA-FasL on their surface resulted in tolerance to donor, but not F344 third-party cardiac allografts. Tolerance was associated with apoptosis of donor reactive T effector cells and induction/expansion of CD4(+)CD25(+)FoxP3(+) T regulatory (Treg) cells. Treg cells played a critical role in the observed tolerance as adoptive transfer of sorted Treg cells from long-term graft recipients into naive unmanipulated ACI rats resulted in indefinite survival of secondary Wistar-Furth grafts. Immunomodulation with allogeneic cells rapidly and efficiently engineered to display on their surface SA-FasL protein provides an effective and clinically applicable means of cell-based therapy with potential application to regenerative medicine, transplantation, and autoimmunity. PMID:18606644

  4. Use of indium-111-labeled cells in measurement of cellular dynamics of experimental cardiac allograft rejection

    SciTech Connect

    Oluwole, S.; Wang, T.; Fawwaz, R.; Satake, K.; Nowygrod, R.; Reemtsma, K.; Hardy, M.A.

    1981-01-01

    This study evaluates the kinetics and utility of infused indium-111-labeled cells in detecting rejection in ACI to Lewis rat heart allografts. Syngeneic leukocytes, lymph node lymphocytes, and platelets were isolated and labeled with indium-111 (/sup 111/In) oxine, respectively, and were infused i.v. into Lewis rats carrying beating ACI or syngeneic hearts from post-transplant days 0 to 6. Recipients were imaged serially at 24 hr after infusion of labeled cells followed by excision of both native and transplanted hearts for direct isotope count. Labeled leukocytes accumulative progressively in the allograft with the scan becoming positive by post-transplant day 4. The ratio of allograft to native heart isotope counts rose from 1.25 on day 1 to 10.07 (P less than 0.0001) on day 7. The Lewis recipients infused with labeled lymphocytes showed a positive scan on days 6 and 7 whereas the allograft to native heart isotope count ratio rose from 0.97 on day 1 to 5.33 (P less than 0.001) on day 7. Recipients infused with /sup 111/In-labeled platelets showed a positive scan on days 5 to 7 and the allograft to native heart isotope count ratio rose sharply from 2.56 on day 4 to 16.98 (P less than 0.005) on day 7. Syngeneic heart grafts failed to demonstrate significant accumulation of any of the labeled cell population. These studies confirm the importance of nonlymphocytic cells in cellular rejection, evaluate the kinetics of graft invasion by the various cell types, and suggest that the techniques used afford a method for a safe and an early detection of allograft rejection.

  5. A peptide tetramer Tk-tPN induces tolerance of cardiac allografting by conversion of type 1 to type 2 immune responses via the Toll-like receptor 2 signal-promoted activation of the MCP1 gene.

    PubMed

    Li, Zuoqing; Yang, Neng; Zhou, Ling; Gu, Peng; Wang, Hui; Zhou, Yun; Zhou, Peijun; Lu, Liming; Chou, Kuang-Yen

    2016-03-01

    The plant protein trichosanthin (Tk) and its derived peptide tetramer Tk-tPN have been shown to stimulate the type 2 immune responses for treating autoimmune disease. This work explores the possibility of using Tk-tPN as a non-toxic immunosuppressant to induce transplantation tolerance using the mechanisms by which T-cell-mediated immune responses are transferred from type 1 to type 2 through innate immunity-related pathways. Immunocytes and cytokine secretions involved in the mouse cardiac allografting model with Tk-tPN treatment were characterized. Identification of critical genes and analysis of their functions through Toll-like receptor (TLR) -initiated signalling and the possible epigenetic changes were performed. Mean survival times of the cardiac allografts were delayed from 7.7 ± 0.3 days (control) to 22.7 ± 3.9 days (P < 0.01) or 79.1 ± 19.2 days (P < 0.0001) when Tk-tPN was introduced into the recipients alone or together with rapamycin, respectively. The grafting tolerance was donor-specific. The secretion pattern of the type 1 cytokine/transcription factor (IL-2(+) IFN-γ(+) T-bet(+)), which is responsible for the acute graft rejection, was shifted to the type 2 factor (IL-4(+) IL-10(+) Gata3+), together with a selective expansion of the IL-4/IL-10-producing CD8+ CD28- regulatory T-cell subset. A TLR2-initiated high expression of chemokine gene MCP1 was detectable simultaneously. Epigenetically Tk/Tk-tPN could also acetylate the histone H3K9 of MCP1 promoter to skew the immunity towards T helper type 2 responses. Tk/Tk-tPN is therefore capable of down-regulating the type 1 response-dominant rejection of cardiac allografts by evoking type 2 immunity through the activation of a TLR2-initiated signalling pathway and MCP1 gene to expand the IL-4/IL-10-secreting CD8+ CD28- regulatory T cells. Tk-tPN could be a promising novel immunosuppressant to induce tolerance in allotransplantation. PMID:26694804

  6. Human umbilical cord mesenchymal stromal cells suppress MHC class II expression on rat vascular endothelium and prolong survival time of cardiac allograft

    PubMed Central

    Qiu, Ying; Yun, Mark M; Han, Xia; Zhao, Ruidong; Zhou, Erxia; Yun, Sheng

    2014-01-01

    Background: Human umbilical cord mesenchymal stromal cells (UC-MSCs) have low immunogenicity and immune regulation. To investigate immunomodulatory effects of human UC-MSCs on MHC class II expression and allograft, we transplanted heart of transgenic rats with MHC class II expression on vascular endothelium. Methods: UC-MSCs were obtained from human umbilical cords and confirmed with flow cytometry analysis. Transgenic rat line was established using the construct of human MHC class II transactivator gene (CIITA) under mouse ICAM-2 promoter control. The induced MHC class II expression on transgenic rat vascular endothelial cells (VECs) was assessed with immunohistological staining. And the survival time of cardiac allograft was compared between the recipients with and without UC-MSC transfusion. Results: Flow cytometry confirmed that the human UC-MSCs were positive for CD29, CD44, CD73, CD90, CD105, CD271, and negative for CD34 and HLA-DR. Repeated infusion of human UC-MSCs reduced MHC class II expression on vascular endothelia of transplanted hearts, and increased survival time of allograft. The UC-MSCs increased regulatory cytokines IL10, transforming growth factor (TGF)-β1 and suppressed proinflammatory cytokines IL2 and IFN-γ in vivo. The UC-MSC culture supernatant had similar effects on cytokine expression, and decreased lymphocyte proliferation in vitro. Conclusions: Repeated transfusion of the human UC-MSCs reduced MHC class II expression on vascular endothelia and prolonged the survival time of rat cardiac allograft. PMID:25126177

  7. Effect of graft preservation and acute rejection on hypoxia-inducible factor-1 in rat cardiac allografts.

    PubMed

    Keränen, M A I; Nykänen, A I; Krebs, R; Tuuminen, R; Sandelin, H; Koskinen, P K; Lemström, K B

    2006-12-01

    Hypoxia plays an integral part in cardiac transplantation as prolonged graft preservation is an individual risk factor for the development of cardiac allograft vasculopathy (CAV). In this study we characterized the role of hypoxia-inducible factor-1 (HIF-1) during prolonged graft preservation, ischemia-reperfusion (I/R), acute rejection, and chronic rejection. Heart transplantations were performed from Dark Agouti (DA) to Wister-Furth (allo) or DA to DA (syn) rats, without immunosuppression (acute rejection model, harvested at day 5) or with cyclosporine (chronic rejection model, harvested at day 60). To study the effect of preservation on HIF-1 regulation, normal DA hearts were subjected to different cold ischemia times with or without 45 minutes of additional warm ischemia. The role of I/R was studied by harvesting syngrafts at different time points after reperfusion. Real-time reverse-transcriptase polymerase chain reaction quantified total HIF-1 mRNA, while enzyme-linked immunosorbent assay and immunohistochemistry quantified and localized HIF-1 protein. Our results show that HIF-1 nuclear immunoreactivity is increased during graft preservation and I/R leads to loss of nuclear HIF-1 immunoreactivity. Acute rejection induced HIF-1 in mRNA level. Our findings thus indicated that HIF-1 is activated during transplantation and suggested that manipulation of the HIF-1 pathway might reveal new therapeutic options to manage CAV. PMID:17175275

  8. The Impact of Ischemia/Reperfusion Injury on Liver Allografts from Deceased after Cardiac Death versus Deceased after Brain Death Donors

    PubMed Central

    Xu, Jin; Sayed, Blayne Amir; Casas-Ferreira, Ana Maria; Srinivasan, Parthi; Heaton, Nigel; Rela, Mohammed; Ma, Yun; Fuggle, Susan; Legido-Quigley, Cristina; Jassem, Wayel

    2016-01-01

    Background and aims The shortage of organs for transplantation has led to increased use of organs procured from donors after cardiac death (DCD). The effects of cardiac death on the liver remain poorly understood, however. Using livers obtained from DCD versus donors after brain death (DBD), we aimed to understand how ischemia/reperfusion (I/R) injury alters expression of pro-inflammatory markers ceramides and influences graft leukocyte infiltration. Methods Hepatocyte inflammation, as assessed by ceramide expression, was evaluated in DCD (n = 13) and DBD (n = 10) livers. Allograft expression of inflammatory and cell death markers, and allograft leukocyte infiltration were evaluated from a contemporaneous independent cohort of DCD (n = 22) and DBD (n = 13) livers. Results When examining the differences between transplant stages in each group, C18, C20, C24 ceramides showed significant difference in DBD (p<0.05) and C22 ceramide (p<0.05) were more pronounced for DCD. C18 ceramide is correlated to bilirubin, INR, and creatinine after transplant in DCD. Prior to transplantation, DCD livers have reduced leukocyte infiltration compared to DBD allografts. Following reperfusion, the neutrophil infiltration and platelet deposition was less prevalent in DCD grafts while cell death and recipients levels of serum aspartate aminotransferase (AST) of DCD allografts had significantly increased. Conclusion These data suggest that I/R injury generate necrosis in the absence of a strong inflammatory response in DCD livers with an appreciable effect on early graft function. The long-term consequences of increased inflammation in DBD and increased cell death in DCD allografts are unknown and warrant further investigation. PMID:26863224

  9. Cardiac allograft vasculopathy: optical coherence guided innovative treatment options with the bioresorbable vascular scaffold: proof of concept.

    PubMed

    Édes, István F; Hajas, Ágota; Sax, Balázs; Bartykowszki, Andrea; Becker, Dávid; Merkely, Béla

    2016-08-01

    The aim of our work was to assess a novel interventional therapy option in cardiac allograft vasculopathy (CAV), a complex form of coronary disease presenting only in heart transplant (HTx) recipients. It is typically a rapidly progressing phenomenon, affecting the entire coronary circulation causing diffuse, severe coronary lesions and has no one unique cause. Treatment options are limited, but where eligible, palliation via percutaneous revascularization (PCI) mainly using new generation drug eluting stents (DES) is recommended. Our working group sought to assess outcomes of CAV PCI using an Absorb (Abbott Vascular, Santa Clara, CA, USA) fully bioresorbable, everolimus eluting vascular scaffold (BVS), under optical coherence tomography (OCT) guidance. Our initial, proof-of-concept case showed a late CAV, macrophage and foam-cell rich lesion, with typical asymmetric intimal hyperplasia and contralateral thin-cap fibroatheroma formation. Post-PCI OCT showed underexpansion, requiring aggressive postdilatation. Ninety-day follow-up CT angiogram identified the scaffold and displayed a patent lumen of the device. BVS use thus seems eligible in CAV, yet needs proper, meticulous implantation. Use may also delay CAV progression as lesion healing is promoted, with restoration of vasomotion and a natural increase in vascular lumen. Furthermore, the chronically present vascular irritation surrounding stent/scaffold struts may subside, as no permanent metal is present as an increased substrate for inflammation. To assess full efficacy, further studies will be needed. PMID:27152623

  10. Captopril and platelet-activating factor (PAF) antagonist prevent cardiac allograft vasculopathy in rats: role of endogenous PAF and PAF-like compounds.

    PubMed

    Crawford, S E; Huang, L; Hsueh, W; Takami, H; Gonzalez-Crussi, F; Backer, C L; Mu, Y; Liu, H; Mavroudis, C

    1999-05-01

    Accelerated coronary artery disease (CAD) is the leading cause of late mortality following cardiac transplantation. The vascular lesions are characterized by myointimal proliferation and perivascular mononuclear inflammatory infiltrates. Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a potent phospholipid mediator produced by inflammatory cells and activated endothelial cells. Angiotensin II is known to activate phospholipase A2, a critical enzyme in PAF synthesis. Using a rat heterotopic cardiac transplant model known to induce graft CAD, we previously reported that chronic administration of captopril, an angiotensin converting enzyme inhibitor, reduces intimal proliferation and maintains luminal patency. The purpose of the current study was to determine if captopril regulates vascular remodeling by suppressing PAF synthesis and whether administration of a PAF antagonist ameliorates graft CAD. Captopril was found to decrease levels of PAF and PAF-like compounds as well as reduce intimal lesions, decrease cellular rejection grade, and diminish allograft heart weights. Treatment with a PAF antagonist significantly decreased proliferation of the intimal component of the vasculopathy and caused regression of the cardiac hypertrophy, but had no significant effect on cellular rejection. In contrast, untreated animals had elevated plasma PAF levels, elevated heart weights, and severe myointimal proliferation with luminal stenosis 21 days post-transplantation. These observations suggest that graft CAD is mediated, in part, by PAF and PAF-like compounds, and suppression of endogenous PAF may prevent cardiac allograft vasculopathy. PMID:10363692

  11. Effects of tolerance induction on the actions of interferon-gamma on porcine cardiac allografts.

    PubMed

    Hoerbelt, R; Benjamin, L C; Shoji, T; Johnston, D R; Muniappan, A; Guenther, D A; Allan, J S; Houser, S L; Madsen, J C

    2006-12-01

    It is well known that interferon-gamma (IFN-gamma) not only plays a critical role in antigen-dependent but also in antigen-independent tissue injury; however, it is not clear how tolerance induction affects the actions of IFN-gamma in the transplant setting. To address this question, we compared the effects of IFN-gamma on porcine recipients of near-syngeneic, rejecting, and tolerant heart transplants. IFN-gamma was infused continuously into the left anterior descending artery of hearts transplanted into 3 groups of major histocompatibility complex (MHC) inbred miniature swine, each treated with a 12-day course of cyclosporine A (CyA). Group 1 recipients received a MHC class I disparate heart, group 2 recipients received a near-syngeneic heart, and group 3 recipients were cotransplanted with a MHC class I disparate heart and kidney, which uniformly induces tolerance to both grafts. An additional group of animals was not transplanted but received intracoronary IFN-gamma infusion into their native hearts. IFN-gamma perfusion not only accelerated the acute rejection of MHC class I disparate hearts (mean survival time = 19 +/- 7.21 vs 38 +/- 8.19 days, P = .025), but caused near-syngeneic heart transplants, which otherwise survive indefinitely, to reject within 35 days (n = 3). In contrast, IFN-gamma perfusion had no demonstrable effects on interstitial rejection, the development of vascular lesions, or graft survival in tolerant heart plus kidney allograft recipients (n = 4) or in autologous hearts (n = 2). These results suggest that tolerance induction mitigates the damaging effects of IFN-gamma itself and that the beneficial effects of tolerance induction on acute and chronic rejection may extend to antigen-independent factors like ischemia/reperfusion injury. PMID:17175220

  12. Platelet factor 4 limits Th17 differentiation and cardiac allograft rejection.

    PubMed

    Shi, Guanfang; Field, David J; Ko, Kyung-ae; Ture, Sara; Srivastava, Kalyan; Levy, Scott; Kowalska, M Anna; Poncz, Mortimer; Fowell, Deborah J; Morrell, Craig N

    2014-02-01

    Th cells are the major effector cells in transplant rejection and can be divided into Th1, Th2, Th17, and Treg subsets. Th differentiation is controlled by transcription factor expression, which is driven by positive and negative cytokine and chemokine stimuli at the time of T cell activation. Here we discovered that chemokine platelet factor 4 (PF4) is a negative regulator of Th17 differentiation. PF4-deficient and platelet-deficient mice had exaggerated immune responses to cardiac transplantation, including increased numbers of infiltrating Th17 cells and increased plasma IL-17. Although PF4 has been described as a platelet-specific molecule, we found that activated T cells also express PF4. Furthermore, bone marrow transplantation experiments revealed that T cell-derived PF4 contributes to a restriction in Th17 differentiation. Taken together, the results of this study demonstrate that PF4 is a key regulator of Th cell development that is necessary to limit Th17 differentiation. These data likely will impact our understanding of platelet-dependent regulation of T cell development, which is important in many diseases, in addition to transplantation. PMID:24463452

  13. Permanent acceptance of mouse cardiac allografts with CD40 siRNA to induce regulatory myeloid cells by use of a novel polysaccharide siRNA delivery system.

    PubMed

    Zhang, Q; Ichimaru, N; Higuchi, S; Cai, S; Hou, J; Fujino, M; Nonomura, N; Kobayashi, M; Ando, H; Uno, A; Sakurai, K; Mochizuki, S; Adachi, Y; Ohno, N; Zou, H; Xu, J; Li, X-K; Takahara, S

    2015-03-01

    The CD40/CD154 co-stimulatory pathway is crucial in alloimmune response. We developed a novel small interfering RNA (siRNA) delivery system with a poly-dA extension at the 5'-end of the siRNA sense strand that was stably incorporated into 1,3-β-glucan (schizophyllan, SPG). This was captured and incorporated into dendritic cells (DCs) through its receptor, Dectin-1, specifically silencing CD40 genes (siCD40) to exert immunoregulatory activity. siCD40/SPG-treated CBA mice permanently accepted B10 fully mismatched cardiac allografts. Consistent with graft survival, the infiltration of CD4(+), CD8(+) T cells into the graft was lower, and that the numbers of CD40(low)CD11c(+) DCs cells and CD4(+)Foxp3(+)cells were increased in both the graft and in the recipient spleen. In addition, naive CBA recipients given an adoptive transfer of splenocytes from the primary recipients with siCD40/SPG accepted a heart graft from donor-type B10, but not third-party Balb/c mice. In conclusion, the treatment with siCD40/SPG targeting DCs could generate antigen-specific Tregs, resulting in the permanent acceptance of mouse cardiac allografts. These findings have important implications for clarifying the mechanism underlying the induction of tolerance in DCs, and also highlight the potential of immunomodulation and the feasibility of siRNA-based clinical therapy in the transplantation field. PMID:25567536

  14. Induction of Tolerance to Cardiac Allografts Using Donor Splenocytes Engineered to Display on Their Surface an Exogenous FasL Protein1

    PubMed Central

    Yolcu, Esma S.; Gu, Xiao; Lacelle, Chantale; Zhao, Hong; Bandura-Morgan, Laura; Askenasy, Nadir; Shirwan, Haval

    2008-01-01

    The critical role played by FasL in immune homeostasis renders this molecule as an attractive target for immunomodulation to achieve tolerance to auto and transplantation antigens. Immunomodulation with genetically modified cells expressing FasL was shown to induce tolerance to alloantigens. However, genetic modification of primary cells in a rapid, efficient, and clinically applicable manner proved challenging. Therefore, we tested the efficacy of donor splenocytes rapidly and efficiently engineered to display on their surface a chimeric form of FasL protein (SA-FasL) for tolerance induction to cardiac allografts. Intraperitoneal injection of ACI rats with WF splenocytes displaying SA-FasL on their surface resulted in tolerance to donor, but not F344 third party, cardiac allografts. Tolerance was associated with apoptosis of donor reactive T effector cells and induction/expansion of CD4+CD25+FoxP3+ T regulatory (Treg) cells. Treg cells played a critical role in the observed tolerance as adoptive transfer of sorted Treg cells from long-term graft recipients into naïve unmanipulated ACI rats resulted in indefinite survival of secondary WF grafts. Immunomodulation with allogeneic cells rapidly and efficiently engineered to display on their surface SA-FasL protein provides an effective and clinically applicable means of cell-based therapy with potential application to regenerative medicine, transplantation, and autoimmunity. PMID:18606644

  15. mir-155 regulates cardiac allograft rejection by targing the expression of suppressor of cytokine signaling-1 (DOCS1) in dendritic cells

    PubMed Central

    Gao, Yi; Liu, Fang; Zhou, Qiwei; Guo, Meng; Zhang, Mingjian; Guo, Wenyuan; Wang, Liming; Hu, Liping; Hu, Chaozhou; Shi, Yongzhao; Liu, Yushan; Wang, Quanxing

    2014-01-01

    Previously, we observed that mir-155 is induced during dendritic cell (DC) differentiation. We now demon-strated convincing evidence indicating that mir-155 promotes DC maturation and regulates its capacity for antigen presentation and induction of alloreactive T cell activation. Interestingly, the induction of miR-155 expression in DCs is dependent on the TLR4/Myd88/NF-κB signaling. Our mechanistic studies further revealed that SOCS1 is a direct target for mir-155, and by binding to its 3’UTR, mir-155 is likely to affect SOCS1 translation. Suppression of mir-155 expression in DCs significantly attenuated LPS-induced DC maturation along with reduced capability to stimulate allogeneic T cell proliferation. As a result, administration of antagomiR-155 provided protection for cardiac allografts from rejection. Together, our data support that suppression of miR-155 in DCs could be a viable therapeutic strategy for prevention and treatment of allograft rejection in clinical setting of transplantation. PMID:25550988

  16. Allograft rejection in cattle with bovine leukocyte adhesion deficiency.

    PubMed

    Müller, K E; Rutten, V P; Becker, C K; Hoek, A; Bernadina, W E; Wentink, G H; Figdor, C G

    1995-09-01

    In the present investigation cell-mediated immunity in animals with bovine leukocyte adhesion deficiency (BLAD) was studied by means of skin transplantation experiments. Autograft and allograft behaviour in animals with BLAD was compared with the behaviour of simultaneously transplanted autografts and allografts in healthy controls. Allograft survival time was prolonged in three BLAD cattle (28, 30, and 72 days) compared to six healthy controls (12-14 days). When transplantations were repeated on one animal with BLAD using skin grafts from the same donor, accelerated rejection was observed (allograft survival time decreased from 72 days at primary to 35 days at secondary and to 21 days at tertiary transplantation), suggesting the development of immunological memory. Graft-infiltrating lymphocytes that were obtained from allograft biopsies during the period of rejection, were shown to be from recipient origin (beta 2-integrin negative). Our findings demonstrate that, although prolonged allograft survival is observed in cattle with BLAD, skin allografts are ultimately rejected. PMID:8533316

  17. Uptake of donor lymphocytes treated with 8-methoxypsoralen and ultraviolet A light by recipient dendritic cells induces CD4{sup +}CD25{sup +}Foxp3{sup +} regulatory T cells and down-regulates cardiac allograft rejection

    SciTech Connect

    Zheng, De-Hua; Dou, Li-Ping; Wei, Yu-Xiang; Du, Guo-Sheng; Zou, Yi-Ping; Song, Ji-Yong; Zhu, Zhi-Dong; Cai, Ming; Qian, Ye-Yong; Shi, Bing-Yi

    2010-05-14

    Extracorporeal photopheresis (ECP) is an effective immunomodulatory therapy and has been demonstrated to be beneficial for graft-vs-host disease and solid-organ allograft rejection. ECP involves reinfusion of a patient's autologous peripheral blood leukocytes treated ex vivo with 8-methoxypsoralen and UVA light radiation (PUVA). Previous studies focused only on ECP treatment of recipient immune cells. Our study is the first to extend the target of ECP treatment to donor immune cells. The results of in vitro co-culture experiments demonstrate uptake of donor PUVA-treated splenic lymphocytes (PUVA-SPs) by recipient immature dendritic cells (DCs). Phagocytosis of donor PUVA-SPs does not stimulate phenotype maturation of recipient DCs. In the same co-culture system, donor PUVA-SPs enhanced production of interleukin-10 and interferon-{gamma} by recipient DCs and impaired the subsequent capability of recipient DCs to stimulate recipient naive T cells. Phagocytosis of donor PUVA-SP (PUVA-SP DCs) by recipient DCs shifted T-cell responses in favor of T helper 2 cells. Infusion of PUVA-SP DCs inhibited cardiac allograft rejection in an antigen-specific manner and induced CD4{sup +}CD25{sup high}Foxp3{sup +} regulatory T cells. In conclusion, PUVA-SP DCs simultaneously deliver the donor antigen and the regulatory signal to the transplant recipient, and thus can be used to develop a novel DC vaccine for negative immune regulation and immune tolerance induction.

  18. An N-(alkylcarbonyl)anthranilic acid derivative prolongs cardiac allograft survival synergistically with cyclosporine A in a high-responder rat model.

    PubMed

    Chen, Jibing; Xia, Junjie; Axelsson, Bengt; Fritzson, Ingela; Ekberg, Henrik; Törngren, Marie; Qi, Zhongquan

    2010-08-01

    We investigated the immunosuppressive effects of the dihydroortate dehydrogenase (DHODH) inhibitor compounds ABR-222417 and ABR-224050 from Active Biotech (Sweden). We verified the inhibitory effects of these compounds on the proliferation of CD4(+) and CD8(+) T-cells in vivo by using superantigen staphylococcus enterotoxin A (SEA)-mediated proliferation test. To evaluate their efficacy, the compounds were screened in a low-responder heart allograft transplantation model in rats [heart from Piebald Virol Glaxo (PVG) transplanted to Dark Agouti (DA)]. The immunosuppressive effects of the compounds were then investigated in a high-responder model (DA to PVG). Treatment with ABR-222417 (30 mg/kg) was more efficient than that with ABR-224050 (10 mg/kg), and the former provided a longer graft median survival time (MST, 29.5 days) than the latter (MST, 18.5 days). Furthermore, there was a marked increase in graft survival time (53 days) when low doses of ABR-222417 and cyclosporine A (CsA) were used in combination. No sign of tolerability problems was detected using this combination or when ABR-222417 was used singly at a higher dose. Furthermore, T-cell proliferation studies in vitro support that the anti proliferative effect of ABR-222417 is caused by inhibition of de novo pyrimidine synthesis, which is the consequence of DHODH inhibition. These results show that ABR-222417 had marked immunosuppressive effects on the heart allograft transplantation and that it exerts an even more powerful inhibitory effect on graft rejection when used in combination with CsA, with good tolerability. PMID:20553870

  19. Functional Immune Anatomy of the Liver-As an Allograft.

    PubMed

    Demetris, A J; Bellamy, C O C; Gandhi, C R; Prost, S; Nakanuma, Y; Stolz, D B

    2016-06-01

    The liver is an immunoregulatory organ in which a tolerogenic microenvironment mitigates the relative "strength" of local immune responses. Paradoxically, necro-inflammatory diseases create the need for most liver transplants. Treatment of hepatitis B virus, hepatitis C virus, and acute T cell-mediated rejection have redirected focus on long-term allograft structural integrity. Understanding of insults should enable decades of morbidity-free survival after liver replacement because of these tolerogenic properties. Studies of long-term survivors show low-grade chronic inflammatory, fibrotic, and microvascular lesions, likely related to some combination of environment insults (i.e. abnormal physiology), donor-specific antibodies, and T cell-mediated immunity. The resultant conundrum is familiar in transplantation: adequate immunosuppression produces chronic toxicities, while lightened immunosuppression leads to sensitization, immunological injury, and structural deterioration. The "balance" is more favorable for liver than other solid organ allografts. This occurs because of unique hepatic immune physiology and provides unintended benefits for allografts by modulating various afferent and efferent limbs of allogenic immune responses. This review is intended to provide a better understanding of liver immune microanatomy and physiology and thereby (a) the potential structural consequences of low-level, including allo-antibody-mediated injury; and (b) how liver allografts modulate immune reactions. Special attention is given to the microvasculature and hepatic mononuclear phagocytic system. PMID:26848550

  20. Cardiac Lymphoma.

    PubMed

    Jeudy, Jean; Burke, Allen P; Frazier, Aletta Ann

    2016-07-01

    Lymphoma of the heart and pericardium may develop in up to 25% of patients with disseminated nodal disease, but primary cardiac lymphoma is rare. The majority are diffuse large B-cell lymphomas, which arise in immunocompetent older individuals, men twice as often as women. Subsets are found in immunocompromised patients, including those with HIV-AIDS or allograft recipients. Cardiac lymphomas tend to arise in the wall of the right heart, especially right atrium, with contiguous infiltration of epicardium and pericardium. Pericardial implants and effusions are common. The disease is often multifocal in the heart, but cardiac valves are usually spared. PMID:27265603

  1. Smooth muscle cells of the coronary arterial tunica media express tumor necrosis factor-alpha and proliferate during acute rejection of rabbit cardiac allografts.

    PubMed Central

    Tanaka, H.; Swanson, S. J.; Sukhova, G.; Schoen, F. J.; Libby, P.

    1995-01-01

    Graft coronary arteriosclerosis (GCA) frequently limits the long-term success of cardiac transplantation. The pathogenic mechanisms of and stimuli that provoke GCA remain uncertain. Whatever the initiating factors, deranged control of smooth muscle cells (SMC) proliferation likely contributes to the intimal hyperplasia that produces obstructive lesions. To identify mediators that may contribute to ongoing modulation of SMC functions during acute rejection and to explore the mechanisms of the pathogenesis of graft coronary arteriosclerosis, we studied the kinetics of proliferation and the expression of tumor necrosis factor-alpha (TNF-alpha), a proinflammatory and SMC growth-promoting cytokine, in coronary arterial SMCs in rabbit hearts transplanted heterotopically without immunosuppression. Hearts were harvested at 2 (n = 5), 5 (n = 5), and 8.2 +/- 0.4 (mean +/- SD, n = 5) days after transplantation, just before graft failure as judged clinically. SMC proliferation was assessed by continuous bromodeoxyuridine labeling (BrdU 10 mg/kg/d. s.q.). Whole heart cross sections were stained immunohistochemically with monoclonal antibodies that recognize TNF-alpha, BrdU, and SMCs (muscle alpha-actin). Major epicardial coronary arteries (five to nine profiles in each animal) were evaluated. Histological rejection grades by the International Society for Heart and Lung Transplantation scale at 2, 5, and 10 days were 1.6 +/- 0.9, 2.8 +/- 1.1, and 4.0 +/- 0.0, respectively. Medial SMCs in normal hearts and 2 days after transplant expressed little or no TNF-alpha and displayed negligible BrdU incorporation. At 5 days after transplantation, some medial SMCs stained for TNF-alpha and had a low BrdU labeling index (0.5 +/- 0.8%). At 8.2 days after transplant, almost all medial SMCs expressed TNF-alpha intensely and had a high labeling index (29.8 +/- 8.0%). These results demonstrate that acute rejection activates medial SMCs in coronary arteries to express TNF-alpha and that SMC

  2. Immune Privilege of Corneal Allografts

    PubMed Central

    Niederkorn, Jerry Y.; Larkin, D. Frank P.

    2013-01-01

    Corneal transplantation has been performed successfully for over 100 years. Normally, HLA typing and systemic immunosuppressive drugs are not utilized, yet 90% of corneal allografts survive. In rodents, corneal allografts representing maximal histoincompatibility enjoy >50% survival even without immunosuppressive drugs. By contrast, other categories of transplants are invariably rejected in such donor/host combinations. The acceptance of corneal allografts compared to other categories of allografts is called immune privilege. The cornea expresses factors that contribute to immune privilege by preventing the induction and expression of immune responses to histocompatibility antigens on the corneal allograft. Among these are soluble and cell membrane molecules that block immune effector elements and also apoptosis of T lymphocytes. However, some conditions rob the corneal allograft of its immune privilege and promote rejection, which remains the leading cause of corneal allograft failure. Recent studies have examined new strategies for restoring immune privilege to such high-risk hosts. PMID:20482389

  3. Allograft Pancreatectomy: Indications and Outcomes.

    PubMed

    Nagai, S; Powelson, J A; Taber, T E; Goble, M L; Mangus, R S; Fridell, J A

    2015-09-01

    This study evaluated the indications, surgical techniques, and outcomes of allograft pancreatectomy based on a single center experience. Between 2003 and 2013, 47 patients developed pancreas allograft failure, excluding mortality with a functioning pancreas allograft. Early graft loss (within 14 days) occurred in 16, and late graft loss in 31. All patients with early graft loss eventually required allograft pancreatectomy. Nineteen of 31 patients (61%) with late graft loss underwent allograft pancreatectomy. The main indication for early allograft pancreatectomy included vascular thrombosis with or without severe pancreatitis, whereas one recipient required urgent allograft pancreatectomy for gastrointestinal hemorrhage secondary to an arterioenteric fistula. In cases of late allograft pancreatectomy, graft failure with clinical symptoms such as abdominal discomfort, pain, and nausea were the main indications (13/19 [68%]), simultaneous retransplantation without clinical symptoms in 3 (16%), and vascular catastrophes including pseudoaneurysm and enteric arterial fistula in 3 (16%). Postoperative morbidity included one case each of pulmonary embolism leading to mortality, formation of pseudoaneurysm requiring placement of covered stent, and postoperative bleeding requiring relaparotomy eventually leading to femoro-femoral bypass surgery 2 years after allograftectomy. Allograft pancreatectomy can be performed safely, does not preclude subsequent retransplantation, and may be lifesaving in certain instances. PMID:25912792

  4. Extramedullary hematopoiesis in renal allograft

    PubMed Central

    Chen, Guilan; Ali, Reza; Shuldberg, Mark M.; Bastani, Bahar; Brink, David S.

    2013-01-01

    Extramedullary hematopoiesis (EMH), defined as the presence of hematopoietic elements outside of the medullary cavity of bone, has been reported in patients with various hematopoietic neoplasms including myelofibrosis. EMH commonly occurs in the liver and spleen (resulting in hepatosplenomegaly) and uncommonly involves the kidney. EMH involving the allograft kidney has not been reported in English literature. Herein, we report the first case of EMH in allograft kidney in a patient with myelofibrosis. The clinical and pathological findings are described. Through comparison of the medullary neoplastic infiltrate with the renal allograft infiltrate, we postulate the neoplastic nature of the infiltrate in the allograft kidney. PMID:26120442

  5. Early right coronary vasospasm presenting with malignant arrhythmias in a heart transplantation recipient without allograft vasculopathy.

    PubMed

    Pistono, M; Brentana, L; Gnemmi, M; Imparato, A; Temporelli, P L; Zingarelli, E; Patané, F; Giannuzzi, P

    2009-01-24

    In heart transplant recipients, the aetiology of coronary vasospasm is largely unknown but it has been reported to be related to coronary vasculopathy or allograft rejection. We report a case of acute, reversible coronary vasospasm which caused malignant arrhythmias in a cardiac transplant recipient one month after transplantation without evidence of coronary vasculopathy or allograft rejection. The patient had a normal post-operative course with no other complications; this case supports the hypothesis that coronary vasospasm is not necessarily related to epicardial coronary artery disease or allograft rejection, but rather may be due to an abnormal reversible vasoreactivity. PMID:17950482

  6. Infiltration of Macrophages Correlates with Severity of Allograft Rejection and Outcome in Human Kidney Transplantation

    PubMed Central

    Bourier, Felix; Kühne, Louisa; Banas, Miriam C.; Rümmele, Petra; Wurm, Simone; Banas, Bernhard

    2016-01-01

    Objective Despite substantial progress in recent years, graft survival beyond the first year still requires improvement. Since modern immunosuppression addresses mainly T-cell activation and proliferation, we studied macrophage infiltration into the allografts of 103 kidney transplant recipients during acute antibody and T-cell mediated rejection. Macrophage infiltration was correlated with both graft function and graft survival until month 36 after transplantation. Results Macrophage infiltration was significantly elevated in antibody-mediated and T-cell mediated rejection, but not in kidneys with established IFTA. Treatment of rejection with steroids was less successful in patients with more prominent macrophage infiltration into the allografts. Macrophage infiltration was accompanied by increased cell proliferation as well as antigen presentation. With regard to the compartmental distribution severity of T-cell-mediated rejection was correlated to the amount of CD68+ cells especially in the peritubular and perivascular compartment, whereas biopsies with ABMR showed mainly peritubular CD68 infiltration. Furthermore, severity of macrophage infiltration was a valid predictor of resulting creatinine values two weeks as well as two and three years after renal transplantation as illustrated by multivariate analysis. Additionally performed ROC curve analysis showed that magnitude of macrophage infiltration (below vs. above the median) was a valid predictor for the necessity to restart dialysis. Having additionally stratified biopsies in accordance to the magnitude of macrophage infiltration, differential CD68+ cell infiltration was reflected by striking differences in overall graft survival. Conclusion The differences in acute allograft rejection have not only been reflected by different magnitudes of macrophage infiltration, but also by compartment-specific infiltration pattern and subsequent impact on resulting allograft function as well as need for dialysis

  7. Effects of IFNγ administration on allograft rejection in ginbuna crucian carp.

    PubMed

    Shibasaki, Yasuhiro; Hatanaka, Chihiro; Matsuura, Yuta; Miyazawa, Ryuichiro; Yabu, Takeshi; Moritomo, Tadaaki; Nakanishi, Teruyuki

    2016-09-01

    In vertebrates, the rejection of allografts is primarily accomplished by cell-mediated immunity. We recently identified four IFNγ isoforms with antiviral activity in ginbuna crucian carp, Carassius auratus langsdorfii. However, involvement of the IFNγ isoforms in cell-mediated immunity, especially in T cell function remains unknown. Here we investigate expression of the IFNγ isoforms and effects of administration of recombinant IFNγ (rgIFNγ) isoforms in ginbuna scale allograft rejection. All four IFNγ isoforms showed significantly higher expression with the progression of graft rejection. Administration of rgIFNγrel 1 but not rgIFNγrel 2, rgIFNγ1 nor rgIFNγ2 enhanced allograft rejection. The number of CD4(+) and CD8α(+) cells increased in early stages of rejection, while sIgM(+) cells were higher than controls at day 0 and 5 in the rgIFNγrel 1 administrated group. Expression of IFNγ1 and IFNγ2 mRNA was significantly up-regulated by rgIFNγrel 1 administration, while that of IFNγrel 1 and IFNγrel 2 was not. These results suggest different contributions of the four IFNγ isoforms toward the immune responses comprising allograft rejection. PMID:27156851

  8. Sphingosine-1-phosphate receptor 1 agonist SEW2871 prolongs heterotopic heart allograft survival in mice.

    PubMed

    Ni, Qian; Yuan, Baohong; Liu, Tao; Lan, Fang; Luo, Xiaochun; Lu, Xiaoyan; Huang, Ping; Dai, Liangcheng; Jin, Xiaobao; Yin, Hui

    2015-05-01

    Sphingosine-1-phosphate (S1P) is a biologically active metabolite of plasma-membrane sphingolipids that is essential for immune cell trafficking. Recent studies have revealed immunomodulatory functions of S1P and its receptors (S1PR1-S1PR5) in many inflammatory conditions, such as asthma and autoimmunity. Here, we explore the efficacy of SEW2871, a selective S1PR1 agonist, in the prevention of acute allograft rejection in a murine cardiac transplantation model. Treatment of recipient mice with SEW2871 significantly prolongs cardiac allograft survival as compared to those recipients treated with control vehicle. The enhanced graft survival is associated with reduced circulating lymphocytes and allograft inflammatory cell infiltration. The cytokine analysis showed decreased allograft expression of TNF-α, IFN-γ and IL-2 in the SEW2871-treated mice. Moreover, administration of SEW2871 increases the percentage of CD4(+) T regulatory cells and FoxP3 expression in spleen of allograft recipients. Therefore, SEW2871 plays a critical role in regulation of lymphocyte trafficking and development, which directly contributes to prolongation of the allograft survival. PMID:25776899

  9. Depression of Complement Regulatory Factors in Rat and Human Renal Grafts Is Associated with the Progress of Acute T-Cell Mediated Rejection

    PubMed Central

    Yamanaka, Kazuaki; Kakuta, Yoichi; Miyagawa, Shuji; Nakazawa, Shigeaki; Kato, Taigo; Abe, Toyofumi; Imamura, Ryoichi; Okumi, Masayoshi; Maeda, Akira; Okuyama, Hiroomi; Mizuno, Masashi; Nonomura, Norio

    2016-01-01

    Background The association of complement with the progression of acute T cell mediated rejection (ATCMR) is not well understood. We investigated the production of complement components and the expression of complement regulatory proteins (Cregs) in acute T-cell mediated rejection using rat and human renal allografts. Methods We prepared rat allograft and syngeneic graft models of renal transplantation. The expression of Complement components and Cregs was assessed in the rat grafts using quantitative real-time PCR (qRT-PCR) and immunofluorescent staining. We also administered anti-Crry and anti-CD59 antibodies to the rat allograft model. Further, we assessed the relationship between the expression of membrane cofactor protein (MCP) by immunohistochemical staining in human renal grafts and their clinical course. Results qRT-PCR results showed that the expression of Cregs, CD59 and rodent-specific complement regulator complement receptor 1-related gene/protein-y (Crry), was diminished in the rat allograft model especially on day 5 after transplantation in comparison with the syngeneic model. In contrast, the expression of complement components and receptors: C3, C3a receptor, C5a receptor, Factor B, C9, C1q, was increased, but not the expression of C4 and C5, indicating a possible activation of the alternative pathway. When anti-Crry and anti-CD59 mAbs were administered to the allograft, the survival period for each group was shortened. In the human ATCMR cases, the group with higher MCP expression in the grafts showed improved serum creatinine levels after the ATCMR treatment as well as a better 5-year graft survival rate. Conclusions We conclude that the expression of Cregs in allografts is connected with ATCMR. Our results suggest that controlling complement activation in renal grafts can be a new strategy for the treatment of ATCMR. PMID:26928779

  10. Aortic valve allografts in sheep

    PubMed Central

    Borrie, John; Hill, G. L.

    1968-01-01

    Some of the mechnical and biological problems surrounding the use of fresh allograft inverted aortic valves as mitral valve substitutes are described. Certain aspects of the problem have been studied experimentally. In three sheep `fresh' aortic valve allografts were inserted, using cardiopulmonary bypass, into the main pulmonary artery, and were observed from 5 to 7 months after operation. The animals survived normally. Their normal pulmonary valves remained in situ. The technique is described. At subsequent necropsy, macroscopically the valves were found to be free from vegetation, and the cusps were pliable and apparently normal. Microscopically, the supporting allograft myocardium showed necrosis and early calcification. The valve cusp showed hyalinization of collagen, although beneath the endocardium this hyalinized collagen contained moderate numbers of fibroblasts with no evidence of proliferation. The endocardium and arterial intima of the allograft showed evidence of ingrowth from adjacent normal host endocardial tissues. The allograft itself was invested in a loose layer of fibro-fatty tissue, which, in view of the necrotic state of the graft myocardium, could well have been a reparative reaction rather than a homograft reaction. It is concluded that, although the cusps could function normally, the necrosis of the myocardium might in time lead to late failure of the graft. Further studies with the valve inserted at mitral level are indicated. Images PMID:5656757

  11. Osteochondral Allograft of the Talus

    PubMed Central

    Bisicchia, Salvatore; Rosso, Federica; Amendola, Annunziato

    2014-01-01

    Osteochondral lesions of the talus are being recognized as an increasingly common injury. They are most commonly located postero-medially or antero-laterally, while centrally located lesions are uncommon. Large osteochondral lesions have significant biomechanical consequences and often require resurfacing with osteochondral autograft transfer, mosaicplasty, autologous chondrocyte implantation (or similar methods) or osteochondral allograft transplantation. Allograft procedures have become popular due to inherent advantages over other resurfacing techniques. Cartilage viability is one of the most important factors for successful clinical outcomes after transplantation of osteochondral allografts and is related to storage length and intra-operative factors. While there is abundant literature about osteochondral allograft transplantation in the knee, there are few papers about this procedure in the talus. Failure of non-operative management, initial debridement, curettage or microfractures are an indication for resurfacing. Patients should have a functional ankle motion, closed growth plates, absence of cartilage lesions on the tibial side. This paper reviews the published literature about osteochondral allograft transplantation of the talus focusing on indications, pre-operative planning, surgical approaches, postoperative management, results and complications of this procedure. PMID:25328456

  12. Biomechanical properties of bone allografts

    SciTech Connect

    Pelker, R.R.; Friedlaender, G.E.; Markham, T.C.

    1983-04-01

    The biomechanical properties of allograft bone can be altered by the methods chosen for its preservation and storage. These effects are minimal with deep-freezing or low-level radiation. Freeze-drying, however, markedly diminishes the torsional and bending strength of bone allografts but does not deleteriously affect the compressive or tensile strength. Irradiation of bone with more than 3.0 megarad or irradiation combined with freeze-drying appears to cause a significant reduction in breaking strength. These factors should be considered when choosing freeze-dried or irradiated allogeneic bone that will be subjected to significant loads following implantation.

  13. Allograft pancreas: pale acinar nodules.

    PubMed

    Troxell, Megan L; Drachenberg, Cinthia

    2016-08-01

    Microscopic pale-staining acinar nodules were characterized in native pancreas in the 1980s under a variety of names but have been infrequently reported since. We retrospectively studied the frequency and characteristics of pale acinar nodules in allograft pancreas biopsies, as compared to a sampling of native pancreas specimens at our center. Pale acinar nodules were present in 13% (9/69) of allograft biopsies from 22% (7/32) of transplant patients, and 23% (5/22) of native pancreas surgical specimens, although more nodules per pancreas area were present in allograft needle biopsies. Acinar nodules had size of 100 to 700 μm, were periodic acid-Schiff pale, were synaptophysin negative, stained more weakly with keratin CAM 5.2 compared to surrounding parenchyma, and had a low proliferative rate. Ultrastructural evaluation revealed paucity of zymogen granules with dilated cistern-like structures. In our experience, pale acinar nodules have similar features in allograft and native pancreas specimens, yet remain of uncertain etiology and significance. PMID:27063474

  14. Emphysema in the renal allograft

    SciTech Connect

    Potter, J.L.; Sullivan, B.M.; Fluornoy, J.G.; Gerza, C.

    1985-04-01

    Two diabetic patients in whom emphysematous pyelonephritis developed after renal transplantation are described. Clinical recognition of this unusual and serious infection is masked by the effects of immunosuppression. Abdominal radiographic, ultrasound, and computed tomography findings are discussed. The clinical presentation includes urinary tract infection, sepsis, and acute tubular malfunction of the allograft in insulin-dependent diabetics.

  15. Leiomyoma in a Renal Allograft.

    PubMed

    Li, Yan Jun; Siriwardana, Amila Rohan; Symons, James Lawrence Penn; O'Neill, Gordon Francis; Qiu, Min Ru; Furlong, Timothy John

    2016-01-01

    Leiomyomas are smooth muscle tumours that are rarely found in the kidney. There is one report of a leiomyoma in a kidney transplant in a paediatric recipient. Here, we report an adult renal transplant recipient who developed an Epstein-Barr virus-positive leiomyoma in his allograft 15 years after transplantation. The patient was converted to everolimus for posttransplant immunosuppression management and there was no sign of progression over a year. PMID:27195169

  16. Leiomyoma in a Renal Allograft

    PubMed Central

    Li, Yan Jun; Siriwardana, Amila Rohan; Symons, James Lawrence Penn; O'Neill, Gordon Francis; Qiu, Min Ru; Furlong, Timothy John

    2016-01-01

    Leiomyomas are smooth muscle tumours that are rarely found in the kidney. There is one report of a leiomyoma in a kidney transplant in a paediatric recipient. Here, we report an adult renal transplant recipient who developed an Epstein-Barr virus-positive leiomyoma in his allograft 15 years after transplantation. The patient was converted to everolimus for posttransplant immunosuppression management and there was no sign of progression over a year. PMID:27195169

  17. Cutting edge: blockade of the CD28/B7 costimulatory pathway inhibits intestinal allograft rejection mediated by CD4+ but not CD8+ T cells.

    PubMed

    Newell, K A; He, G; Guo, Z; Kim, O; Szot, G L; Rulifson, I; Zhou, P; Hart, J; Thistlethwaite, J R; Bluestone, J A

    1999-09-01

    The effect of blocking the CD28/B7 costimulatory pathway on intestinal allograft rejection was examined in mice. Murine CTLA4Ig failed to prevent the rejection of allografts transplanted into wild-type or CD4 knockout (KO) mice but did inhibit allograft rejection by CD8 KO recipients. This effect was associated with decreased intragraft mRNA for IFN-gamma and TNF-alpha and increased mRNA for IL-4 and IL-5. This altered pattern of cytokine production was not observed in allografts from murine CTLA4Ig-treated CD4 KO mice. These data demonstrate that blockade of the CD28/B7 pathway has different effects on intestinal allograft rejection mediated by CD4+ and CD8+ T cells and suggest that these T cell subsets have different costimulatory requirements in vivo. The results also suggest that the inhibition of CD4+ T cell-mediated allograft rejection by CTLA4Ig may be related to down-regulation of Th1 cytokines and/or up-regulation of Th2 cytokines. PMID:10452966

  18. Skin allografts in lethally irradiated animals repopulated with syngeneic hemopoietic cells

    SciTech Connect

    Schwadron, R.B.

    1983-01-01

    Total body irradiation and repopulation with syngeneic hemopoietic cells can be used to induce tolerance to major histocompatibility complex (MHC) mismatched heart and kidney grafts in rats and mice. However, this protocol does not work for MHC mismatched skin grafts in rats or mice. Furthermore, LEW rats that accept WF cardiac allografts after irradiation and repopulation reject subsequent WF skin grafts. Treatment of skin allograft donors with methotrexate prior to grafting onto irradiated and reconstituted mice resulted in doubling of the mean survival time. Analysis of which antigens provoked skin graft rejection by irradiation and reconstituted animals revealed the importance of I region antigens. Cardiac allograft acceptance by irradiated and reconstituted animals is mediated by suppressor cells found in the spleen. Adoptively tolerant LEW rats accepted WF skin grafts in 50% of grafted animals. Analysis of this phenomenon revealed that the adoptive transfer procedure itself was important in achieving skin allograft acceptance by these animals. In general, it seems that the lack of ability of irradiated and reconstituted animals to accept fully MHC disparate skin grafts results from the inability of these animals to suppress lymph node effector cells against I region antigen seen on highly immunogenic allogeneic Langerhans cells in the skin.

  19. Mast Cell-Mediated Mechanisms of Nociception

    PubMed Central

    Aich, Anupam; Afrin, Lawrence B.; Gupta, Kalpna

    2015-01-01

    Mast cells are tissue-resident immune cells that release immuno-modulators, chemo-attractants, vasoactive compounds, neuropeptides and growth factors in response to allergens and pathogens constituting a first line of host defense. The neuroimmune interface of immune cells modulating synaptic responses has been of increasing interest, and mast cells have been proposed as key players in orchestrating inflammation-associated pain pathobiology due to their proximity to both vasculature and nerve fibers. Molecular underpinnings of mast cell-mediated pain can be disease-specific. Understanding such mechanisms is critical for developing disease-specific targeted therapeutics to improve analgesic outcomes. We review molecular mechanisms that may contribute to nociception in a disease-specific manner. PMID:26690128

  20. Cell-mediated immunity in anorexia nervosa.

    PubMed Central

    Cason, J; Ainley, C C; Wolstencroft, R A; Norton, K R; Thompson, R P

    1986-01-01

    Twelve patients with anorexia nervosa were studied for cell-mediated immunity in terms of delayed hypersensitivity reactions to recall antigens, lymphocyte transformation responses to T-cell mitogens, and numbers of circulating leucocytes and T-cell subpopulations. Compared to controls, all patients had reduced cutaneous reactions and four were anergic. There was a mild leucopenia in patients and both T4+ and T3+ numbers were slightly reduced. Mean peak transformation responses for patients were slightly lower than controls for phytohaemagglutinin, but not for concanavalin A; however, patients required greater doses of mitogens to elicit peak transformation responses. Plasmas from patients did not contain inhibitors of transformation responses. We conclude that there are functional cellular abnormalities associated with the under-nutrition of anorexia nervosa. PMID:3742879

  1. Cell-mediated immunity in epidermodysplasia verruciformis.

    PubMed

    Gliński, W; Jablonska, S; Langner, A; Obalek, S; Haftek, M; Proniewska, M

    1976-01-01

    Investigations were performed in 6 cases of epidermodysplasia verruciformis and 2 healthy family members. Nonspecific cell-mediated immunity (CMI) was studied by measuring response to phytohemagglutinin (PHA) and concanavalin A (Con A), percentrages of E- and EAC-rosette-forming lymphocytes, bacterial skin tests, and allergic reactions to dinitrochloro-benzene (DNCB). Impairment of CMI was manifested by reduction in the percentage of E rosettes, and lowered response to PHA, and- to a lesser degree- to Con A. The immune response to DNCB sensitization was invariably negative. Impairment of CMI was greater in cases of long duration and with extensive lesions. The cases of similar duration and extent of lesions, which never showed tendency to tumor formation, were not different in CMI in comparison with cases with numerous tumors. Only in cases with very advanced tumors CMI was impaired parallel to the gravity of the patient's general condition. PMID:1017532

  2. Allografts in Soft Tissue Reconstructive Procedures

    PubMed Central

    Giedraitis, Andrius; Arnoczky, Steven P.; Bedi, Asheesh

    2014-01-01

    Context Allografts offer several important advantages over autografts in musculoskeletal reconstructive procedures, such as anterior cruciate ligament reconstruction. Despite growing widespread use of allograft tissue, serious concerns regarding safety and functionality remain. We discuss the latest knowledge of the potential benefits and risks of allograft use and offer a critical review of allograft tissue regulation, management, and sterilization to enable the surgeon to better inform athletes considering reconstructive surgery options. Evidence Acquisition A review of sources published in the past 10 years is the primary basis of this research. Study Design: Observational analysis (cohort study). Level of Evidence: Level 3. Results Comparable outcome data for autografts and allografts do not support universal standards for anterior cruciate ligament reconstruction, and physician recommendation and bias appear to significantly influence patient preference and satisfaction. Sterilization by gamma and electron-beam irradiation diminishes the biomechanical integrity of allograft tissue, but radioprotective agents such as collagen cross-linking and free radical scavengers appear to have potential in mitigating the deleterious effects of irradiation and preserving tissue strength and stability. Conclusion Allografts offer greater graft availability and reduced morbidity in orthopaedic reconstructive procedures, but greater expansion of their use by surgeons is challenged by the need to maintain tissue sterility and biomechanical functionality. Advances in the radioprotection of irradiated tissue may lessen concerns regarding allograft safety and structural stability. PMID:24790696

  3. Allograft Replacement for Absent Native Tissue

    PubMed Central

    Chaudhury, Salma; Wanivenhaus, Florian; Fox, Alice J.; Warren, Russell F.; Doyle, Maureen; Rodeo, Scott A.

    2013-01-01

    Context: Structural instability due to poor soft tissue quality often requires augmentation. Allografts are important biological substitutes that are used for the symptomatic patient in the reconstruction of deficient ligaments, tendons, menisci, and osteochondral defects. Interest in the clinical application of allografts has arisen from the demand to obtain stable anatomy with restoration of function and protection against additional injury, particularly for high-demand patients who participate in sports. Traditionally, allografts were employed to reinforce weakened tissue. However, they can also be employed to substitute deficient or functionally absent tissue, particularly in the sports medicine setting. Objective: This article presents a series of 6 cases that utilized allografts to restore functionally deficient anatomic architecture, rather than just simply augmenting the degenerated or damaged native tissue. Detailed discussions are presented of the use of allografts as a successful treatment strategy to replace functionally weakened tissue, often after failed primary repairs. PMID:24427387

  4. Osteochondral Allografts in the Ankle Joint

    PubMed Central

    Vannini, Francesca; Buda, Roberto; Ruffilli, Alberto; Cavallo, Marco; Giannini, Sandro

    2013-01-01

    Purpose: The aim of this systematic review is to report about the clinical use of partial and total fresh osteochondral allograft in the ankle joint. The state of the art of allografts with regard to basic science, procurement and storage methods, immunogenicity, generally accepted indications and contraindications, and the rationale of the allografting procedure have been described. Methods: All studies published in PubMed from 2000 to January 2012 addressing fresh osteochondral allograft procedures in the ankle joint were identified, including those that fulfilled the following criteria: (a) level I-IV evidence addressing the areas of interest outlined above; (b) measures of functional, clinical, or imaging outcome; and (c) outcome related to ankle cartilage lesions or ankle arthritis treated by allografts. Results: The analysis showed a progressively increasing number of articles from 2000. The number of selected articles was 14; 9 of those focused on limited dimension allografts (plugs, partial) and 5 on bipolar fresh osteochondral allografts. The evaluation of evidence level showed 14 case series and no randomized studies. Conclusions: Fresh osteochondral allografts are now a versatile and suitable option for the treatment of different degrees of osteochondral disease in the ankle joint and may even be used as total joint replacement. Fresh osteochondral allografts used for total joint replacement are still experimental and might be considered as a salvage procedure in otherwise unsolvable situations. A proper selection of the patients is therefore a key point. Moreover, the patients should be adequately informed about the possible risks, benefits, and alternatives to the allograft procedure. PMID:26069666

  5. Cellular and Functional Imaging of Cardiac Transplant Rejection

    PubMed Central

    Wu, Yijen L.; Ye, Qing

    2011-01-01

    Heart transplantation is now an established treatment for patients suffering from end-stage heart diseases. With the advances in immunosuppressive treatment, the survival rate for transplant patients has improved greatly. However, allograft rejection, both acute and chronic, after heart transplantation is still a limitation leading to morbidity and mortality. The current clinical gold standard for screening rejection is endomyocardial biopsy (EMB), which is not only invasive, but also error-prone, due to the limited sample size and the site location of sampling. It would be highly desirable to have reliable and noninvasive alternatives for EMB in monitoring cardiac allograft rejection. The objective of this review is to highlight how cardiovascular imaging can contribute to noninvasively detecting and to evaluating both acute and chronic allograft rejection after heart transplantation, in particular, cardiovascular MRI (CMRI); and how CMRI can assess both immune cell infiltration at the rejecting organ, and the cardiac dysfunctions resulting from allograft rejection. PMID:21359095

  6. Precision Subtypes of T Cell-Mediated Rejection Identified by Molecular Profiles

    PubMed Central

    Kadota, Paul Ostrom; Hajjiri, Zahraa; Finn, Patricia W.; Perkins, David L.

    2015-01-01

    Among kidney transplant recipients, the treatment of choice for acute T cell-mediated rejection (TCMR) with pulse steroids or antibody protocols has variable outcomes. Some rejection episodes are resistant to an initial steroid pulse, but respond to subsequent antibody protocols. The biological mechanisms causing the different therapeutic responses are not currently understood. Histological examination of the renal allograft is considered the gold standard in the diagnosis of acute rejection. The Banff Classification System was established to standardize the histopathological diagnosis and to direct therapy. Although widely used, it shows variability among pathologists and lacks criteria to guide precision individualized therapy. The analysis of the transcriptome in allograft biopsies, which we analyzed in this study, provides a strategy to develop molecular diagnoses that would have increased diagnostic precision and assist the development of individualized treatment. Our hypothesis is that the histological classification of TCMR contains multiple subtypes of rejection. Using R language algorithms to determine statistical significance, multidimensional scaling, and hierarchical, we analyzed differential gene expression based on microarray data from biopsies classified as TCMR. Next, we identified KEGG functions, protein–protein interaction networks, gene regulatory networks, and predicted therapeutic targets using the integrated database ConsesnsusPathDB (CPDB). Based on our analysis, two distinct clusters of biopsies termed TCMR01 and TCMR02 were identified. Despite having the same Banff classification, we identified 1933 differentially expressed genes between the two clusters. These genes were further divided into three major groups: a core group contained within both the TCMR01 and TCMR02 subtypes, as well as genes unique to TCMR01 or TCMR02. The subtypes of TCMR utilized different biological pathways, different regulatory networks and were predicted to

  7. Cell mediated immune regulation in autoimmunity.

    PubMed

    Gillissen, G; Pusztai-Markos, Z

    1979-01-01

    Autoimmunity is the term for the immune conditions characterized by a specific humoral or cell mediated response to the body's own tissues. The termination of the natural state of self tolerance may lead to immunopathological manifestations with clinical consequences, i.e. autoimmune diseases. In a very general sense, one may classify autoimmune diseases into two groups with respect to the underlying mechanism: 1. There are autoimmune diseases which develop in the presence of a normal intact regulation mechanism. 2. Another group whose development must be understood on the basis of a cellular dysfunction. In the first case, dequestered or semi-sequestered autoantigens are liberated as a consequence of exogenic influences inducing the sensitization of immunocompetent cells. The immune system then reacts with these autoantigens in the same way as with foreign substances. This kind of autoimmune disease will, however, not be dealt with here. In the second case, autoantigens are normally, i.e. in healthy individuals, accessible to the immunocompetent cells. To understand the reason for the development of an autoimmune reaction one must first clarify the mechanism of self tolerance. Then one must examine the way in which a break of this physiological state takes place. One of the major unanswered questions is the relative importance of antibody-mediated and cell-mediated immune mechanisms in the onset and further development of autoimmune diseases. Recently it has been suggested that a dysfunction at the cellular level might represent the basic cause which induces the termination of selftolerance. Most of the conceptions about the mechanism by which autoimmune diseases are triggered were gained through experiments with animals. It is, however, difficult to use these experimental results to explain human diseases; in humans many questions are still open. Undoubtedly, the mechanisms of induction and maintenance of self tolerance and also the ways in which autoimmune

  8. Radiation sterilization of skin allograft

    NASA Astrophysics Data System (ADS)

    Kairiyama, E.; Horak, C.; Spinosa, M.; Pachado, J.; Schwint, O.

    2009-07-01

    In the treatment of burns or accidental loss of skin, cadaveric skin allografts provide an alternative to temporarily cover a wounded area. The skin bank facility is indispensable for burn care. The first human skin bank was established in Argentina in 1989; later, 3 more banks were established. A careful donor selection is carried out according to the national regulation in order to prevent transmissible diseases. As cadaveric human skin is naturally highly contaminated, a final sterilization is necessary to reach a sterility assurance level (SAL) of 10 -6. The sterilization dose for 106 batches of processed human skin was determined on the basis of the Code of Practice for the Radiation Sterilization of Tissue Allografts: Requirements for Validation and Routine Control (2004) and ISO 11137-2 (2006). They ranged from 17.6 to 33.4 kGy for bioburdens of >10-162.700 CFU/100 cm 2. The presence of Gram negative bacteria was checked for each produced batch. From the analysis of the experimental results, it was observed that the bioburden range was very wide and consequently the estimated sterilization doses too. If this is the case, the determination of a tissue-specific dose per production batch is necessary to achieve a specified requirement of SAL. Otherwise if the dose of 25 kGy is preselected, a standardized method for substantiation of this dose should be done to confirm the radiation sterilization process.

  9. Meniscal allograft transplantation in rabbit.

    PubMed

    Vilela, Liana M; Del Carlo, Ricardo J; Melo Filho, Edson V; Favarato, Lukiya S C; Duarte, Tatiana S; Pontes, Kelly C S; Cunha, Daise N Q

    2015-01-01

    This study evaluated the technique for meniscal allograft transplantation using allografts preserved in glycerin 98% in rabbits. Euthanasia was performed at 70 days to compare the transplanted (TM1 to TM16) versus the contralateral meniscus (OM1 to OM16). Sixteen menisci, 8 transplanted and 8 contralateral, were submitted to gross examination, histomorphometric analysis for identification and quantification of cellular type, and for quantification and distribution of collagen fibers. A revascularization study was conducted in all of the other samples. Lengths of the OM varied from 0.9 to 1.0 cm and two TM were smaller. All TM were completely attached to the synovial membrane, except for one case that presented partial fixation. Both, TM and OM had similar amounts of chondrocytes, fibroblasts and fibrocytes, and at the horns, chondrocytes were predominant. The collagen fibers in TM were well organized throughout the body, and disorganized at the horns. These fibers in OM were organized. The amounts of collagen type I and III, and the vascularization of the perimeniscal tissue and of the edge were similar in OM and TM. These results demonstrated graft integration and thus this transplantation technique and preservation method may be recommended. PMID:26648544

  10. Preserved saphenous vein allografts for vascular access.

    PubMed

    Piccone, V A; Sika, J; Ahmed, N; LeVeen, H H; DiScala, V

    1978-09-01

    Preserved venous allografts were used as an alternate access procedure in 70 patients receiving dialysis during a three year period. The clinical experience with allograft fistulas revealed an extremely high initial patency rate; absence of infection postoperatively and during three years of dialysis; suitability for dialysis a week after implantation, thus greatly obviating the need for Silastic shunts; a low long term thrombosis rate and the weakly antigenic allograft veins produced no accelerated rejection of subsequently transplanted kidneys. Surviving patients average 172 dialysis treatments per allograft. Allograft fistulas constituted 45 per cent of the last 100 vascular procedures, an indication of the extent of usage. Microscopic examination of grafts retrieved from patients who died during the late follow-up period demonstrated that structural components of the wall of the vein were still identifiable. Allograft venous fistulas offer dependable, safe vascular access, especially in the infection prone patient with diabetes who is receiving dialysis treatment. The clinical results of allograft fistulas suggests a major role for this technique in vascular access operations. PMID:684591

  11. Tubular and endothelial chimerism in renal allografts using fluorescence and chromogenic in situ hybridization (FISH, CISH) technology.

    PubMed

    Varga, Zsuzsanna; Gaspert, Ariana; Behnke, Silvia; von Teichman, Adriana; Fritzsche, Florian; Fehr, Thomas

    2012-04-01

    The role of endothelial and tubular chimerism in renal allograft adaptation and rejection varies in different studies. We addressed the correlation between different clinico-pathological settings and sex-chromosomal endothelial and/or tubular chimerism in renal allografts. We examined the presence or absence of the X and Y chromosomes by fluorescence and chromogenic in situ hybridization (FISH, CISH) methodology on paraffin embedded kidney biopsies in 16 gender mismatched renal transplants (1 to 12 years post-transplantation). Twelve patients were male, four female. Four groups were selected: (i) Vascular calcineurin inhibitor toxicity without rejection; (ii) T-cell mediated vascular rejection; (iii) antibody mediated rejection; and (iv) C4d-positivity in AB0-incompatible transplants with or without rejection. Twelve non-transplant kidney biopsies (8 female, 4 male) were used as controls. Tubular chimerism was detected more frequently (69%) than endothelial chimerism (12%) in renal transplants. One of 12 control patients had tubular and endothelial chimeric cells (8%). The Y chromosome occurred in 8/12 male recipients (67%) in tubular epithelial cells and in 5/12 male recipients (42%) in endothelial cells. Double X chromosomes were detected in 3/4 female recipients in tubular epithelium. Tubular chimerism occurred more often with endothelial chimerism and capillaritis without correlation with other parameters, such as rejection. Combined Y chromosomal tubular and lymphatic endothelial chimerism correlated with T-cell mediated vascular rejection in two out of three patients (66%). Combined Y chromosomal tubular and peritubular capillary chimerism correlated with antibody mediated C4d+ rejection in one out of two patients (50%). Tubular and/or endothelial chimerism occur frequently in gender mismatched renal allografts and, when combined, this is associated with T-cell mediated rejection. PMID:22449229

  12. Future of allografts in sports medicine.

    PubMed

    Harner, Christopher D; Lo, Marvin Y

    2009-04-01

    Allografts play a prominent role in sports medicine, and their usage has increased dramatically over the past few decades, but the role of allograft in the future of sports medicine largely depends on several factors: (1) the ability of the tissue banking industry to convince both surgeons and the general population that tissue procurement is safe and nearly disease-free, (2) the ability to sterilize tissue with minimal compromise to tissue integrity, (3) successful clinical outcomes with allograft, and (4) the advent of artificial scaffolds and ligaments that function as well. PMID:19306738

  13. Liver allograft rejection in sensitized recipients. Observations in a clinically relevant small animal model.

    PubMed Central

    Nakamura, K.; Murase, N.; Becich, M. J.; Furuya, T.; Todo, S.; Fung, J. J.; Starzl, T. E.; Demetris, A. J.

    1993-01-01

    A sequential analysis of liver allograft rejection in sensitized rats using immunopathological and ultrastructural microscopy is described. Lewis rats were primed with four ACI skin grafts and challenged with an arterialized ACI orthotopic liver allograft 14 to 17 weeks later. The sensitization resulted in a mix of IgG and IgM lymphocytotoxic antibodies at a titer of 1:512 at the time of transplantation. Specificity analysis of pretransplant immune sera revealed a predominance of IgG anti-class I major histocompatibility complex (RT1) antibodies with a minor IgG fraction showing apparent endothelial cell specificity (non-RT1). This level of sensitization was associated with accelerated graft failure in 3 to 5 days from mixed humoral and cellular rejection. Sequential analysis of serial posttransplant graft biopsies revealed diffuse vascular IgG deposition and platelet thrombi in portal veins and periportal sinusoids within 3 minutes after reperfusion. This was followed by endothelial cell hypertrophy and vacuolization, periportal hepatocyte necrosis, arterial spasm, focal large bile duct necrosis, and hilar mast cell infiltration and degranulation. However, the liver allografts did not fail precipitously and hyperacute rejection was not seen. Kupffer cell phagocytosis of the sinusoidal platelets began as early as 30 minutes posttransplant and by 24 hours, the platelet thrombi had decreased. Cholangioles appeared focally at the edge of the limiting plates by 2 to 3 days, apparently in response to earlier periportal hepatocyte damage. A mononuclear portal and perivenular infiltrate became evident at 3 days, and graft failure was attributed to both antibody and cell-mediated rejection (Furuya et al: Preformed lymphocytotoxic antibodies: Hepatology 1992, 16: 1415-1422). The model described resembles observations in crossmatch positive human liver allograft recipients. The mechanisms of hepatic graft resistance to antibody mediated rejection and the possible long term

  14. Cell-mediated immune deficiency in Hodgkin's disease.

    PubMed

    Kumar, R K; Penny, R

    1982-10-01

    Disturbances of the immune system frequently accompany the development of lymphomas in man. In the early stages of non-Hodgkin's lymphomas, abnormalities of immunological function are usually minimal, but impairment of both antibody- and cell-mediated immunity is often noted in advanced disease. In contrast, while antibody-mediated immune responses in patients with Hodgkin's disease usually remain intact until late in the course of the illness, cell-mediated immune dysfunction is an early and consistent feature. Here Rakesh Kumar and Ronald Penny discuss the abnormalities of cell-mediated immunity in Hodgkin's disease. PMID:25290229

  15. The composition of the microbiota modulates allograft rejection.

    PubMed

    Lei, Yuk Man; Chen, Luqiu; Wang, Ying; Stefka, Andrew T; Molinero, Luciana L; Theriault, Betty; Aquino-Michaels, Keston; Sivan, Ayelet S; Nagler, Cathryn R; Gajewski, Thomas F; Chong, Anita S; Bartman, Caroline; Alegre, Maria-Luisa

    2016-07-01

    Transplantation is the only cure for end-stage organ failure, but without immunosuppression, T cells rapidly reject allografts. While genetic disparities between donor and recipient are major determinants of the kinetics of transplant rejection, little is known about the contribution of environmental factors. Because colonized organs have worse transplant outcome than sterile organs, we tested the influence of host and donor microbiota on skin transplant rejection. Compared with untreated conventional mice, pretreatment of donors and recipients with broad-spectrum antibiotics (Abx) or use of germ-free (GF) donors and recipients resulted in prolonged survival of minor antigen-mismatched skin grafts. Increased graft survival correlated with reduced type I IFN signaling in antigen-presenting cells (APCs) and decreased priming of alloreactive T cells. Colonization of GF mice with fecal material from untreated conventional mice, but not from Abx-pretreated mice, enhanced the ability of APCs to prime alloreactive T cells and accelerated graft rejection, suggesting that alloimmunity is modulated by the composition of microbiota rather than the quantity of bacteria. Abx pretreatment of conventional mice also delayed rejection of major antigen-mismatched skin and MHC class II-mismatched cardiac allografts. This study demonstrates that Abx pretreatment prolongs graft survival, suggesting that targeting microbial constituents is a potential therapeutic strategy for enhancing graft acceptance. PMID:27322054

  16. Haptoglobin Enhances Cardiac Transplant Rejection

    PubMed Central

    Shen, Hua; Heuzey, Elizabeth; Mori, Daniel; Wong, Christine; Colangelo, Christopher; Chung, Lisa M.; Bruce, Can; Slizovskiy, Ilya B.; Booth, Carmen J.; Kreisel, Daniel; Goldstein, Daniel R.

    2015-01-01

    Rationale Early graft inflammation enhances both acute and chronic rejection of heart transplants, but it is unclear how this inflammation is initiated. Objective To identify specific inflammatory modulators and determine their underlying molecular mechanisms after cardiac transplantation. Methods and Results We used a murine heterotopic cardiac transplant model to identify inflammatory modulators of early graft inflammation. Unbiased mass spectrometric analysis of cardiac tissue before and up to 72 hours after transplantation revealed that 22 proteins including haptoglobin, a known anti-oxidant, are significantly upregulated in our grafts. Through the use of haptoglobin deficient mice, we show that 80% of haptoglobin deficient recipients treated with peri-operative administration of the costimulatory blocking agent CTLA4 immunoglobulin exhibited > 100 days survival of full major histocompatibility complex mismatched allografts, whereas all similarly treated wild type recipients rejected their transplants by 21 days post transplantation. We found that haptoglobin modifies the intra-allograft inflammatory milieu by enhancing levels of the inflammatory cytokine IL-6 and the chemokine MIP-2 but impair levels of the immunosuppressive cytokine IL-10. Haptoglobin also enhances dendritic cell graft recruitment and augments anti-donor T cell responses. Moreover, we confirmed that the protein is present in human cardiac allograft specimens undergoing acute graft rejection. Conclusions Our findings provide new insights into the mechanisms of inflammation after cardiac transplantation and suggest that, in contrast to its prior reported anti-oxidant function in vascular inflammation, haptoglobin is an enhancer of inflammation after cardiac transplantation. Haptoglobin may also be a key component in other sterile inflammatory conditions. PMID:25801896

  17. Infectious Triggers of Chronic Lung Allograft Dysfunction.

    PubMed

    Gregson, Aric L

    2016-07-01

    Survival after lung transplantation is limited in large part due to the high incidence of chronic rejection, known as chronic lung allograft dysfunction (CLAD). Pulmonary infections are a frequent complication in lung transplant recipients, due both to immunosuppressive medications and constant exposure of the lung allograft to the external environment via the airways. Infection is a recognized risk factor for the development of CLAD, and both acute infection and chronic lung allograft colonization with microorganisms increase the risk for CLAD. Acute infection by community acquired respiratory viruses, and the bacteria Pseudomonas aeruginosa and Staphylococcus aureus are increasingly recognized as important risk factors for CLAD. Colonization by the fungus Aspergillus may also augment the risk of CLAD. Fostering this transition from healthy lung to CLAD in each of these infectious episodes is the persistence of an inflammatory lung allograft environment. PMID:27221821

  18. Radiation sterilization of tissue allografts: A review

    PubMed Central

    Singh, Rita; Singh, Durgeshwer; Singh, Antaryami

    2016-01-01

    Tissue substitutes are required in a number of clinical conditions for treatment of injured and diseased tissues. Tissues like bone, skin, amniotic membrane and soft tissues obtained from human donor can be used for repair or reconstruction of the injured part of the body. Allograft tissues from human donor provide an excellent alternative to autografts. However, major concern with the use of allografts is the risk of infectious disease transmission. Therefore, tissue allografts should be sterilized to make them safe for clinical use. Gamma radiation has several advantages and is the most suitable method for sterilization of biological tissues. This review summarizes the use of gamma irradiation technology as an effective method for sterilization of biological tissues and ensuring safety of tissue allografts. PMID:27158422

  19. Radiation sterilization of tissue allografts: A review.

    PubMed

    Singh, Rita; Singh, Durgeshwer; Singh, Antaryami

    2016-04-28

    Tissue substitutes are required in a number of clinical conditions for treatment of injured and diseased tissues. Tissues like bone, skin, amniotic membrane and soft tissues obtained from human donor can be used for repair or reconstruction of the injured part of the body. Allograft tissues from human donor provide an excellent alternative to autografts. However, major concern with the use of allografts is the risk of infectious disease transmission. Therefore, tissue allografts should be sterilized to make them safe for clinical use. Gamma radiation has several advantages and is the most suitable method for sterilization of biological tissues. This review summarizes the use of gamma irradiation technology as an effective method for sterilization of biological tissues and ensuring safety of tissue allografts. PMID:27158422

  20. 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.

  1. Cell-mediated immunity in experimental Nocardia asteroides infection.

    PubMed Central

    Sundararaj, T; Agarwal, S C

    1977-01-01

    Experimental mycetoma-like lesions developed in guinea pigs after subcutaneous injection of Nocardia asteroides. Although delayed hypersensitivity appeared earlier, increased macrophage migration inhibition and microbicidal activity appeared after 7 weeks. When the lesions healed, high cell-mediated immunity was present. Cell-mediated immunity was transferred to normal recipient guinea pigs from healed donor guinea pigs by spleen cell transfer. Recipient guinea pigs showed marked protection against challenge with N. asteroides. PMID:321348

  2. The Critical Role of Bioenergetics in Donor Cardiac Allograft Preservation.

    PubMed

    Schipper, David A; Marsh, Katherine M; Ferng, Alice S; Duncker, Dirk J; Laman, Jon D; Khalpey, Zain

    2016-06-01

    The traditional philosophy of ex vivo organ preservation has been to limit metabolic activity by storing organs in hypothermic, static conditions. This methodology cannot provide longevity of hearts for more than 4-6 h and is thereby insufficient to expand the number of available organs. Albeit at lower rate, the breakdown of ATP still occurs during hypothermia. Furthermore, cold static preservation does not prevent the permanent damage that occurs upon reperfusion known as ischemia-reperfusion (IR) injury. This damage is caused by increased reactive oxygen species (ROS) production in combination with mitochondrial permeability transition pore (mPTP) opening, highlighting the importance of mitochondria in ischemic storage. There has recently been a major paradigm shift in the field, with emerging research supporting changes in traditional storage approaches. Novel research suggests achieving metabolic homeostasis instead of attempting to limit metabolic activity which reduces IR injury and improves graft preservation. Maintaining high ATP levels and circumventing cold organ storage would be a much more sophisticated standard for organ storage and should be the focus of future research in organ preservation. Given the link between mPTP, Ca2(+), and ROS, managing Ca2(+) influx into the mitochondria during conditioning might be the next critical step towards preventing irreversible IR injury. PMID:27164961

  3. Radionuclide surveillance of the allografted pancreas

    SciTech Connect

    George, E.A.; Salimi, Z.; Carney, K.; Castaneda, M.; Garvin, P.J.

    1988-04-01

    To determine the value of scintigraphy to detect posttransplantation complications of the allografted pancreas, we retrospectively reviewed 209 scintigrams obtained with /sup 99m/Tc-sulfur colloid (/sup 99m/Tc-SC) and /sup 99m/Tc-glucoheptonate (/sup 99m/Tc-GH). The scintigraphic studies were performed in 37 recipients of simultaneous renal and pancreatic allografts harvested from the same donor. /sup 99m/Tc-SC was used as an indicator of thrombotic vasculitis; pancreatic perfusion and blood-pool parameters were monitored with /sup 99m/Tc-GH. In 11 of the 37 recipients, scintigraphic abnormalities suggested posttransplantation infarction. Recurrent episodes of acute rejection of the pancreatic allograft, which always coincided with acute rejection of the renal allograft, were monitored in 24 recipients. Rejection-induced ischemic pancreatitis was suggested in 12 of the 24 recipients and persisted in 10 recipients for several weeks after improvement of renal allograft rejection. Pancreatic atrophy was suggested scintigraphically in 16 of the 24 recipients with recurrent episodes of rejection. Spontaneous pancreatic-duct obstruction and obstructive pancreatitis were associated with a scintigraphic pattern similar to that of rejection-induced ischemic pancreatitis. We concluded that the specific radionuclides used in this series are useful for the surveillance and assessment of posttransplantation pancreatic infarction, acute rejection, pancreatitis, and atrophy

  4. Circulating NK-cell subsets in renal allograft recipients with anti-HLA donor-specific antibodies.

    PubMed

    Crespo, M; Yelamos, J; Redondo, D; Muntasell, A; Perez-Saéz, M J; López-Montañés, M; García, C; Torio, A; Mir, M; Hernández, J J; López-Botet, M; Pascual, J

    2015-03-01

    Detection of posttransplant donor-specific anti-HLA antibodies (DSA) constitutes a risk factor for kidney allograft loss. Together with complement activation, NK-cell antibody-dependent cell mediated cytotoxicity (ADCC) has been proposed to contribute to the microvascular damage associated to humoral rejection. In the present observational exploratory study, we have tried to find a relationship of circulating donor-specific and non donor-specific anti-HLA antibodies (DSA and HLA non-DSA) with peripheral blood NK-cell subsets and clinical features in 393 renal allograft recipients. Multivariate analysis indicated that retransplantation and pretransplant sensitization were associated with detection of posttransplant DSA. Recipient female gender, DR mismatch and acute rejection were significantly associated with posttransplant DSA compared to HLA non-DSA. In contrast with patients without detectable anti-HLA antibodies, DSA and HLA non-DSA patients displayed lower proportions of NK-cells, associated with increased CD56(bright) and NKG2A(+) subsets, the latter being more marked in DSA cases. These differences appeared unrelated to retransplantation, previous acute rejection or immunosuppressive therapy. Although preliminary and observational in nature, our results suggest that the assessment of the NK-cell immunophenotype may contribute to define signatures of alloreactive humoral responses in renal allograft recipients. PMID:25656947

  5. Autograft Substitutes: Conduits and Processed Nerve Allografts.

    PubMed

    Safa, Bauback; Buncke, Gregory

    2016-05-01

    Manufactured conduits and allografts are viable alternatives to direct suture repair and nerve autograft. Manufactured tubes should have gaps less than 10 mm, and ideally should be considered as an aid to the coaptation. Processed nerve allograft has utility as a substitute for either conduit or autograft in sensory nerve repairs. There is also a growing body of evidence supporting their utility in major peripheral nerve repairs, gap repairs up to 70 mm in length, as an alternative source of tissue to bolster the diameter of a cable graft, and for the management of neuromas in non-reconstructable injuries. PMID:27094886

  6. Meniscal allograft transplantation: rationale for treatment.

    PubMed

    Smith, N A; Costa, M L; Spalding, T

    2015-05-01

    The anatomy and microstructure of the menisci allow the effective distribution of load across the knee. Meniscectomy alters the biomechanical environment and is a potent risk factor for osteoarthritis. Despite a trend towards meniscus-preserving surgery, many tears are irreparable, and many repairs fail. Meniscal allograft transplantation has principally been carried out for pain in patients who have had a meniscectomy. Numerous case series have reported a significant improvement in patient-reported outcomes after surgery, but randomised controlled trials have not been undertaken. It is scientifically plausible that meniscal allograft transplantation is protective of cartilage, but this has not been established clinically to date. PMID:25922450

  7. Acute allograft rejection and immunosuppression: influence on endogenous melatonin secretion.

    PubMed

    Cardell, Markus; Jung, Florian Johannes; Zhai, Wei; Hillinger, Sven; Welp, Andre; Manz, Bernhard; Weder, Walter; Korom, Stephan

    2008-04-01

    Melatonin displays a dose-dependent immunoregulatory effect in vitro and in vivo. Exogenous high-dose melatonin therapy exerted an immunosuppressive effect, abrogating acute rejection (AR), significantly prolonging transplant survival. Endogenous melatonin secretion, in response to heterotopic rat cardiac allograft transplantation (Tx), was investigated during the AR response and under standardized immunosuppressive maintenance therapy with cyclosporin A (CsA) and rapamycin (RPM). Recipients of syngeneic transplants, and recipients of allogeneic grafts, either untreated or receiving immunosuppressive therapy constituted the experimental groups. Endogenous circadian melatonin levels were measured at 07:00, 19:00, and 24:00 hr, using a novel radioimmunoassay (RIA) procedure, under standardized 12-hr-light/dark-conditions (light off: 19:00 hr; light on: 07:00 hr), before and after Tx. Neither the operative trauma, nor the challenge with a perfused allograft or the AR response influenced endogenous melatonin peak secretion. Immunosuppressive therapy with CsA led to a significant increase in peak secretion, measured for days 7 (212 +/- 40.7 pg/mL; P < 0.05), 14 (255 +/- 13.9 pg/mL; P < 0.001), and 21 (219 +/- 34 pg/mL; P < 0.01) after Tx, as compared with naïve animals (155 +/- 25.8 pg/mL). In contrast, treatment with RPM significantly decreased the melatonin peak post-Tx up to day 7 (87 +/- 25.2 pg/mL; P < 0.001), compared with naïve animals (155 +/- 25.8 pg/mL). These findings imply a robust nature of the endogenous circadian melatonin secretion kinetics, even against the background of profound allogeneic stimuli. Immunosuppressive maintenance therapy with CsA and RPM modulated early melatonin secretion, indicating a specific secondary action of these drugs. Further studies are necessary to disclose the long-term effect of immunosuppressive therapy on circadian melatonin secretion in transplant recipients. PMID:18339121

  8. In situ expression of cytokines in human heart allografts.

    PubMed Central

    Van Hoffen, E.; Van Wichen, D.; Stuij, I.; De Jonge, N.; Klöpping, C.; Lahpor, J.; Van Den Tweel, J.; Gmelig-Meyling, F.; De Weger, R.

    1996-01-01

    Although allograft rejection, the major complication of human organ transplantation, has been extensively studied, little is known about the exact cellular localization of the cytokine expression inside the graft during rejection. Therefore, we used in situ hybridization and immunohistochemistry to study local cytokine mRNA and protein expression in human heart allografts, in relation to the phenotypical characteristics of the cellular infiltrate. Clear expression of mRNA for interleukin (IL)-6, IL-8, IL-9, and IL-10 and weak expression for IL-2, IL-4, IL-5, and tumor necrosis factor (TNF)-alpha was detected in biopsies exhibiting high rejection grades (grade 3A/B). Also at lower grades of rejection, mRNA for IL-6 and IL-9 was present. Some mRNA for IL-1 beta, TNF-beta, and interferon (IFN)-gamma was detected in only a few biopsies. Using immunohistochemistry, IL-2, IL-3, and IL-10 protein was detected in biopsies with high rejection grades, whereas few cells expressed IL-6, IL-8, and IFN-gamma. In biopsies with lower grades of rejection, a weaker expression of these cytokines was observed. IL-4 was hardly detected in any of the biopsies. The level of IL-12 expression was equal in all biopsies. Although mRNA expression of several cytokines was expressed at a low level compared with the protein level of those cytokines, there was a good correlation between localization of cytokine mRNA and protein. Expression of IL-2, IL-4, IL-5, TNF-alpha, and IFN-gamma was mainly detected in lymphocytes. IL-3, IL-6, IL-10, and IL-12 were not detected or not only detected in lymphocytes but also in other stromal elements (eg, macrophages). Macrophage production of IL-3 and IL-12 was confirmed by immunofluorescent double labeling with CD68. We conclude that cardiac allograft rejection is not simply regulated by T helper cell cytokine production, but other intragraft elements contribute considerably to this process. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:8952534

  9. Detection of cell mediated immune response to avian influenza viruses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In birds, lymphomyeloid tissues develop from epithelial (Bursa of Fabricus or thymus) or mesenchymal tissue which are populated by heamatopoietic stem cells. These stem cells develop directly into immunologically competent B (bursa) and T (thymus) cells. Cell-mediated immunity (CMI) is a part of the...

  10. EFFECTS OF ENVIRONMENTAL CONTAMINANTS ON CELL MEDIATED IMMUNITY

    EPA Science Inventory

    The effect of lead and cadmium on cell-mediated immunity was studied in peritoneal macrophages, B-, and T-lymphocytes of mice. Lead and cadmium were administered in drinking water for 10 weeks in short-term experiments and up to 18 months to deal with immune responses in aged mic...

  11. The Impact of Infection on Chronic Allograft Dysfunction and Allograft Survival After Solid Organ Transplantation.

    PubMed

    Martin-Gandul, C; Mueller, N J; Pascual, M; Manuel, O

    2015-12-01

    Infectious diseases after solid organ transplantation (SOT) are a significant cause of morbidity and reduced allograft and patient survival; however, the influence of infection on the development of chronic allograft dysfunction has not been completely delineated. Some viral infections appear to affect allograft function by both inducing direct tissue damage and immunologically related injury, including acute rejection. In particular, this has been observed for cytomegalovirus (CMV) infection in all SOT recipients and for BK virus infection in kidney transplant recipients, for community-acquired respiratory viruses in lung transplant recipients, and for hepatitis C virus in liver transplant recipients. The impact of bacterial and fungal infections is less clear, but bacterial urinary tract infections and respiratory tract colonization by Pseudomonas aeruginosa and Aspergillus spp appear to be correlated with higher rates of chronic allograft dysfunction in kidney and lung transplant recipients, respectively. Evidence supports the beneficial effects of the use of antiviral prophylaxis for CMV in improving allograft function and survival in SOT recipients. Nevertheless, there is still a need for prospective interventional trials assessing the potential effects of preventive and therapeutic strategies against bacterial and fungal infection for reducing or delaying the development of chronic allograft dysfunction. PMID:26474168

  12. Meniscal Allograft Transplantation: State of the Art.

    PubMed

    Trentacosta, Natasha; Graham, William C; Gersoff, Wayne K

    2016-06-01

    Meniscal allograft transplantation has evolved over the years to provide a state-of-the-art technique for the sports medicine surgeon to utilize in preserving contact mechanics and function of the knee in irreparable meniscal pathology. However, this procedure continues to spark considerable debate on proper tissue processing techniques, acceptable indications, methods of implantation, and potential long-term outcomes. PMID:27135295

  13. [Chronic complications in cardiac transplantation. Clinical implications and future strategies].

    PubMed

    Magaña-Serrano, José Antonio; Argüero-Sánchez, Rubén

    2005-01-01

    Chronic complications are situations which limit the long-term utility of cardiac transplantation. The allograft vasculopathy is the most important cause of death at 5 years alter transplantation. Another conditions are systemic arterial hypertension, nephropathies, diabetes mellitus, dyslipidemies and malignant neoplasies. The present manuscript summarizes the characteristics, clinical presentation and therapeutic strategies for this conditions. PMID:16524076

  14. Donation after cardiac death in abdominal organ transplantation.

    PubMed

    Reich, David J; Guy, Stephen R

    2012-01-01

    This article reviews the field of donation after cardiac death, focusing on the history, ethicolegal issues, clinical outcomes, best practices, operative techniques, and emerging strategies to optimize utilization of this resource. Donation after cardiac death is one effective way to decrease the organ shortage and has contributed the largest recent increase in abdominal organ allografts. Currently, donation after cardiac death organs confer an increased risk of ischemic cholangiopathy after liver transplant and of delayed graft function after kidney transplant. As this field matures, risk factors for donation after cardiac death organ transplant will be further identified and clinical outcomes will improve as a result of protocol standardization and ongoing research. PMID:22678860

  15. Cardiac Rehabilitation

    MedlinePlus

    ... from the NHLBI on Twitter. What Is Cardiac Rehabilitation? Cardiac rehabilitation (rehab) is a medically supervised program ... be designed to meet your needs. The Cardiac Rehabilitation Team Cardiac rehab involves a long-term commitment ...

  16. Informed consent is not routinely documented for procedures using allografts.

    PubMed

    Porter, Scott E; Stull, Douglass; Kneisl, Jeffrey S; Frick, Steven L

    2004-06-01

    Patients who receive musculoskeletal allografts may have severe postoperative infections develop. Media reports have heightened public awareness of the risk of allograft use. Explaining these risks to patients preoperatively has become more important as attention to informed consent issues has increased. This study retrospectively investigated the patterns of informed consent for allograft bone used during elective orthopaedic procedures at a major teaching hospital. Forty-seven (32%) of 148 patients had preoperative discussions of allograft risks and benefits documented with a signed preoperative consent. In nearly 70% of the cases in which structural allograft was used, preoperative consent was documented. Only 8% of cases in which nonstructural, highly processed allograft was used had documented preoperative consent. Forty-eight (32%) of 148 patients were treated with allograft and autograft. Consent was obtained for the harvesting and use of autograft from 90% of these patients. In none of these patients was consent obtained for the allograft used. Although risks of disease transmission vary widely with the degree of allograft processing and the source of its procurement, informed consent for any allograft use should be a routine part of preoperative discussions of risks and benefits in elective orthopaedic surgeries. PMID:15232464

  17. Factors Predicting Meniscal Allograft Transplantation Failure

    PubMed Central

    Parkinson, Ben; Smith, Nicholas; Asplin, Laura; Thompson, Peter; Spalding, Tim

    2016-01-01

    Background: Meniscal allograft transplantation (MAT) is performed to improve symptoms and function in patients with a meniscal-deficient compartment of the knee. Numerous studies have shown a consistent improvement in patient-reported outcomes, but high failure rates have been reported by some studies. The typical patients undergoing MAT often have multiple other pathologies that require treatment at the time of surgery. The factors that predict failure of a meniscal allograft within this complex patient group are not clearly defined. Purpose: To determine predictors of MAT failure in a large series to refine the indications for surgery and better inform future patients. Study Design: Cohort study; Level of evidence, 3. Methods: All patients undergoing MAT at a single institution between May 2005 and May 2014 with a minimum of 1-year follow-up were prospectively evaluated and included in this study. Failure was defined as removal of the allograft, revision transplantation, or conversion to a joint replacement. Patients were grouped according to the articular cartilage status at the time of the index surgery: group 1, intact or partial-thickness chondral loss; group 2, full-thickness chondral loss 1 condyle; and group 3, full-thickness chondral loss both condyles. The Cox proportional hazards model was used to determine significant predictors of failure, independently of other factors. Kaplan-Meier survival curves were produced for overall survival and significant predictors of failure in the Cox proportional hazards model. Results: There were 125 consecutive MATs performed, with 1 patient lost to follow-up. The median follow-up was 3 years (range, 1-10 years). The 5-year graft survival for the entire cohort was 82% (group 1, 97%; group 2, 82%; group 3, 62%). The probability of failure in group 1 was 85% lower (95% CI, 13%-97%) than in group 3 at any time. The probability of failure with lateral allografts was 76% lower (95% CI, 16%-89%) than medial allografts at

  18. Effect of space flight on cell-mediated immunity

    NASA Technical Reports Server (NTRS)

    Mandel, A. D.; Balish, E.

    1977-01-01

    The cell-mediated immune response to Listeria monocytogenes was studied in rats subjected to 20 days of flight aboard the Soviet biosatellite Kosmos 7820. Groups of rats were immunized with 1,000,000 formalin-killed Listeria suspended in Freunds Complete Adjuvant, 5 days prior to flight. Immunized rats subjected to the same environmental factors as the flight rats, except flight itself, and immunized and nonimmunized rats held in a normal animal colony served as controls. Following recovery, lymphocyte cultures were harvested from spleens of all rats, cultured in vitro in the presence of L. monocytogenes antigens, Phytohemagglutinin, Conconavlin A, or purified protein derivative (PPD), and measured for their uptake of H-3-thymidine. Although individual rats varied considerably, all flight and immunized control rats gave a blastogenic response to the Listeria antigens and PPD. With several mitogens, the lymphocytes of flight rats showed a significantly increased blastogenic response over the controls. The results of this study do not support a hypothesis of a detrimental effect of space flight on cell-mediated immunity. The data suggest a possible suppressive effect of stress and gravity on an in vitro correlate of cell-mediated immunity.

  19. Comparison of frozen and freeze-dried particulate bone allografts.

    PubMed

    Malinin, Theodore; Temple, H Thomas

    2007-10-01

    Freeze-dried and frozen particulate bone allografts are used interchangeably on the assumption that the biologic behavior of these grafts is similar. Dissimilarities in biologic behavior and differences in the rate and extent of bone incorporation of freeze-dried and frozen particulate grafts were demonstrated in a comparative study using a non-human primate model. Freeze-dried particulate allografts induced new bone formation and healing of the osseous defects much faster than the frozen allografts. PMID:17658506

  20. [Extensor mechanism allograft reconstruction after total knee replacement].

    PubMed

    Bürde, C; Sweeney, Patrick

    2007-04-01

    We present three cases in which we used a complete extensor mechanism allograft for the reconstruction of an insufficient extensor mechanism after total knee arthroplasty (and failed reconstruction with local tissue in two of these cases). Early results are encouraging. Allograft reconstruction can be taken into consideration as an alternative to arthrodesis in those "worst-case scenarios". Late failure may occur in about 20%, probably due to a lack of revitalisation in the centre of the allograft. PMID:17262182

  1. 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.

  2. Transplant allograft vasculopathy: Role of multimodality imaging in surveillance and diagnosis.

    PubMed

    Payne, Gregory A; Hage, Fadi G; Acharya, Deepak

    2016-08-01

    Cardiac allograft vasculopathy (CAV) is a challenging long-term complication of cardiac transplantation and remains a leading long-term cause of graft failure, re-transplantation, and death. CAV is an inflammatory vasculopathy distinct from traditional atherosclerotic coronary artery disease. Historically, the surveillance and diagnosis of CAV has been dependent on serial invasive coronary angiography with intravascular imaging. Although commonly practiced, angiography is not without significant limitations. Technological advances have provided sophisticated imaging techniques for CAV assessment. It is now possible to assess the vascular lumen, vessel wall characteristics, absolute blood flow, perfusion reserve, myocardial contractile function, and myocardial metabolism and injury in a noninvasive, expeditious manner with little risk. The current article will review key imaging modalities for the surveillance, diagnosis, and prognosis of CAV and discuss coronary physiology of transplanted hearts with emphasis on the clinical implications for provocative and vasodilator stress testing. PMID:26711101

  3. Urinary Calprotectin and Posttransplant Renal Allograft Injury

    PubMed Central

    Bistrup, Claus; Marcussen, Niels; Pagonas, Nikolaos; Seibert, Felix S.; Arndt, Robert; Zidek, Walter; Westhoff, Timm H.

    2014-01-01

    Objective Current methods do not predict the acute renal allograft injury immediately after kidney transplantation. We evaluated the diagnostic performance of urinary calprotectin for predicting immediate posttransplant allograft injury. Methods In a multicenter, prospective-cohort study of 144 incipient renal transplant recipients, we postoperatively measured urinary calprotectin using an enzyme-linked immunosorbent assay and estimated glomerular filtration rate (eGFR) after 4 weeks, 6 months, and 12 months. Results We observed a significant inverse association of urinary calprotectin concentrations and eGFR 4 weeks after transplantation (Spearman r = −0.33; P<0.001). Compared to the lowest quartile, patients in the highest quartile of urinary calprotectin had an increased risk for an eGFR less than 30 mL/min/1.73 m2 four weeks after transplantation (relative risk, 4.3; P<0.001; sensitivity, 0.92; 95% CI, 0.77 to 0.98; specificity, 0.48; 95% CI, 0.31 to 0.66). Higher urinary calprotectin concentrations predicted impaired kidney function 4 weeks after transplantation, as well as 6 months and 12 months after transplantation. When data were analyzed using the urinary calprotectin/creatinine-ratio similar results were obtained. Urinary calprotectin was superior to current use of absolute change of plasma creatinine to predict allograft function 12 months after transplantation. Urinary calprotectin predicted an increased risk both in transplants from living and deceased donors. Multivariate linear regression showed that higher urinary calprotectin concentrations and older donor age predicted lower eGFR four weeks, 6 months, and 12 months after transplantation. Conclusions Urinary calprotectin is an early, noninvasive predictor of immediate renal allograft injury after kidney transplantation. PMID:25402277

  4. Procurement of hand and arm allografts.

    PubMed

    Cetrulo, Curtis L; Kovach, Stephen J

    2013-12-01

    Upper extremity transplantation has been at the forefront of vascularized composite allotransplantation. There have been more hand and upper extremity transplants than any other kinds of vascularized composite allotransplantation. However, it is a new and evolving field. Reconstructive surgeons are relative newcomers to the field of transplantation, and the procurement of upper extremity allografts has many subtleties that will differ depending on the intended recipient. However, there are certain principles that can be adhered to that this review serves to elucidate. PMID:24310234

  5. Zygomycosis in a renal allograft recipient

    PubMed Central

    Lakshminarayana, G.; Rajesh, R.; Kurian, G.; Unni, V. N.

    2009-01-01

    Invasive fungal infections can cause considerable morbidity and mortality in immunocompromised patients. Zygomycosis is a type of invasive fungal infection with a rapid course and grave prognosis. Renal transplant recipients with concomitant diabetes mellitus are most susceptible to this infection. We report here a case of disseminated zygomycosis (Rhizopus sp.) in a renal allograft recipient with posttransplant diabetes mellitus (PTDM). This is the first reported case of zygomycosis caused by Rhizopus species. PMID:20352010

  6. Monocytic suppressive cells mediate cardiovascular transplantation tolerance in mice

    PubMed Central

    Garcia, Mercedes Rodriguez; Ledgerwood, Levi; Yang, Yu; Xu, Jiangnan; Lal, Girdhari; Burrell, Bryna; Ma, Ge; Hashimoto, Daigo; Li, Yansui; Boros, Peter; Grisotto, Marcos; van Rooijen, Nico; Matesanz, Rafael; Tacke, Frank; Ginhoux, Florent; Ding, Yaozhong; Chen, Shu-Hsia; Randolph, Gwendalyn; Merad, Miriam; Bromberg, Jonathan S.; Ochando, Jordi C.

    2010-01-01

    One of the main unresolved questions in solid organ transplantation is how to establish indefinite graft survival that is free from long-term treatment with immunosuppressive drugs and chronic rejection (i.e., the establishment of tolerance). The failure to achieve this goal may be related to the difficulty in identifying the phenotype and function of the cell subsets that participate in the induction of tolerance. To address this issue, we investigated the suppressive roles of recipient myeloid cells that may be manipulated to induce tolerance to transplanted hearts in mice. Using depleting mAbs, clodronate-loaded liposomes, and transgenic mice specific for depletion of CD11c+, CD11b+, or CD115+ cells, we identified a tolerogenic role for CD11b+CD115+Gr1+ monocytes during the induction of tolerance by costimulatory blockade with CD40L-specific mAb. Early after transplantation, Gr1+ monocytes migrated from the bone marrow into the transplanted organ, where they prevented the initiation of adaptive immune responses that lead to allograft rejection and participated in the development of Tregs. Our results suggest that mobilization of bone marrow CD11b+CD115+Gr1+ monocytes under sterile inflammatory conditions mediates the induction of indefinite allograft survival. We propose that manipulating the common bone marrow monocyte progenitor could be a useful clinical therapeutic approach for inducing transplantation tolerance. PMID:20551515

  7. Cardiac Catheterization

    MedlinePlus

    ... from the NHLBI on Twitter. What Is Cardiac Catheterization? Cardiac catheterization (KATH-eh-ter-ih-ZA-shun) is a ... disease. Doctors also can use ultrasound during cardiac catheterization to see blockages in the coronary arteries. Ultrasound ...

  8. Use of local allograft irradiation following renal transplantation

    SciTech Connect

    Halperin, E.C.; Delmonico, F.L.; Nelson, P.W.; Shipley, W.U.; Cosimi, A.B.

    1984-07-01

    Over a 10 year period, 67 recipients of 71 renal allografts received graft irradiation following the diagnosis of rejection. The majority of kidneys were treated with a total dose of 600 rad, 150 rad per fraction, in 4 daily fractions. Fifty-three kidneys were irradiated following the failure of standard systemic immunosuppression and maximally tolerated antirejection measures to reverse an episode of acute rejection. Twenty-two (42%) of these allografts were noted to have stable (i.e. no deterioration) or improved function 1 month following the treatment with irradiation. Eleven (21%) of these allografts maintained function 1 year following transplantation. Biopsies were obtained of 41 allografts. Of the 24 renal allografts with predominantly cellular rejection, 10 (42%) had the process reversed or stabilized at 1 month following irradiation. Five (21%) of these allografts were functioning at 1 year following irradiation. Rejection was reversed or stabilized in 6 of 17 (35%) allografts at 1 month when the histologic features of renal biopsy suggested predominantly vascular rejection. Local graft irradiation has helped maintain a limited number of allografts in patients whose rejection has failed to respond to systemic immunosuppression. Irradiation may also benefit patients with ongoing rejection in whom further systemic immunosuppression is contra-indicated.

  9. Subclinical Rejection Phenotypes at 1 Year Post-Transplant and Outcome of Kidney Allografts.

    PubMed

    Loupy, Alexandre; Vernerey, Dewi; Tinel, Claire; Aubert, Olivier; Duong van Huyen, Jean-Paul; Rabant, Marion; Verine, Jérôme; Nochy, Dominique; Empana, Jean-Philippe; Martinez, Frank; Glotz, Denis; Jouven, Xavier; Legendre, Christophe; Lefaucheur, Carmen

    2015-07-01

    Kidney allograft rejection can occur in clinically stable patients, but long-term significance is unknown. We determined whether early recognition of subclinical rejection has long-term consequences for kidney allograft survival in an observational prospective cohort study of 1307 consecutive nonselected patients who underwent ABO-compatible, complement-dependent cytotoxicity-negative crossmatch kidney transplantation in Paris (2000-2010). Participants underwent prospective screening biopsies at 1 year post-transplant, with concurrent evaluations of graft complement deposition and circulating anti-HLA antibodies. The main analysis included 1001 patients. Three distinct groups of patients were identified at the 1-year screening: 727 (73%) patients without rejection, 132 (13%) patients with subclinical T cell-mediated rejection (TCMR), and 142 (14%) patients with subclinical antibody-mediated rejection (ABMR). Patients with subclinical ABMR had the poorest graft survival at 8 years post-transplant (56%) compared with subclinical TCMR (88%) and nonrejection (90%) groups (P<0.001). In a multivariate Cox model, subclinical ABMR at 1 year was independently associated with a 3.5-fold increase in graft loss (95% confidence interval, 2.1 to 5.7) along with eGFR and proteinuria (P<0.001). Subclinical ABMR was associated with more rapid progression to transplant glomerulopathy. Of patients with subclinical TCMR at 1 year, only those who further developed de novo donor-specific antibodies and transplant glomerulopathy showed higher risk of graft loss compared with patients without rejection. Our findings suggest that subclinical TCMR and subclinical ABMR have distinct effects on long-term graft loss. Subclinical ABMR detected at the 1-year screening biopsy carries a prognostic value independent of initial donor-specific antibody status, previous immunologic events, current eGFR, and proteinuria. PMID:25556173

  10. Surgical techniques and radiological findings of meniscus allograft transplantation.

    PubMed

    Lee, Hoseok; Lee, Sang Yub; Na, Young Gon; Kim, Sung Kwan; Yi, Jae Hyuck; Lim, Jae Kwang; Lee, So Mi

    2016-08-01

    Meniscus allograft transplantation has been performed over the past 25 years to relieve knee pain and improve knee function in patients with an irreparable meniscus injury. The efficacy and safety of meniscus allograft transplantation have been established in numerous experimental and clinical researches. However, there is a lack of reviews to aid radiologists who are routinely interpreting images and evaluating the outcome of the procedures, and also meniscus allograft transplantation is not widely performed in most hospitals. This review focuses on the indications of the procedure, the different surgical techniques used for meniscus allograft transplantation according to the involvement of the lateral and medial meniscus, and the associated procedures. The postoperative radiological findings and surgical complications of the meniscus allograft transplantation are also described in detail. PMID:27423673

  11. Graft vasculopathy in the skin of a human hand allograft: implications for diagnosis of rejection of vascularized composite allografts.

    PubMed

    Kanitakis, Jean; Karayannopoulou, Georgia; Lanzetta, Marco; Petruzzo, Palmina

    2014-11-01

    Whereas vascularized composite allografts often undergo acute rejections early in the postgraft period, rejection manifesting with severe vascular changes (graft vasculopathy) has only been observed on three occasions in humans. We report a hand-allografted patient who developed severe rejection following discontinuation of the immunosuppressive treatment. It manifested clinically with erythematous maculopapules on the skin and pathologically with graft vasculopathy that affected both large vessels and smaller cutaneous ones. The observation that graft vasculopathy can affect skin vessels shows that it is amenable to diagnosis with usual skin biopsy as recommended for the follow-up of these allografts. Graft vasculopathy developing in the setting of vascularized composite allografts likely represents chronic rejection due to under-immunosuppression and, if confirmed, should be included in a future update of the Banff classification of vascularized composite allograft rejection. PMID:25041139

  12. Paracrine action of HO-1-modified mesenchymal stem cells mediates cardiac protection and functional improvement.

    PubMed

    Zeng, Bin; Ren, Xiaofeng; Lin, Guosheng; Zhu, Chengang; Chen, Honglei; Yin, Jiechao; Jiang, Hong; Yang, Bo; Ding, Danhua

    2008-10-01

    The aim has been to determine whether the supernatants of mesenchymal stem cells (MSCs) transfected with adenovirus carrying human heme oxygenase-1 (hHO-1) gene protect cardiomyocytes from ischemic injury. We have found that hHO-1 infected MSCs (hHO-1-MSCs) increased expression of hHO-1 protein. Apoptosis of cultured hHO-1-MSCs exposed to hypoxia was suppressed. Several cytokines, including HGF, bFGF, TGF-beta, VEGF and IL-1beta, were produced by hHO-1-MSCs, some being significantly enhanced under hypoxia stimulation. Meanwhile, those cytokines reduced caspase-3 level and activity in cultured adult rat ventricular cardiomyocytes (ARVCs) exposed to hypoxia. Supernatants obtained from hHO-1-MSCs improved left ventricular function, limited myocardial infarct size, increased microvessel density, and inhibited apoptosis of cardiomyocytes in rat myocardial infarction. It can be concluded hHO-1-modified MSCs prevent myocardial cell injury via secretion of paracrine-acting mediators. PMID:18692581

  13. ACL reconstruction with BPTB autograft and irradiated fresh frozen allograft*

    PubMed Central

    Sun, Kang; Tian, Shao-qi; Zhang, Ji-hua; Xia, Chang-suo; Zhang, Cai-long; Yu, Teng-bo

    2009-01-01

    Objective: To analyze the clinical outcomes of arthroscopic anterior cruciate ligament (ACL) reconstruction with irradiated bone-patellar tendon-bone (BPTB) allograft compared with non-irradiated allograft and autograft. Methods: All BPTB allografts were obtained from a single tissue bank and the irradiated allografts were sterilized with 2.5 mrad of irradiation prior to distribution. A total of 68 patients undergoing arthroscopic ACL reconstruction were prospectively randomized consecutively into one of the two groups (autograft and irradiated allograft groups). The same surgical technique was used in all operations done by the same senior surgeon. Before surgery and at the average of 31 months of follow-up (ranging from 24 to 47 months), patients were evaluated by the same observer according to objective and subjective clinical evaluations. Results: Of these patients, 65 (autograft 33, irradiated allograft 32) were available for full evaluation. When the irradiated allograft group was compared to the autograft group at the 31-month follow-up by the Lachman test, the anterior drawer test (ADT), the pivot shift test, and KT-2000 arthrometer test, statistically significant differences were found. Most importantly, 87.8% of patients in the autograft group and just only 31.3% in the irradiated allograft group had a side-to-side difference of less than 3 mm according to KT-2000. The failure rate of the ACL reconstruction with irradiated allograft (34.4%) was higher than that with autograft (6.1%). The anterior and rotational stabilities decreased significantly in the irradiated allograft group. According to the overall International Knee Documentation Committee (IKDC), functional and subjective evaluations, and activity level testing, no statistically significant differences were found between the two groups. Besides, patients in the irradiated allograft group had a shorter operation time and a longer duration of postoperative fever. When the patients had a fever, the

  14. Autograft Versus Nonirradiated Allograft Tissue for Anterior Cruciate Ligament Reconstruction

    PubMed Central

    Mariscalco, Michael W.; Magnussen, Robert A.; Mehta, Divyesh; Hewett, Timothy E.; Flanigan, David C.; Kaeding, Christopher C.

    2014-01-01

    Background An autograft has traditionally been the gold standard for anterior cruciate ligament reconstruction (ACLR), but the use of allograft tissue has increased in recent years. While numerous studies have demonstrated that irradiated allografts are associated with increased failure rates, some report excellent results after ACLR with nonirradiated allografts. The purpose of this systematic review was to determine whether the use of nonirradiated allograft tissue is associated with poorer outcomes when compared with autografts. Hypothesis Patients undergoing ACLR with autografts versus nonirradiated allografts will demonstrate no significant differences in graft failure risk, laxity on postoperative physical examination, or differences in patient-oriented outcome scores. Study Design Systematic review. Methods A systematic review was performed to identify prospective or retrospective comparative studies (evidence level 1, 2, or 3) of autografts versus nonirradiated allografts for ACLR. Outcome data included graft failure based on clinical findings and instrumented laxity, postoperative laxity on physical examination, and patient-reported outcome scores. Studies were excluded if they did not specify whether the allograft had been irradiated. Quality assessment and data extraction were performed by 2 examiners. Results Nine studies comparing autografts and nonirradiated allografts were included. Six of the 9 studies compared bone– patellar tendon–bone (BPTB) autografts with BPTB allografts. Two studies compared hamstring tendon autografts to hamstring tendon allografts, and 1 study compared hamstring tendon autografts to tibialis anterior allografts. The mean patient age in 7 of 9 studies ranged from 24.5 to 32 years, with 1 study including only patients older than 40 years and another not reporting patient age. The mean follow-up duration was 24 to 94 months. Six of 9 studies reported clinical graft failure rates, 8 of 9 reported postoperative instrumented

  15. Minimizing the risk of chronic allograft nephropathy.

    PubMed

    Weir, Matthew R; Wali, Ravinder K

    2009-04-27

    Chronic allograft nephropathy, now defined as interstital fibrosis and tubular atrophy not otherwise specified, is a near universal finding in transplant kidney biopsies by the end of the first decade posttransplantation. After excluding death with functioning graft, caused by cardiovascular disease or malignancy, chronic allograft nephropathy is the leading cause of graft failure. Original assumptions were that this was not a modifiable process but inexorable, likely due to past kidney injuries. However, newer understandings suggest that acute or subacute processes are involved, and with proper diagnosis, appropriate interventions can be instituted. Our method involved a review of the primary and secondary prevention trials in calcineurin inhibitor withdrawal. Some of the more important causes of progressive graft deterioration include subclinical cellular or humoral rejection, and chronic calcineurin inhibitor toxicity. Early graft biopsy, assessment of histology, and changes in immunosuppression may be some of the most important measures available to protect graft function. The avoidance of clinical inertia in pursuing subtle changes in graft function is critical. Modification in maintenance immunosuppression may benefit many patients with early evidence of graft deterioration. PMID:19384181

  16. Establishment of Stable, Cell-Mediated Immunity that Makes "Susceptible" Mice Resistant to Leishmania major

    NASA Astrophysics Data System (ADS)

    Bretscher, Peter A.; Wei, Guojian; Menon, Juthika N.; Bielefeldt-Ohmann, Helle

    1992-07-01

    Cell-mediated, but not antibody-mediated, immune responses protect humans against certain pathogens that produce chronic diseases such as leishmaniasis. Effective vaccination against such pathogens must therefore produce an immunological "imprint" so that stable, cell-mediated immunity is induced in all individuals after natural infection. BALB/c mice "innately susceptible" to Leishmania major produce antibodies after substantial infection. In the present study, "susceptible" mice injected with a small number of parasites mounted a cell-mediated response and acquired resistance to a larger, normally pathogenic, challenge. This vaccination strategy may be applicable in diseases in which protection is dependent on cell-mediated immunity.

  17. Iontophoresis as a means of delivering antibiotics into allograft bone.

    PubMed

    Day, R E; Megson, S; Wood, D

    2005-11-01

    Allograft bone is widely used in orthopaedic surgery, but peri-operative infection of the graft remains a common and disastrous complication. The efficacy of systemic prophylactic antibiotics is unproven, and since the graft is avascular it is likely that levels of antibiotic in the graft are low. Using an electrical potential to accelerate diffusion of antibiotics into allograft bone, high levels were achieved in specimens of both sheep and human allograft. In human bone these ranged from 187.1 mg/kg in endosteal (sd 15.7) to 124.6 (sd 46.2) in periosteal bone for gentamicin and 31.9 (sd 8.9) in endosteal and 2.9 (sd 1.1) in periosteal bone for flucloxacillin. The antibiotics remained active against bacteria in vitro after iontophoresis and continued to elute from the allograft for up to two weeks. Structural allograft can be supplemented directly with antibiotics using iontophoresis. The technique is simple and inexpensive and offers a potential means of reducing the rate of peri-operative infection in allograft surgery. Iontophoresis into allograft bone may also be applicable to other therapeutic compounds. PMID:16260682

  18. Depressed cell-mediated immunity in coeliac disease.

    PubMed Central

    Scott, B B; Losowsky, M S

    1976-01-01

    Fourteen coeliac patients on a gluten free diet (GFD) and 10 on a normal diet were studied by lymphocyte transformation in response to PHA to assess the integrity of cell-mediated immunity (CMI). Transformation was depressed in the majority taking a normal diet, with improvement after a GFD. In some patients the depression may have been due to a serum factor, as transformation was more nearly normal when the lymphocytes were cultured in pooled AB serum than in their own serum. There was no correlation between transformation and nutritional deficiencies. Mantoux tests were performed in some of these and other coeliac patients and there was a very significant reduction in the incidence of positive tests compared with controls. These findings provide evidence of depressed CMI in coeliac patients taking a normal diet with improvement on a GFD and may be of relevance to the high risk of malignancy in coeliac disease, further strengthening the case for a strict GFD. PMID:1087262

  19. Nonspecific cell-mediated immunity in patients with epidermodysplasia verruciformis.

    PubMed

    Pereira de Oliveira, Walmar Roncalli; Carrasco, Solange; Neto, Cyro Festa; Rady, Peter; Tyring, Stephen K

    2003-03-01

    Epidermodysplasia verruciformis (EV) is a rare disease that usually begins in childhood and is characterized by a generalized infection by human papilloma virus (HPV), frequent associations with cutaneous carcinomas, and abnormalities of cell-mediated immunity (CMI). We studied nonspecific CMI in 13 patients with EV by bacterial skin tests, allergic reactions to dinitrochlorobenzene (DNCB), measurement of responses to phytohemagglutinin (PHA), and quantification of T lymphocytes and T lymphocytes subsets in peripheral blood. Impairment of CMI was manifested by the cutaneous anergy to a variety of common skin antigens and, by the reduction of the lymphocyte transformation to PHA. There were no correlation between the severity of cases and abnormalities of CMI in our patients, however; the impairment of CMI was lower in cases of short duration, suggesting that the impairment of CMI in EV might reflect a long period of disease. PMID:12692356

  20. Acute and Chronic Allograft Dysfunction in Kidney Transplant Recipients.

    PubMed

    Goldberg, Ryan J; Weng, Francis L; Kandula, Praveen

    2016-05-01

    Allograft dysfunction after a kidney transplant is often clinically asymptomatic and is usually detected as an increase in serum creatinine level with corresponding decrease in glomerular filtration rate. The diagnostic evaluation may include blood tests, urinalysis, transplant ultrasonography, radionuclide imaging, and allograft biopsy. Whether it occurs early or later after transplant, allograft dysfunction requires prompt evaluation to determine its cause and subsequent management. Acute rejection, medication toxicity from calcineurin inhibitors, and BK virus nephropathy can occur early or later. Other later causes include transplant glomerulopathy, recurrent glomerulonephritis, and renal artery stenosis. PMID:27095641

  1. Expression of decoy receptor 3 in kidneys is associated with allograft survival after kidney transplant rejection.

    PubMed

    Weng, Shuo-Chun; Shu, Kuo-Hsiung; Wu, Ming-Ju; Wen, Mei-Chin; Hsieh, Shie-Liang; Chen, Nien-Jung; Tarng, Der-Cherng

    2015-01-01

    Decoy receptor 3 (DcR3) expression in kidneys has been shown to predict progression of chronic kidney disease. We prospectively investigated a cohort comprising 96 renal transplant recipients (RTRs) undergoing graft kidney biopsies. Computer-assisted quantitative immunohistochemical staining value of DcR3 in renal tubular epithelial cells (RTECs) was used to determine the predictive role of DcR3 in kidney disease progression. The primary end point was doubling of serum creatinine and/or graft failure. A multivariate Cox proportional hazards model was used to assess the risk of DcR3 expression in rejected kidney grafts toward the renal end point. In total, RTRs with kidney allograft rejection were evaluated and the median follow-up was 30.9 months. The greater expression of DcR3 immunoreactivity in RTECs was correlated with a higher rate of the histopathological concordance of acute T cell-mediated rejection. Compared with 65 non-progressors, 31 progressors had higher DcR3 expression (HDE) regardless of the traditional risk factors. Cox regression analysis showed HDE was significantly associated with the risk of renal end point with a hazard ratio of 3.19 (95% confidence interval, 1.40 to 7.27; P = 0.006) after adjusting for other variables. In repetitive biopsies, HDE in tissue showed rapid kidney disease progression due to persistent inflammation. PMID:26335204

  2. Expression of decoy receptor 3 in kidneys is associated with allograft survival after kidney transplant rejection

    PubMed Central

    Weng, Shuo-Chun; Shu, Kuo-Hsiung; Wu, Ming-Ju; Wen, Mei-Chin; Hsieh, Shie-Liang; Chen, Nien-Jung; Tarng, Der-Cherng

    2015-01-01

    Decoy receptor 3 (DcR3) expression in kidneys has been shown to predict progression of chronic kidney disease. We prospectively investigated a cohort comprising 96 renal transplant recipients (RTRs) undergoing graft kidney biopsies. Computer-assisted quantitative immunohistochemical staining value of DcR3 in renal tubular epithelial cells (RTECs) was used to determine the predictive role of DcR3 in kidney disease progression. The primary end point was doubling of serum creatinine and/or graft failure. A multivariate Cox proportional hazards model was used to assess the risk of DcR3 expression in rejected kidney grafts toward the renal end point. In total, RTRs with kidney allograft rejection were evaluated and the median follow-up was 30.9 months. The greater expression of DcR3 immunoreactivity in RTECs was correlated with a higher rate of the histopathological concordance of acute T cell-mediated rejection. Compared with 65 non-progressors, 31 progressors had higher DcR3 expression (HDE) regardless of the traditional risk factors. Cox regression analysis showed HDE was significantly associated with the risk of renal end point with a hazard ratio of 3.19 (95% confidence interval, 1.40 to 7.27; P = 0.006) after adjusting for other variables. In repetitive biopsies, HDE in tissue showed rapid kidney disease progression due to persistent inflammation. PMID:26335204

  3. Electric Pulse Stimulation of Myotubes as an In Vitro Exercise Model: Cell-Mediated and Non-Cell-Mediated Effects

    PubMed Central

    Evers-van Gogh, Inkie J.A.; Alex, Sheril; Stienstra, Rinke; Brenkman, Arjan B.; Kersten, Sander; Kalkhoven, Eric

    2015-01-01

    Regular exercise has emerged as one of the best therapeutic strategies to prevent and treat type-2-diabetes. Exercise-induced changes in the muscle secretome, consisting of myokines and metabolites, may underlie the inter-organ communication between muscle and other organs. To investigate this crosstalk, we developed an in vitro system in which mouse C2C12 myotubes underwent electric pulse stimulation (EPS) to induce contraction. Subsequently the effects of EPS-conditioned media (EPS-CM) on hepatocytes were investigated. Here, we demonstrate that EPS-CM induces Metallothionein 1/2 and Slc30a2 gene expression and reduces Cyp2a3 gene expression in rat hepatocytes. When testing EPS-CM that was generated in the absence of C2C12 myotubes (non-cell EPS-CM) no decrease in Cyp2a3 expression was detected. However, similar inductions in hepatic Mt1/2 and Slc30a2 expression were observed. Non-cell EPS-CM were also applied to C2C12 myotubes and compared to C2C12 myotubes that underwent EPS: here changes in AMPK phosphorylation and myokine secretion largely depended on EPS-induced contraction. Taken together, these findings indicate that EPS can alter C2C12 myotube function and thereby affect gene expression in cells subjected to EPS-CM (Cyp2a3). However, EPS can also generate non-cell-mediated changes in cell culture media, which can affect gene expression in cells subjected to EPS-CM too. While EPS clearly represents a valuable tool in exercise research, care should be taken in experimental design to control for non-cell-mediated effects. PMID:26091097

  4. Osteochondral Allograft Transplantation in the Knee.

    PubMed

    Zouzias, Ioannis C; Bugbee, William D

    2016-06-01

    The technique of osteochondral allograft (OCA) transplantation has been used to treat a wide spectrum of cartilage deficiencies in the knee. Its use has been supported by basic science and clinical studies that show it is a safe and effective treatment option. What sets fresh OCA transplantation apart from other cartilage procedures in the knee, is the ability to treat large defects with mature hyaline cartilage. Studies looking at transplantation of fresh OCAs in the general population have shown reliable pain relief and return to activities of daily living. Reports of cartilage injuries in athletes have risen over the years and more research is needed in evaluating the successfulness of OCA transplantation in the athletic population. PMID:27135291

  5. Dysplasia Epiphysealis Hemimelica Treated with Osteochondral Allograft: A Case Report

    PubMed Central

    Anthony, Chris A.; Wolf, Brian R.

    2015-01-01

    Background Dysplasia epiphysealis hemimelica (DEH), or Trevor's disease, is a developmental disorder of the pediatric skeleton characterized by asymmetric osteochondral overgrowth. Methods We present the case of a five year old boy with a two year history of right knee pain and evidence of DEH on imaging who underwent initial arthroscopic resection of his lesion with subsequent recurrence. The patient then underwent osteochondral allograft revision surgery and was asymptomatic at two year follow-up with a congruent joint surface. Results To our knowledge, this is the first reported case of a DEH lesion treated with osteochondral allograft and also the youngest reported case of osteochondral allograft placement in the literature. Conclusions Osteochondral allograft may be a viable option in DEH and other deformities of the pediatric knee. Level of Evidence Level V PMID:26361443

  6. CD3+ CD57+ lymphocytes are not likely to be involved in antigen-specific rejection processes in long-term allograft recipients.

    PubMed Central

    Reipert, B; Scheuch, C; Lukowsky, A; Reinke, P; Fietze, E; Döcke, W D; Staffa, G; Czerlinksi, S; Hetzer, R; Volk, H D

    1992-01-01

    Cytofluorometric investigation of peripheral blood lymphocytes in 380 long-term (greater than 1 year posttransplantation) allograft recipients showed a significant increase in the proportion of CD3+57+ lymphocytes (greater than 20%) in 20% of patients with renal allografts, 66% of patients with cardiac allografts and 44% of patients with liver allografts. Most of these CD3+57+ cells expressed the CD8 antigen and a variable proportion the HLA-DR antigen. A retrospective analysis showed a poorer prognosis for the clinical outcome in those patients with elevated numbers of CD3+57+ cells in peripheral blood. However, CD57+ lymphocytes could rarely be detected in renal infiltrates by immunohistology. Using the Southern blot technique to analyse the T cell receptor rearrangement of separated CD57+ cells, no clonal or oligoclonal expansion of T cell clones could be detected. Nevertheless, there might be a bias towards the use of particular TCR-V beta gene families in at least some patients, as shown by analysis with monoclonal antibodies. In summary, CD57+ T cells are not likely to be directly involved in the rejection process. The data support the idea of a polyclonal and/or superantigen-driven expansion, but not of an antigen-driven expansion of these cells. Images Fig. 3 PMID:1378363

  7. Recurrent Hepatitis C in Liver Allografts

    PubMed Central

    Demetris, A. J.; Eghtesad, B.; Marcos, A.; Ruppert, K.; Nalesnik, M. A.; Randhawa, P.; Wu, T.; Krasinskas, A.; Fontes, P.; Cacciarelli, T.; Shakil, A. O.; Murase, N.; Fung, J. J.; Starzl, T. E.

    2010-01-01

    Rationale and Design The accuracy of a prospective histopathologic diagnosis of rejection and recurrent hepatitis C (HCV) was determined in 48 HCV RNA-positive liver allograft recipients enrolled in an “immunosuppression minimization protocol” between July 29, 2001 and January 24, 2003. Prospective entry of all pertinent treatment, laboratory, and histopathology results into an electronic database enabled a retrospective analysis of the accuracy of histopathologic diagnoses and the pathophysiologic relationship between recurrent HCV and rejection. Results Time to first onset of acute rejection (AR) (mean, 107 days; median, 83 days; range, 7–329 days) overlapped with the time to first onset of recurrent HCV (mean, 115 days; median, 123 days; range, 22–315 days), making distinction between the two difficult. AR and chronic rejection (CR) with and without co-existent HCV showed overlapping but significantly different liver injury test profiles. One major and two minor errors occurred (positive predictive values for AR = 91%; recurrent HCV = 100%); all involved an overdiagnosis of AR in the context of recurrent HCV. Retrospective analysis of the mistakes showed that major errors can be avoided altogether and the impact of unavoidable minor errors can be minimized by strict adherence to specific histopathologic criteria, close clinicopathologic correlation including examination of HCV RNA levels, and a conservative approach to the use of additional immunosuppression. In addition, histopathologic diagnoses of moderate and severe AR and CR were associated with relatively low HCV RNA levels, whereas relatively high HCV RNA levels were associated with a histopathologic diagnosis of hepatitis alone, particularly the cholestatic variant of HCV. Conclusions Liver allograft biopsy interpretation can rapidly and accurately distinguish between recurrent HCV and AR/CR. In addition, the histopathologic observations suggest that the immune mechanism responsible for HCV

  8. Adenosine decreases post-ischaemic cardiac TNF-alpha production: anti-inflammatory implications for preconditioning and transplantation.

    PubMed Central

    Meldrum, D R; Cain, B S; Cleveland, J C; Meng, X; Ayala, A; Banerjee, A; Harken, A H

    1997-01-01

    Tumour necrosis factor-alpha (TNF-alpha) is an autocrine contributor to myocardial dysfunction and cardiomyocyte death in ischaemia-reperfusion injury (I/R), sepsis, chronic heart failure and cardiac allograft rejection. Cardiac resident macrophages, infiltrating leucocytes, and cardiomyocytes themselves produce TNF-alpha. Although adenosine reduces macrophage TNF-alpha production and protects myocardium against I/R, it remains unknown whether I/R induces an increase in cardiac TNF-alpha in a crystalloid-perfused model (in the absence of blood), and, whether adenosine decreases cardiac TNF-alpha and protects function after I/R. To study this, isolated rat hearts were crystalloid-perfused using the Langendorff method and subjected to I/R, with or without adenosine pretreatment. Post-ischaemic cardiac TNF-alpha (enzyme-linked immunosorbent assay and bioassay) and function were determined (Langendorff). I/R increased cardiac TNF-alpha and impaired myocardial function. Adenosine decreased cardiac TNF-alpha and improved post-ischaemic functional recovery. This study demonstrates that: first, I/R induces an increase in cardiac tissue TNF-alpha in a crystalloid-perfused model: second, adenosine decreases cardiac TNF-alpha and improves post-ischaemic myocardial function; third, decreased cardiac TNF-alpha may represent a mechanism by which adenosine protects myocardium; and fourth, adenosine-induced suppression of cardiac TNF-alpha may provide an anti-inflammatory link to preconditioning and have implications for cardiac allograft preservation. PMID:9497488

  9. A Case of Intraparenchymal Pseudoaneurysms in Kidney Allograft.

    PubMed

    Lorentz, Liam Antony; Hlabangana, Linda Tebogo; Davies, Malcom

    2016-01-01

    BACKGROUND Percutaneous needle biopsy is routinely performed for renal allograft management. Vascular complications of the procedure include pseudoaneurysm and arterio-venous fistulae formation. Delayed diagnosis of these complications is due to their mostly asymptomatic and indolent nature. CASE REPORT We present a case of extensive intraparenchymal pseudoaneurysm formation within the inferior pole of the allograft, diagnosed two years following the most recent biopsy procedure. CONCLUSIONS Renal pseudoaneurysms may only be diagnosed years after their formation as they are typically asymptomatic. PMID:27510594

  10. Musculoskeletal allograft risks and recalls in the United States.

    PubMed

    Mroz, Thomas E; Joyce, Michael J; Steinmetz, Michael P; Lieberman, Isador H; Wang, Jeffrey C

    2008-10-01

    There have been several improvements to the US tissue banking industry over the past decade. Tissue banks had limited active government regulation until 1993, at which time the US Food and Drug Administration began regulatory oversight because of reports of disease transmission from allograft tissues. Reports in recent years of disease transmission associated with the use of allografts have further raised concerns about the safety of such implants. A retrospective review of allograft recall data was performed to analyze allograft recall by tissue type, reason, and year during the period from January 1994 to June 30, 2007. During the study period, more than 96.5% of all allograft tissues recalled were musculoskeletal. The reasons underlying recent musculoskeletal tissue recalls include insufficient or improper donor evaluation, contamination, recipient infection, and positive serologic tests. Infectious disease transmission following allograft implantation may occur if potential donors are not adequately evaluated or screened serologically during the prerecovery phase and if the implant is not sterilized before implantation. PMID:18832599

  11. UPDATE: CARDIAC XENOTRANSPLANTATION

    PubMed Central

    Ekser, Burcin; Cooper, David K.C.

    2009-01-01

    Purpose of review To review the latest development in cardiac xenotransplantation in small and large animal models and related in vitro studies. Recent findings With the recent introduction of α1,3-galactosyltransferase gene-knockout (GT-KO) pig organs for xenotransplantation, improved cardiac graft survival has been obtained. However, this experience has demonstrated the importance of pig antigens other than Galα1,3Gal (Gal) antigens (so-called nonGal antigens) as targets for primate anti-pig antibodies. Several in vitro studies have confirmed that, although the incidence and levels of anti-nonGal antibodies in non-human primates and humans are significantly less when compared with total anti-pig antibodies (i.e., anti-Gal + anti-nonGal), they can result in complement-mediated lysis of GT-KO pig cells. More recently, it has been demonstrated that regulatory T cells (Treg) suppress the cellular xenogeneic response, thus potentially preventing or reducing T cell-mediated rejection. The importance of thrombotic microangiopathy as a feature of the immune/inflammatory response and incompatibilities between the coagulation-anticoagulation systems of pig and primate are receiving increasing attention. Development of GT-KO pigs transgenic for one or more ‘anti-thrombotic’ genes, e.g., CD39 or tissue factor pathway inhibitor, may contribute to overcoming these problems. Summary Although GT-KO pigs have provided an advance over wild-type pigs as a source of Organs for transplantation into primates, further genetic modification of GT-KO pigs is required to overcome the remaining immune barriers before a clinical trial of cardiac xenotransplantation can be contemplated. PMID:19060538

  12. 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.

  13. Lung Regeneration: Endogenous and Exogenous Stem Cell Mediated Therapeutic Approaches.

    PubMed

    Akram, Khondoker M; Patel, Neil; Spiteri, Monica A; Forsyth, Nicholas R

    2016-01-01

    The tissue turnover of unperturbed adult lung is remarkably slow. However, after injury or insult, a specialised group of facultative lung progenitors become activated to replenish damaged tissue through a reparative process called regeneration. Disruption in this process results in healing by fibrosis causing aberrant lung remodelling and organ dysfunction. Post-insult failure of regeneration leads to various incurable lung diseases including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. Therefore, identification of true endogenous lung progenitors/stem cells, and their regenerative pathway are crucial for next-generation therapeutic development. Recent studies provide exciting and novel insights into postnatal lung development and post-injury lung regeneration by native lung progenitors. Furthermore, exogenous application of bone marrow stem cells, embryonic stem cells and inducible pluripotent stem cells (iPSC) show evidences of their regenerative capacity in the repair of injured and diseased lungs. With the advent of modern tissue engineering techniques, whole lung regeneration in the lab using de-cellularised tissue scaffold and stem cells is now becoming reality. In this review, we will highlight the advancement of our understanding in lung regeneration and development of stem cell mediated therapeutic strategies in combating incurable lung diseases. PMID:26797607

  14. Lung Regeneration: Endogenous and Exogenous Stem Cell Mediated Therapeutic Approaches

    PubMed Central

    Akram, Khondoker M.; Patel, Neil; Spiteri, Monica A.; Forsyth, Nicholas R.

    2016-01-01

    The tissue turnover of unperturbed adult lung is remarkably slow. However, after injury or insult, a specialised group of facultative lung progenitors become activated to replenish damaged tissue through a reparative process called regeneration. Disruption in this process results in healing by fibrosis causing aberrant lung remodelling and organ dysfunction. Post-insult failure of regeneration leads to various incurable lung diseases including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. Therefore, identification of true endogenous lung progenitors/stem cells, and their regenerative pathway are crucial for next-generation therapeutic development. Recent studies provide exciting and novel insights into postnatal lung development and post-injury lung regeneration by native lung progenitors. Furthermore, exogenous application of bone marrow stem cells, embryonic stem cells and inducible pluripotent stem cells (iPSC) show evidences of their regenerative capacity in the repair of injured and diseased lungs. With the advent of modern tissue engineering techniques, whole lung regeneration in the lab using de-cellularised tissue scaffold and stem cells is now becoming reality. In this review, we will highlight the advancement of our understanding in lung regeneration and development of stem cell mediated therapeutic strategies in combating incurable lung diseases. PMID:26797607

  15. Carbonic anhydrase enzymes regulate mast cell-mediated inflammation.

    PubMed

    Henry, Everett K; Sy, Chandler B; Inclan-Rico, Juan M; Espinosa, Vanessa; Ghanny, Saleena S; Dwyer, Daniel F; Soteropoulos, Patricia; Rivera, Amariliz; Siracusa, Mark C

    2016-08-22

    Type 2 cytokine responses are necessary for the development of protective immunity to helminth parasites but also cause the inflammation associated with allergies and asthma. Recent studies have found that peripheral hematopoietic progenitor cells contribute to type 2 cytokine-mediated inflammation through their enhanced ability to develop into mast cells. In this study, we show that carbonic anhydrase (Car) enzymes are up-regulated in type 2-associated progenitor cells and demonstrate that Car enzyme inhibition is sufficient to prevent mouse mast cell responses and inflammation after Trichinella spiralis infection or the induction of food allergy-like disease. Further, we used CRISPR/Cas9 technology and illustrate that genetically editing Car1 is sufficient to selectively reduce mast cell development. Finally, we demonstrate that Car enzymes can be targeted to prevent human mast cell development. Collectively, these experiments identify a previously unrecognized role for Car enzymes in regulating mast cell lineage commitment and suggest that Car enzyme inhibitors may possess therapeutic potential that can be used to treat mast cell-mediated inflammation. PMID:27526715

  16. Natural killer cell mediated cytotoxic responses in the Tasmanian devil.

    PubMed

    Brown, Gabriella K; Kreiss, Alexandre; Lyons, A Bruce; Woods, Gregory M

    2011-01-01

    The Tasmanian devil (Sarcophilus harrisii), the world's largest marsupial carnivore, is under threat of extinction following the emergence of an infectious cancer. Devil facial tumour disease (DFTD) is spread between Tasmanian devils during biting. The disease is consistently fatal and devils succumb without developing a protective immune response. The aim of this study was to determine if Tasmanian devils were capable of forming cytotoxic antitumour responses and develop antibodies against DFTD cells and foreign tumour cells. The two Tasmanian devils immunised with irradiated DFTD cells did not form cytotoxic or humoral responses against DFTD cells, even after multiple immunisations. However, following immunisation with xenogenic K562 cells, devils did produce cytotoxic responses and antibodies against this foreign tumour cell line. The cytotoxicity appeared to occur through the activity of natural killer (NK) cells in an antibody dependent manner. Classical NK cell responses, such as innate killing of DFTD and foreign cancer cells, were not observed. Cells with an NK-like phenotype comprised approximately 4 percent of peripheral blood mononuclear cells. The results of this study suggest that Tasmanian devils have NK cells with functional cytotoxic pathways. Although devil NK cells do not directly recognise DFTD cancer cells, the development of antibody dependent cell-mediated cytotoxicity presents a potential pathway to induce cytotoxic responses against the disease. These findings have positive implications for future DFTD vaccine research. PMID:21957452

  17. Cell-mediated immunity in the course of cervical ectropion.

    PubMed

    De Luca Brunori, I; Facchini, V; Filippeschi, M; Battini, L; Giusti, G; Romani, L; Scida, P; Urbano, M

    1994-01-01

    In the present study we evaluated cellular immunitary response in course of asymptomatic ectropion. Biopsies of the injured and healthy zones of the exocervix were carried out. All biopsies were examined by an immuno-histo-chemical method (Avidin-Biotin Complex, ABC) with monoclonal antibodies, in order to phenotype T lymphocytic subpopulations, in particular T helper lymphocytes (CD4), T suppressor lymphocytes (CD8) and Langerhans cells (CD1), which are basic elements of the monocytic-macrophagic series. Our preliminary findings showed a reduction of CD4, CD8 and CD1 lymphocytic subpopulations in ectropion zones, while these subpopulations are normally present in healthy zones of the exocervix. These findings support the hypothesis that, in ectropion, as in HPV infections and in CIN, a localized immuno-deficiency may appear and depress immuno-surveillance and cell-mediated response. In conclusion, it may be supposed that ectropion represents a non-stable lesion, which therefore needs suitable therapeutic intervention. PMID:7915218

  18. Quadriceps tendon allografts as an alternative to Achilles tendon allografts: a biomechanical comparison.

    PubMed

    Mabe, Isaac; Hunter, Shawn

    2014-12-01

    Quadriceps tendon with a patellar bone block may be a viable alternative to Achilles tendon for anterior cruciate ligament reconstruction (ACL-R) if it is, at a minimum, a biomechanically equivalent graft. The objective of this study was to directly compare the biomechanical properties of quadriceps tendon and Achilles tendon allografts. Quadriceps and Achilles tendon pairs from nine research-consented donors were tested. All specimens were processed to reduce bioburden and terminally sterilized by gamma irradiation. Specimens were subjected to a three phase uniaxial tension test performed in a custom environmental chamber to maintain the specimens at a physiologic temperature (37 ± 2 °C) and misted with a 0.9 % NaCl solution. There were no statistical differences in seven of eight structural and mechanical between the two tendon types. Quadriceps tendons exhibited a significantly higher displacement at maximum load and significantly lower stiffness than Achilles tendons. The results of this study indicated a biomechanical equivalence of aseptically processed, terminally sterilized quadriceps tendon grafts with bone block to Achilles tendon grafts with bone block. The significantly higher displacement at maximum load, and lower stiffness observed for quadriceps tendons may be related to the failure mode. Achilles tendons had a higher bone avulsion rate than quadriceps tendons (86 % compared to 12 %, respectively). This was likely due to observed differences in bone block density between the two tendon types. This research supports the use of quadriceps tendon allografts in lieu of Achilles tendon allografts for ACL-R. PMID:24414293

  19. Cell-mediated immune responses to respiratory syncytial virus infection

    PubMed Central

    Geevarghese, Bessey; Weinberg, Adriana

    2014-01-01

    We evaluated the cell-mediated immune (CMI) response to RSV acute infection including the magnitude, kinetics and correlates with morbidity and age. Twenty-nine RSV-infected patients with mean ± SD age of 15 ± 14 months were enrolled during their first week of disease. Th1, Th2, Th9, Th17 and Th22 responses were measured at entry and 2 and 6 weeks later. All subjects were hospitalized for a median (range) of 5 (3–11) days. RSV-specific effector and memory Th1 CMI measured by lymphocyte proliferation and IFNγ ELISPOT significantly increased over time (P ≤ 0.03). In contrast, Th22 responses decreased over time (P ≤ 0.03). Other changes did not reach statistical significance. The severity of RSV disease measured by the length of hospitalization positively correlated with the magnitude of Th9, Th22 and TNFα inflammatory responses (rho ≥ 0.4; P ≤ 0.04) and negatively with memory CMI (rho = –0.45; P = 0.04). The corollary of this observation is that robust Th1 and/or low Th9, Th22, and TNFα inflammatory responses may be associated with efficient clearance of RSV infection and therefore desirable characteristics of an RSV vaccine. Young age was associated with low memory and effector Th1 responses (rho ≥ 0.4; P ≤ 0.04) and high Th2, Th9, Th17, Th22 and TNFα inflammatory responses (rho ≤ –0.4; P ≤ 0.04), indicating that age at vaccination may be a major determinant of the CMI response pattern. PMID:24513666

  20. Comparative evaluation of pelvic allograft selection methods.

    PubMed

    Bousleiman, Habib; Paul, Laurent; Nolte, Lutz-Peter; Reyes, Mauricio

    2013-05-01

    This paper presents a firsthand comparative evaluation of three different existing methods for selecting a suitable allograft from a bone storage bank. The three examined methods are manual selection, automatic volume-based registration, and automatic surface-based registration. Although the methods were originally published for different bones, they were adapted to be systematically applied on the same data set of hemi-pelvises. A thorough experiment was designed and applied in order to highlight the advantages and disadvantages of each method. The methods were applied on the whole pelvis and on smaller fragments, thus producing a realistic set of clinical scenarios. Clinically relevant criteria are used for the assessment such as surface distances and the quality of the junctions between the donor and the receptor. The obtained results showed that both automatic methods outperform the manual counterpart. Additional advantages of the surface-based method are in the lower computational time requirements and the greater contact surfaces where the donor meets the recipient. PMID:23299829

  1. Autophagy in allografts rejection: A new direction?

    PubMed

    Sun, Hukui; Cheng, Dayan; Ma, Yuanyuan; Wang, Huaiquan; Liang, Ting; Hou, Guihua

    2016-03-18

    Despite the introduction of new and effective immunosuppressive drugs, acute cellular graft rejection is still a major risk for graft survival. Modulating the dosage of immunosuppressive drugs is not a good choice for all patients, new rejection mechanisms discovery are crucial to limit the inflammatory process and preserve the function of the transplant. Autophagy, a fundamental cellular process, can be detected in all subsets of lymphocytes and freshly isolated naive T lymphocytes. It is required for the homeostasis and function of T lymphocytes, which lead to cell survival or cell death depending on the context. T cell receptor (TCR) stimulation and costimulator signals induce strong autophagy, and autophagy deficient T cells leads to rampant apoptosis upon TCR stimulation. Autophagy has been proved to be activated during ischemia-reperfusion (I/R) injury and associated with grafts dysfunction. Furthermore, Autophagy has also emerged as a key mechanism in orchestrating innate and adaptive immune response to self-antigens, which relates with negative selection and Foxp3(+) Treg induction. Although, the role of autophagy in allograft rejection is unknown, current data suggest that autophagy indeed sweeps across both in the graft organs and recipients lymphocytes after transplantation. This review presents the rationale for the hypothesis that targeting the autophagy pathway could be beneficial in promoting graft survival after transplantation. PMID:26876576

  2. Arthroscopic posterior cruciate ligament reconstruction with allograft versus autograft

    PubMed Central

    Sun, Xiujiang; Zhang, Jianfeng; Qu, Xiaoyi

    2015-01-01

    Introduction The aim of the study was to compare and analyze retrospectively the outcomes of arthroscopic posterior cruciate ligament reconstruction with autograft versus allograft. Material and methods Seventy-one patients who underwent arthroscopic posterior cruciate ligament reconstruction with an autograft or allograft met our inclusion criteria. There were 36 patients in the autograft group and 35 patients in the allograft group. All the patients were evaluated by physical examination and a functional ligament test. Comparative analysis was done in terms of operation time, incision length, fever time, postoperative infection rate, incidence of numbness and dysesthesia around the incision, as well as a routine blood test. Results The average follow-up of the autograft group was 3.2 ±0.2 years and that of the allograft group was 3.3 ±0.6 years; there was no significant difference (p > 0.05). No differences existed in knee range of motion, Lysholm scores, International Knee Documentation Committee standard evaluation form and Tegner activity score at final follow-up (p > 0.05), except that patients in the allograft group had a shorter operation time and incision length and a longer fever time (p < 0.05). We found a difference in posterior drawer test and KT-2000 arthrometer assessment (p < 0.05). The posterior tibia displacement averaged 3.8 ±1.5 mm in the autograft group and 4.8 ±1.7 mm in the allograft group (p < 0.05). The incidence of numbness and dysesthesia around the incision in the autograft group was higher than that in the allograft group (p < 0.05). There was no infection postoperatively. The white blood cells and neutrophils in the allograft group increased more than those in the autograft group postoperatively (p < 0.05). Conclusions Both groups of patients had satisfactory outcomes after the operation. However, in the instrumented posterior laxity test, the autograft gave better results than the allograft. No differences in functional scores

  3. Allografts in the treatment of athletic injuries of the shoulder.

    PubMed

    Ho, Jason Y; Miller, Suzanne L

    2007-09-01

    As allogeneic musculoskeletal tissue is readily available, has minimal limitation in size or shape, and carries no donor site morbidity, it has become attractive for use in reconstructive shoulder surgery. Allograft is a viable option for treating osseous defects associated with glenohumeral instability and has been shown to achieve a stable shoulder with good clinical outcomes. Although there are mixed results on the use of allograft as rotator cuff augments or substitutes, new commercially processed materials such as GraftJacket are being tested to address the high failure rates associated with massive rotator cuff repair. Interposition arthroplasty as a treatment for glenohumeral arthritis in the young and active patient is a novel concept in which the arthritic glenoid is biologically resurfaced. Satisfactory results have been described using lateral meniscus and Achilles tendon allograft. Despite the promising reports on the use of allograft in reconstructive shoulder surgery, most of the published literature exists as retrospective, case reports. Additional large, controlled research is needed to prove the efficacy and safety of allograft tissue in the treatment of athletic injuries of the shoulder. PMID:17700375

  4. Monitoring of corneal allograft rejection using laser flare meter

    NASA Astrophysics Data System (ADS)

    Zarnowski, Tomasz; Haszcz, Dariusz; Rakowska, Ewa; Zagorski, Zbigniew

    1998-10-01

    The purpose of this study was to quantify noninvasively, with the use of laser-flare meter the alterations of the blood-aqueous barrier following penetrating keratoplasty. This could diagnose objectively disruption of this barrier in eyes with early allograft rejection, possible even before manifestation of the clinical signs and would help to monitor the efficacy of the treatment. We used the laser flare-meter (Kowa FM-500) to investigate alteration of the blood-aqueous barrier following uncomplicated penetrating keratoplasty (PK) and in corneal allograft rejection. Examination was performed in 50 eyes of 48 patients after uncomplicated PK (7 days to 12 months after PK), in 20 normal control eyes and in 8 patients with acute allograft rejection. Flare values after uncomplicated keratoplasty slowly decreased in time reaching nearly control values 6 - 12 months postoperatively. They were considerably higher for acute allograft rejection compared to eyes following uncomplicated PK and normal control group. Actually, they tended to diminish gradually after systemic and topical administration of steroids and/or immunosuppressants. Application of laser tyndalometry has been proven to be highly useful in the follow up of patients after perforating keratoplasty-especially high risk grafts, it helps to detect objectively early allograft rejection and is beneficial in monitoring the effectiveness of the treatment.

  5. Osteochondral and Meniscal Allograft Transplantation in the Football (Soccer) Player

    PubMed Central

    Williams, Riley J.; Gersoff, Wayne K.; Bugbee, William D.

    2012-01-01

    Knee injuries are common in football, frequently involving damage to the meniscus and articular cartilage. These injuries can cause significant disability, result in loss of playing time, and predispose players to osteoarthritis. Osteochondral allografting is an increasingly popular treatment option for osteoarticular lesions in athletes. Osteochondral allografts provide mature, orthotopic hyaline cartilage on an osseous scaffold that serves as an attachment vehicle, which is rapidly replaced via creeping substitution, leading to reliable graft integration that allows for simplified rehabilitation and accelerated return to sport. The indications for meniscal replacement in football players are currently still evolving. Meniscus allografts offer potential functional, analgesic, and chondroprotective benefits in the meniscectomized knee. In the player at the end of his or her professional/competitive career, meniscal allografts can play a role in averting progression of chondropenia and facilitating knee function and an active lifestyle. This article is intended to present a concise overview of the limited published results for osteochondral and meniscal allografting in the athletic population and to provide a practical treatment algorithm that is of relevance to the clinician as well as the patient/football player, based on current consensus of opinion. PMID:26069605

  6. Significant prolongation of segmental pancreatic allograft survival in two species

    SciTech Connect

    Du Toit, D.F.; Heydenrych, J.J.

    1988-06-01

    A study was conducted to assess the suppression of segmental pancreatic allograft rejection by cyclosporine (CSA) alone in baboons and dogs, and subtotal marrow irradiation (TL1) alone and TL 1 in combination with CSA in baboons. Total pancreatectomy in the dog and primate provided a reliable diabetic model, induced an absolute deficiency of insulin and was uniformly lethal if not treated. Continuous administration of CSA in baboons resulted in modest allograft survival. As in baboons, dogs receiving CSA 25 mg/kg/d rendered moderate graft prolongation but a dose of 40 mg/kg/d resulted in significant graft survival (greater than 100 days) in 5 of 8 allograft recipients. Irradiation alone resulted in minimal baboon pancreatic allograft survival of 20 baboons receiving TL1 1,000 rad and CSA, 3 had graft survival greater than of 100 days. Of 15 baboons receiving TL1 800 rad and CSA, 6 had graft survival of greater than 100 days. In conclusion, CSA administration in dogs and TL1 in combination with CSA in baboons resulted in highly significant segmental pancreatic allograft survival.

  7. Imaging mouse lung allograft rejection with 1H MRI

    PubMed Central

    Guo, Jinbang; Huang, Howard J.; Wang, Xingan; Wang, Wei; Ellison, Henry; Thomen, Robert P.; Gelman, Andrew E.; Woods, Jason C.

    2014-01-01

    Purpose To demonstrate that longitudinal, non-invasive monitoring via MRI can characterize acute cellular rejection (ACR) in mouse orthotopic lung allografts. Methods Nineteen Balb/c donor to C57BL/6 recipient orthotopic left lung transplants were performed, further divided into control-Ig vs anti-CD4/anti-CD8 treated groups. A two-dimensional multi-slice gradient-echo pulse sequence synchronized with ventilation was used on a small-animal MR scanner to acquire proton images of lung at post-operative days 3, 7 and 14, just before sacrifice. Lung volume and parenchymal signal were measured, and lung compliance was calculated as volume change per pressure difference between high and low pressures. Results Normalized parenchymal signal in the control-Ig allograft increased over time, with statistical significance between day 14 and day 3 post transplantation (0.046→0.789, P < 0.05), despite large inter-mouse variations; this was consistent with histopathologic evidence of rejection. Compliance of the control-Ig allograft decreased significantly over time (0.013→0.003, P < 0.05), but remained constant in mice treated with anti-CD4/anti-CD8 antibodies. Conclusion Lung allograft rejection in individual mice can be monitored by lung parenchymal signal changes and by lung compliance through MRI. Longitudinal imaging can help us better understand the time course of individual lung allograft rejection and response to treatment. PMID:24954886

  8. Micronutrient supplementation and T-cell mediated immune responses in patients with tuberculosis in Tanzania

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Limited studies exist regarding whether incorporating micronutrient supplements during tuberculosis (TB) treatment may improve cell-mediated immune response. We examine the effect of micronutrient supplementation on lymphocyte proliferation response to mycobacteria or T cell mitogens in a randomize...

  9. Analysis of T cell responses in liver allograft recipients. Evidence for deletion of donor-specific cytotoxic T cells in the peripheral circulation.

    PubMed Central

    Mathew, J M; Marsh, J W; Susskind, B; Mohanakumar, T

    1993-01-01

    Analysis of cell-mediated lympholysis in long-term liver allograft recipients indicated that there was a donor-specific unresponsiveness that could not be reversed by the addition of rIL-2 and/or mixed lymphocyte culture supernatant or by nonspecific stimulation of the cultures with PHA. Stimulation of recipient cells with semisyngeneic cells having both donor and third-party HLA antigens failed to reveal the presence of cytotoxic T cells (CTL) specific to the donor, whereas the CTL response to third-party antigens remained normal. Removal of B lymphocytes from the responding cell population did not influence the responses. Furthermore, limiting dilution analysis showed that the liver transplant recipients did not have detectable levels of CTL precursors (CTLp) reactive to the donor antigens, whereas their CTLp to third-party antigens remained normal. Donor-specific CTLp were present before and during the early post-transplant period; these cells were eliminated from the peripheral circulation by 10 mo after transplantation. Taken together, these results indicate that there is a deletion of CTLp specific to donor MHC antigens in the peripheral circulation of long-term liver allograft recipients that may account in part for the success of liver transplantation across MHC barriers. Images PMID:8450068

  10. Effect of Storage Temperature on Allograft Bone

    PubMed Central

    Fölsch, Christian; Mittelmeier, Wolfram; Bilderbeek, Uwe; Timmesfeld, Nina; von Garrel, Thomas; Peter Matter, Hans

    2012-01-01

    Background The recommendations for storage temperature of allogeneic bone are varying between −20 °C and −70 °C and down to −80 °C. The necessary temperature of storage is not exactly defined by scientific data, and the effect of different storage temperatures onto the biomechanical and the biological behavior is discussed controversially. Methods The historical development of storage temperature of bone banks is described. A survey on literature concerning the biomechanical and biological properties of allograft bone depending on the procurement and storage temperature is given as well as on national and international regulations on storage conditions of bone banks (European Council, American Association of Tissue Banks (AATB), European Association of Tissue Banks (EATB)). Results Short-term storage up to 6 months is recommended with −20 °C and −40 °C for a longer period (AATB), and EATB recommends storage at −40 °C and even −80 °C while the regulations of the German German Medical Association (Bundesärztekammer) from 2001 recommend storage at −70 °C. Duration of storage at −20 °C can be maintained at least for 2 years. The potential risk of proteolysis with higher storage temperatures remains, but a definite impairment of bone ingrowth due to a storage at −20 °C was not shown in clinical use, and no adverse biomechanical effects of storage at −20 °C could be proven. Conclusion Biomechanical studies showed no clinically relevant impairment of biomechanical properties of cancellous bone due to different storage temperatures. Sterilization procedures bear the advantage of inactivating enzymatic activity though reducing the risk of proteolysis. In those cases a storage temperature of −20 °C can be recommended for at least a period of 2 years, and the risk of undesired effects seems to be low for native unprocessed bone. PMID:22896765

  11. Porous allograft bone scaffolds: doping with strontium.

    PubMed

    Zhao, Yantao; Guo, Dagang; Hou, Shuxun; Zhong, Hongbin; Yan, Jun; Zhang, Chunli; Zhou, Ying

    2013-01-01

    Strontium (Sr) can promote the process of bone formation. To improve bioactivity, porous allograft bone scaffolds (ABS) were doped with Sr and the mechanical strength and bioactivity of the scaffolds were evaluated. Sr-doped ABS were prepared using the ion exchange method. The density and distribution of Sr in bone scaffolds were investigated by inductively coupled plasma optical emission spectrometry (ICP-OES), X-ray photoelectron spectroscopy (XPS), and energy-dispersive X-ray spectroscopy (EDS). Controlled release of strontium ions was measured and mechanical strength was evaluated by a compressive strength test. The bioactivity of Sr-doped ABS was investigated by a simulated body fluid (SBF) assay, cytotoxicity testing, and an in vivo implantation experiment. The Sr molar concentration [Sr/(Sr+Ca)] in ABS surpassed 5% and Sr was distributed nearly evenly. XPS analyses suggest that Sr combined with oxygen and carbonate radicals. Released Sr ions were detected in the immersion solution at higher concentration than calcium ions until day 30. The compressive strength of the Sr-doped ABS did not change significantly. The bioactivity of Sr-doped material, as measured by the in vitro SBF immersion method, was superior to that of the Sr-free freeze-dried bone and the Sr-doped material did not show cytotoxicity compared with Sr-free culture medium. The rate of bone mineral deposition for Sr-doped ABS was faster than that of the control at 4 weeks (3.28 ± 0.23 µm/day vs. 2.60 ± 0.20 µm/day; p<0.05). Sr can be evenly doped into porous ABS at relevant concentrations to create highly active bone substitutes. PMID:23922703

  12. Porous Allograft Bone Scaffolds: Doping with Strontium

    PubMed Central

    Zhao, Yantao; Guo, Dagang; Hou, Shuxun; Zhong, Hongbin; Yan, Jun; Zhang, Chunli; Zhou, Ying

    2013-01-01

    Strontium (Sr) can promote the process of bone formation. To improve bioactivity, porous allograft bone scaffolds (ABS) were doped with Sr and the mechanical strength and bioactivity of the scaffolds were evaluated. Sr-doped ABS were prepared using the ion exchange method. The density and distribution of Sr in bone scaffolds were investigated by inductively coupled plasma optical emission spectrometry (ICP-OES), X-ray photoelectron spectroscopy (XPS), and energy-dispersive X-ray spectroscopy (EDS). Controlled release of strontium ions was measured and mechanical strength was evaluated by a compressive strength test. The bioactivity of Sr-doped ABS was investigated by a simulated body fluid (SBF) assay, cytotoxicity testing, and an in vivo implantation experiment. The Sr molar concentration [Sr/(Sr+Ca)] in ABS surpassed 5% and Sr was distributed nearly evenly. XPS analyses suggest that Sr combined with oxygen and carbonate radicals. Released Sr ions were detected in the immersion solution at higher concentration than calcium ions until day 30. The compressive strength of the Sr-doped ABS did not change significantly. The bioactivity of Sr-doped material, as measured by the in vitro SBF immersion method, was superior to that of the Sr-free freeze-dried bone and the Sr-doped material did not show cytotoxicity compared with Sr-free culture medium. The rate of bone mineral deposition for Sr-doped ABS was faster than that of the control at 4 weeks (3.28±0.23 µm/day vs. 2.60±0.20 µm/day; p<0.05). Sr can be evenly doped into porous ABS at relevant concentrations to create highly active bone substitutes. PMID:23922703

  13. Cardiac metastases

    PubMed Central

    Bussani, R; De‐Giorgio, F; Abbate, A; Silvestri, F

    2007-01-01

    Tumours metastatic to the heart (cardiac metastases) are among the least known and highly debated issues in oncology, and few systematic studies are devoted to this topic. Although primary cardiac tumours are extremely uncommon (various postmortem studies report rates between 0.001% and 0.28%), secondary tumours are not, and at least in theory, the heart can be metastasised by any malignant neoplasm able to spread to distant sites. In general, cardiac metastases are considered to be rare; however, when sought for, the incidence seems to be not as low as expected, ranging from 2.3% and 18.3%. Although no malignant tumours are known that diffuse preferentially to the heart, some do involve the heart more often than others—for example, melanoma and mediastinal primary tumours. This paper attempts to review the pathophysiology of cardiac metastatic disease, epidemiology and clinical presentation of cardiac metastases, and pathological characterisation of the lesions. PMID:17098886

  14. Lateral Meniscal Allograft Transplantation: The Bone Trough Technique.

    PubMed

    Chahla, Jorge; Olivetto, Javier; Dean, Chase S; Serra Cruz, Raphael; LaPrade, Robert F

    2016-04-01

    The lateral meniscus plays a critical role in the stability and health of the knee. Treating patients who have undergone a total lateral meniscectomy or functional equivalent is challenging, especially young and active patients. Current literature regarding meniscal tears supports that repair should be the first surgical option. Moreover, it is recommended to preserve as much meniscal tissue as possible. In cases in which a total or functional meniscectomy is a pre-existing condition, a lateral meniscal allograft transplantation is a possible option. The purpose of this surgical technique description was to detail the method of lateral meniscal allograft transplantation using a bone trough. PMID:27462536

  15. A Case of Intraparenchymal Pseudoaneurysms in Kidney Allograft

    PubMed Central

    Lorentz, Liam Antony; Hlabangana, Linda Tebogo; Davies, Malcolm

    2016-01-01

    Patient: Male, 31 Final Diagnosis: Intraparenchymal pseudo-aneurysms in kidney transplant Symptoms: Asymptomatic Medication: — Clinical Procedure: Percutaneous renal biopsy Specialty: Transplantology Objective: Diagnostic/therapeutic accidents Background: Percutaneous needle biopsy is routinely performed for renal allograft management. Vascular complications of the procedure include pseudoaneurysm and arterio-venous fistulae formation. Delayed diagnosis of these complications is due to their mostly asymptomatic and indolent nature. Case Report: We present a case of extensive intraparenchymal pseudoaneurysm formation within the inferior pole of the allograft, diagnosed two years following the most recent biopsy procedure. Conclusions: Renal pseudoaneurysms may only be diagnosed years after their formation as they are typically asymptomatic. PMID:27510594

  16. Sensitized recipients exhibit accelerated but not hyperacute rejection of vascularized composite tissue allografts1

    PubMed Central

    Wu, Shengli; Xu, Hong; Chen, Bo; Wen, Yujie; Ikusika, Olayemi M; Ocker, Ashley; Zhao, Hong; Ildstad, Suzanne T

    2013-01-01

    Background Currently, the donor-recipient matching process for vascularized composite tissue allotransplantation (VCTA) closely follows the standard practices for solid organ transplantation. Sensitization is considered a contraindication to VCTA. However, the role of sensitization in VCTA rejection is largely unstudied. Methods Major histocompatibility-mismatched ACI (RT1a) donors and WF (RT1u) recipients were used to determine if sensitization would lead to hyperacute rejection in VCTA as in other organs, such as kidneys. WF rats were presensitized to ACI antigens by skin transplantation and received heterotopic osteomyocutaneous VCTA flaps. Kidney transplants served as controls. Results Production of anti-donor antibody was detected in WF recipients after rejection of the ACI skin grafts. Sensitized WF rats rejected VCTA grafts from ACI rats significantly faster (P < 0.05) than unsensitized recipients, but not hyperacutely. Rejection in the sensitized recipients was not prevented by immunosuppression with FK506 and mycophenolate mofetil. In contrast, kidney allografts from ACI rats were hyperacutely rejected within 30 minutes by sensitized recipients. To confirm the role of antibody-mediated rejection in the sensitized recipients, serum from presensitized rats was adoptively transferred into naïve WF rats. Hyperacute rejection occurred only in transplanted kidneys but not VCTA. Histological examination of tissues from acceleratedly rejected VCTA showed dense lymphocytic infiltrates, and no antibody deposition. Conclusions VCTA are rejected in an accelerated fashion but not hyperacutely in the presence of allosensitization and preformed anti-donor antibody. The rejection of VCTA in sensitized recipients is mainly cell-mediated and differs mechanistically from that for renal transplants. PMID:21822173

  17. Reconstruction of an atrophied posterior mandible with the inlay technique and allograft block versus allograft particulate: a case report.

    PubMed

    Checchi, Vittorio; Mazzoni, Annalisa; Breschi, Lorenzo; Felice, Pietro

    2015-01-01

    This case report describes the bilateral reconstruction of a severely atrophic posterior mandible in a 30-year-old woman using allograft block versus particulate grafting in the inlay technique. Three months later, four dental implants were placed and bone core biopsy specimens were taken for histologic evaluation. During implant placement, the grafted sites were stable with good clinical osseointegration. The histologic analysis showed the presence of compact bone revealing areas of demarcation between grafted bone, newly formed bone, and bone-regenerated areas. Allografts might serve as an alternative to autogenous and heterologous grafting in posterior mandible augmentation using the inlay technique. PMID:25738350

  18. Plasminogen regulates cardiac repair after myocardial infarction through its non-canonical function in stem cell homing to the infarcted heart

    PubMed Central

    Gong, Yanqing; Zhao, Yujing; Li, Ying; Fan, Yi; Hoover-Plow, Jane

    2014-01-01

    Objective The purpose of this study was to investigate the role of Plasminogen (Plg) in stem cell-mediated cardiac repair and regeneration after myocardial infarction (MI) Background MI induces irreversible tissue damage, eventually leading to heart failure. Bone marrow (BM)-derived stem cells promote tissue repair and regeneration after MI. Thrombolytic treatment with Plg activators significantly improves the clinical outcome in MI by restoring cardiac perfusion. However, the role of Plg in stem cell-mediated cardiac repair remains unclear. Methods MI was induced in Plg deficient (Plg−/−) and wild-type (Plg+/+) mice by ligation of left anterior descending coronary artery (LAD). Stem cells were visualized by in vivo tracking of GFP-expressing BM cells after BM transplantation. Cardiac function, stem cell homing, signaling pathways downstream of Plg were examined. Results G-CSF, a stem cell mobilizer, significantly promoted BM-derived stem cells (GFP+c-kit+ cells) recruitment into infarcted heart and stem cell-meidated cardiac repair in Plg+/+ mice. However, Plg deficiency markedly inhibited stem cell homing and cardiac repair, suggesting that Plg is critical for stem cell-mediated cardiac repair. Moreover, Plg regulated CXCR4 expression in stem cells in vivo and in vitro through MMP-9. Lentiviral reconstitution of CXCR4 expression in BM cells rescued stem cell homing to the infarcted heart in Plg-deficient mice, indicating that a critical role of CXCR4 in Plg-mediated stem cell homing after MI. Conclusions These findings have identified a novel role of Plg in stem cell-mediated cardiac repair after MI. Thus, targeting Plg may offer a new therapeutic strategy for stem cell-mediated cardiac repair after MI. PMID:24681141

  19. Arthroscopic Allograft Cartilage Transfer for Osteochondral Defects of the Talus

    PubMed Central

    Min, Kyong S.; Ryan, Paul M.

    2015-01-01

    Arthroscopic treatment of osteochondral defects is well established but has had mixed results in larger lesions and revision operations. Particulated allograft cartilage transfer may provide an arthroscopic option for lesions that would otherwise have been treated through open approaches or osteotomies. The procedure is performed under noninvasive distraction with standard arthroscopic portals. PMID:26052496

  20. Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection.

    PubMed

    Cui, Ye; Liu, Kaifeng; Monzon-Medina, Maria E; Padera, Robert F; Wang, Hao; George, Gautam; Toprak, Demet; Abdelnour, Elie; D'Agostino, Emmanuel; Goldberg, Hilary J; Perrella, Mark A; Forteza, Rosanna Malbran; Rosas, Ivan O; Visner, Gary; El-Chemaly, Souheil

    2015-11-01

    Lung transplantation is the only viable option for patients suffering from otherwise incurable end-stage pulmonary diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Despite aggressive immunosuppression, acute rejection of the lung allograft occurs in over half of transplant recipients, and the factors that promote lung acceptance are poorly understood. The contribution of lymphatic vessels to transplant pathophysiology remains controversial, and data that directly address the exact roles of lymphatic vessels in lung allograft function and survival are limited. Here, we have shown that there is a marked decline in the density of lymphatic vessels, accompanied by accumulation of low-MW hyaluronan (HA) in mouse orthotopic allografts undergoing rejection. We found that stimulation of lymphangiogenesis with VEGF-C156S, a mutant form of VEGF-C with selective VEGFR-3 binding, alleviates an established rejection response and improves clearance of HA from the lung allograft. Longitudinal analysis of transbronchial biopsies from human lung transplant recipients demonstrated an association between resolution of acute lung rejection and decreased HA in the graft tissue. Taken together, these results indicate that lymphatic vessel formation after lung transplantation mediates HA drainage and suggest that treatments to stimulate lymphangiogenesis have promise for improving graft outcomes. PMID:26485284

  1. Inhibition of the immune response to experimental fresh osteoarticular allografts

    SciTech Connect

    Rodrigo, J.J.; Schnaser, A.M.; Reynolds, H.M. Jr.; Biggart, J.M. 3d.; Leathers, M.W.; Chism, S.E.; Thorson, E.; Grotz, T.; Yang, Q.M. )

    1989-06-01

    The immune response to osteoarticular allografts is capable of destroying the cartilage--a tissue that has antigens on its cells identical to those on the bone and marrow cells. Osteoarticular allografts of the distal femur were performed in rats using various methods to attempt to temporarily inhibit the antibody response. The temporary systemic immunosuppressant regimens investigated were cyclophosphamide, azathioprine and prednisolone, cyclosporine A, and total lymphoid irradiation. The most successful appeared to be cyclosporine A, but significant side effects were observed. To specifically inhibit the immune response in the allograft antigens without systemically inhibiting the entire immune system, passive enhancement and preadministration of donor blood were tried. Neither was as effective as coating the donor bone with biodegradable cements, a method previously found to be successful. Cyclosporine A was investigated in dogs in a preliminary study of medial compartmental knee allografts and was found to be successful in inhibiting the antibody response and in producing a more successful graft; however, some significant side effects were similarly observed.

  2. Kidney allograft survival in dogs treated with total lymphoid irradiation

    SciTech Connect

    Howard, R.J.; Sutherland, D.E.R.; Lum, C.T.; Lewis, W.I.; Kim, T.H.; Slavin, S.; Najarian, J.S.

    1981-02-01

    Total lymphoid irradiation (TLI) is immunosuppressive and, in rodents, can induce a state where transplantation of allogenic bone marrow results in chimerism and permanent acceptance of organ allografts from the donor strain. Twelve splenectomized dogs were treated with TLI (150 rads per fraction, total dose 1950 to 3000 rads) before bilateral nephrectomy and renal allotransplantation. Eight dogs received bone marrow from the kidney donor. In 13 untreated control dogs renal allografts functioned for a mean +- (SE) of 4.7 +- 0.3 days. In the four TLI treated dogs who did not receive bone marrow the renal allografts functioned for 15 to 76 days (two dogs died with functioning grafts). In the eight TLI treated dogs who received donor bone marrow, two died immediately after transplantation, two rejected at 3 and 13 days, one died at 13 days with a functioning graft, and two have had the grafts function for longer than 500 days. Chimerism was not detected in the one dog tested. The response of peripheral blood lymphocytes to stimulation with phytohemaglutinin and in mixed lymphocyte culture was suppressed for at least one month after TLI. The results confirm the immunosuppressive effect of TLI. The absence of kidney rejection in two recipients of donor bone marrow show the potential of this approach to induce long-term immunologic unresponsiveness as to an organ allograft, but the outcome is unpredictable and further experiments are needed to define the optimal conditions for administration of TLI and bone marrow to the recipients.

  3. Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection

    PubMed Central

    Cui, Ye; Liu, Kaifeng; Monzon-Medina, Maria E.; Padera, Robert F.; Wang, Hao; George, Gautam; Toprak, Demet; Abdelnour, Elie; D’Agostino, Emmanuel; Goldberg, Hilary J.; Perrella, Mark A.; Forteza, Rosanna Malbran; Rosas, Ivan O.; Visner, Gary; El-Chemaly, Souheil

    2015-01-01

    Lung transplantation is the only viable option for patients suffering from otherwise incurable end-stage pulmonary diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Despite aggressive immunosuppression, acute rejection of the lung allograft occurs in over half of transplant recipients, and the factors that promote lung acceptance are poorly understood. The contribution of lymphatic vessels to transplant pathophysiology remains controversial, and data that directly address the exact roles of lymphatic vessels in lung allograft function and survival are limited. Here, we have shown that there is a marked decline in the density of lymphatic vessels, accompanied by accumulation of low-MW hyaluronan (HA) in mouse orthotopic allografts undergoing rejection. We found that stimulation of lymphangiogenesis with VEGF-C156S, a mutant form of VEGF-C with selective VEGFR-3 binding, alleviates an established rejection response and improves clearance of HA from the lung allograft. Longitudinal analysis of transbronchial biopsies from human lung transplant recipients demonstrated an association between resolution of acute lung rejection and decreased HA in the graft tissue. Taken together, these results indicate that lymphatic vessel formation after lung transplantation mediates HA drainage and suggest that treatments to stimulate lymphangiogenesis have promise for improving graft outcomes. PMID:26485284

  4. Cardiac rehabilitation

    MedlinePlus

    ... 123-210. Thomas PD. Exercise-Based, Comprehensive Cardiac Rehabilitation. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine . 9th ed. Philadelphia, PA: Saunders Elsevier; 2011: ...

  5. Cardiac rehabilitation

    MedlinePlus

    ... goal of cardiac rehab is to: Improve your cardiovascular function Improve your overall health and quality of ... E, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine . 10th ed. Philadelphia, PA: Elsevier Saunders; 2015: ...

  6. Cardiac arrest

    MedlinePlus

    ... treatment for cardiac arrest. It is a medical device that gives an electrical shock to the heart. The shock can get the heart beating normally again. Small, portable defibrillators are often available in public areas for ...

  7. Cardiac amyloidosis

    MedlinePlus

    ... the way electrical signals move through the heart (conduction system). This can lead to abnormal heart beats ( ... due to medication) Sick sinus syndrome Symptomatic cardiac conduction system disease (arrhythmias related to abnormal conduction of ...

  8. Cardiac Sarcoidosis

    MedlinePlus

    ... is Cardiac Sarcoidosis? Sarcoidosis is a poorly understood disease that commonly affects the lungs. It can also involve the lymph nodes, liver, spleen, eyes, skin, bones, salivary glands and heart. ...

  9. CIRCUMFERENTIAL PROXIMAL FEMORAL ALLOGRAFTS IN TOTAL HIP ARTHROPLASTY REVISION SURGERY

    PubMed Central

    Roos, Bruno Dutra; Roos, Milton Valdomiro; Júnior, Antero Camisa; Lampert, Henrique Bonotto; da Silva, Matheus Luis

    2015-01-01

    Objective: To evaluate the clinical and radiographic results from patients who underwent femoral reconstruction secondary to loosening of total hip arthroplasty, using circumferential proximal femoral allografts and cemented implants. Methods: A retrospective study was conducted on 32 patients (33 hips) who underwent femoral reconstruction secondary to loosening of total hip arthroplasty, using circumferential proximal femoral allografts and cemented implants. Among these patients, 28 (29 hips) fulfilled all the requirements for this study. The mean follow-up was five years and two months. The clinical evaluation was done in accordance with the Harris Hip Score. Radiographically, the patients were assessed regarding reabsorption and consolidation of the allograft, migration of the greater trochanter, stability of the femoral component and heterotypic calcification. Results: The average preoperative Harris Hip Score was 32 points. At the last postoperative follow-up, the average score was 82 points. Allograft resorption of some degree was seen in nine hips (31%). Regarding consolidation, 24 cases (82.8%) showed full consolidation, three (10.3%) showed partial consolidation and two (6.9%) showed pseudarthrosis. All femoral components were stable. According to the criteria established, 27 cases (93.1%) were considered to be successful reconstructions after a mean follow-up of five years and two months. Conclusion: From the results obtained, it was concluded that use of circumferential proximal femoral allografts in selected cases of femoral reconstruction secondary to loosening of arthroplasty presented a high survival rate from the reconstruction over an average follow-up of five years and two months. PMID:27047896

  10. Safety profile of decellularized, cryopreserved pulmonary allografts when used in the aortic position for neonatal arch reconstruction.

    PubMed

    Knepp, Marc D; Ohye, Richard G; Gajarski, Robert J

    2011-08-01

    Cryopreserved pulmonary allograft is frequently used to reconstruct the hypoplastic aortic arch. A decellularized graft preparation is available as an alternative reconstructive material. This case series profiles our experience using this material for neonatal aortic arch reconstruction. Data from 14 patients who received decellularized pulmonary allograft (DCPA) from 2001 to 2003 included the following: diagnosis; age at implantation; perioperative complications (graft bleeding or dehiscence); intermediate-term results, including infection, recurrent arch gradient (>10 mmHg), graft calcification, or aneurysm; need for graft removal; and cause of death. Eleven (79%) patients survived their initial procedure. Median follow-up was 26 (range: 1-110) months. No early graft dehiscence was reported. No child developed aortic arch obstruction or graft calcification. Twelve patients (86%) underwent postoperative cardiac catheterizations with no measurable arch gradient. No intermediate-term aneurysm, dehiscence, or graft removal occurred. Three early deaths were due to arrhythmia, non-shunt-related hypoxia, and renal failure, and one, intermediate-term death was respiratory syncytial virus related. This series found that DCPA reconstructed arches have a low adverse event profile. No complications occurred. Because this graft material, which may be less immunogenic, has important implications for this subgroup, who are at increased future transplant risk, larger trials evaluating longer-term safety and immunogenicity are warranted. PMID:21479906

  11. Splenic microenvironment and self recognition as factors in allograft rejection in rats. A study using indium-111-labeled cells

    SciTech Connect

    Pollak, R.; Blanchard, J.M.; Lazda, V.A.

    1986-11-01

    Splenectomy facilitates organ allograft survival in some rat strains, and in weak donor-recipient histoincompatible pairs. We have found using a heart spleen twin graft model, using ACI rats as recipients and Lewis rats as donors, that the transplanted heart will survive in most recipients after delayed host splenectomy. The presence of a viable mass of splenic tissue will allow rejection to proceed only when the transplanted spleen is of host origin, and not when it comes from the donor (i.e., when it is allogeneic). The use of 111In-labeled cells has allowed us to show that lymphocyte traffic and trapping is markedly altered in the transplanted allogeneic spleens, when compared with control transplanted syngeneic spleens. Thus, despite the presence of the splenic ''microenvironment,'' cardiac allograft rejection does not occur in the absence of syngeneic splenic tissue. We conclude that the role of the spleen in the immune response is to facilitate the recognition of self and the acquisition of alloreactivity in weak responder rat strains and donor-recipient pairs.

  12. Skin allograft and vascularized composite allograft: potential for long-term efficacy in the context of lymphatic modulation.

    PubMed

    Rinkinen, Jacob; Selley, Ryan; Agarwal, Shailesh; Loder, Shawn; Levi, Benjamin

    2014-01-01

    Tissue transplantation restores form and function in burn patients. The treatment of burn injuries is influenced by severity, location, and the percentage of total body surface area. There have been a number of different techniques developed to temporize and repair the destroyed tissue. However, in patients with large wound burden, sufficient donor site tissue may not be available for autograft harvesting. Such extensive burns necessitate other temporary and permanent options for wound coverage such as skin or vascularized composite allografts (VCA). Rejection of these tissues presents an ongoing problem which is currently managed using a host of systemic immunosuppressive medications. This article discusses the mechanism behind the innate and adaptive immune systems rejection of the allografts. By understanding these pathways, various techniques using immunomodulatory protocols have led to increased allograft survival. However, our primary interest lies in the initial recognition of the graft. We tailor this article to have a specific emphasis on lymphatic modulation as a potential adjunctive therapy. Reviews of the studies evaluating the effect of lymph node modulation on graft survival are described with future implications to allograft transplant research. PMID:25051523

  13. Inaccuracy in selection of massive bone allograft using template comparison method.

    PubMed

    Paul, Laurent; Docquier, Pierre-Louis; Cartiaux, Olivier; Cornu, Olivier; Delloye, Christian; Banse, Xavier

    2008-06-01

    The use of massive bone allografts is increasing year by year and selection method remains unchanged. Superposition of patient's radiograph over allograft image and comparison of distances is the gold standard. Experiment was led to test selection procedure of a major european tissue bank. Four observers were asked to select an allograft for 10 fictive recipients. Nine allografts were provided. To simulate a perfect allograft, recipient himself was inserted in the pool of allografts (trap graft). The 10 potential bone transplants were classified in four categories (from adequate to unacceptable). In addition, observers were asked to choose the three best grafts for a given recipient. Quadratic kappa measuring agreement on classification between two observers ranged between 0.74 (substantial) and 0.47 (moderate). Trap graft was quoted by observers as adequate four times (10%) and was cited eight times (20%) among the three best matching allografts. None of the observers discovered that recipient was among allograft panel. This study demonstrates that current selection method is inaccurate for hemipelvic allograft selection. New methods should be developed and tested to assist tissue banks in bone allograft selection. PMID:18253861

  14. Radioprotection provides functional mechanics but delays healing of irradiated tendon allografts after ACL reconstruction in sheep.

    PubMed

    Seto, Aaron U; Culp, Brian M; Gatt, Charles J; Dunn, Michael

    2013-12-01

    Successful protection of tissue properties against ionizing radiation effects could allow its use for terminal sterilization of musculoskeletal allografts. In this study we functionally evaluate Achilles tendon allografts processed with a previously developed radioprotective treatment based on (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) crosslinking and free radical scavenging using ascorbate and riboflavin, for ovine anterior cruciate ligament reconstruction. Arthroscopic anterior cruciate ligament (ACL) reconstruction was performed using double looped allografts, while comparing radioprotected irradiated and fresh frozen allografts after 12 and 24 weeks post-implantation, and to control irradiated grafts after 12 weeks. Radioprotection was successful at preserving early subfailure mechanical properties comparable to fresh frozen allografts. Twelve week graft stiffness and anterior-tibial (A-T) translation for radioprotected and fresh frozen allografts were comparable at 30 % of native stiffness, and 4.6 and 5 times native A-T translation, respectively. Fresh frozen allograft possessed the greatest 24 week peak load at 840 N and stiffness at 177 N/mm. Histological evidence suggested a delay in tendon to bone healing for radioprotected allografts, which was reflected in mechanical properties. There was no evidence that radioprotective treatment inhibited intra-articular graft healing. This specific radioprotective method cannot be recommended for ACL reconstruction allografts, and data suggest that future efforts to improve allograft sterilization procedures should focus on modifying or eliminating the pre-crosslinking procedure. PMID:23842952

  15. Suppression of cell-mediated immunity after infection with attenuated rubella virus.

    PubMed Central

    Ganguly, R; Cusumano, C L; Waldman, R H

    1976-01-01

    The effects of attenuated rubella virus infection upon cell-mediated immunity of human volunteers were studied. The volunteers received the vaccine either by nose drops or by the subcutaneous route. Changes in cell-mediated immunity in terms of delayed cutaneous sensitivity to recall antigens, phytohemagglutination stimulation, and spontaneous migration inhibitory factor-like activity were studied at various time periods after infection. Spontaneous migration inhibitory factor-like activity was studied on supernatants of the lymphocytes obtained from the volunteers and incubated for 72 h in the absence of any antigens. A significant proportion of the volunteers showed suppression of one or more parameters of cell-medicated immunity tested by week 2 of infection compared to the control; however, there was no correlation between suppression of the various parameters studied. No difference was noticed in the incidence of cell-mediated immunity suppression between nose drops and subcutaneous route groups. PMID:770329

  16. Assessing humoral and cell-mediated immune response in Hawaiian green turtles, Chelonia mydas

    USGS Publications Warehouse

    Work, T.M.; Balazs, G.H.; Rameyer, R.A.; Chang, S.P.; Berestecky, J.

    2000-01-01

    Seven immature green turtles, Chelonia mydas, captured from Kaneohe Bay on the island of Oahu were used to evaluate methods for assessing their immune response. Two turtles each were immunized intramuscularly with egg white lysozyme (EWL) in Freunda??s complete adjuvant, Gerbu, or ISA-70; a seventh turtle was immunized with saline only and served as a control. Humoral immune response was measured with an indirect enzyme linked immunosorbent assay (ELISA). Cell-mediated immune response was measured using in vitro cell proliferation assays (CPA) using whole blood or peripheral blood mononuclear cells (PBM) cultured with concanavalin A (ConA), phytohaemagglutinin (PHA), or soluble egg EWL antigen. All turtles, except for one immunized with Gerbu and the control, produced a detectable humoral immune response by 6 weeks which persisted for at least 14 weeks after a single immunization. All turtles produced an anamnestic humoral immune response after secondary immunization. Antigen specific cell-mediated immune response in PBM was seen in all turtles either after primary or secondary immunization, but it was not as consistent as humoral immune response; antigen specific cell-mediated immune response in whole blood was rarely seen. Mononuclear cells had significantly higher stimulation indices than whole blood regardless of adjuvant, however, results with whole blood had lower variability. Both Gerbu and ISA-70 appeared to potentiate the cell-mediated immune response when PBM or whole blood were cultured with PHA. This is the first time cell proliferation assays have been compared between whole blood and PBM for reptiles. This is also the first demonstration of antigen specific cell-mediated response in reptiles. Cell proliferation assays allowed us to evaluate the cell-mediated immune response of green turtles. However, CPA may be less reliable than ELISA for detecting antigen specific immune response. Either of the three adjuvants appears suitable to safely elicit a

  17. Cell mediated immunity to corn starch in starch-induced granulomatous peritonitis.

    PubMed

    Goodacre, R L; Clancy, R L; Davidson, R A; Mullens, J E

    1976-03-01

    Two patients with histologically diagnosed starch induced granulomatous peritonitis (SGP) have been shown to have cell mediated immunity to corn starch using the techniques of macrophage migration inhibition and lymphocyte DNA synthesis. Control groups of normal subjects, patients with uncomplicated laparotomy, and patients with Crohn's disease were negative in both tests. Lymphocytes from two patients with band adhesions, one of whom had biopsy evidence of a granulomatous reaction to starch, were sensitized to starch. Cell mediated immunity to starch may contribute to the pathogenesis of SGP, and some band adhesions may be a chronic low grade manifestation of this disorder. PMID:1269987

  18. Isolated heart transplantation for familial transthyretin (TTR) V122I cardiac amyloidosis.

    PubMed

    Thenappan, Thenappan; Fedson, Savitri; Rich, Jonathan; Murks, Catherine; Husain, Aliya; Pogoriler, Jennifer; Anderson, Allen S

    2014-06-01

    Transthyretin (TTR) cardiac amyloidosis is characterized by deposition of either mutant or wild type TTR amyloid protein in the myocardium ultimately leading to progressive cardiomyopathy and heart failure. The most common TTR gene mutation that leads to TTR cardiac amyloidosis is the valine-to-isoleucine substitution at position 122 (V122I or Ile122). Currently, the only definitive treatment suggested for mutant TTR cardiac amyloidosis is the combined or sequential liver-heart transplantation in eligible patients, since liver is the source of TTR production. Here, we report a case of heterozygous Val122L mutated TTR-related cardiac amyloidosis treated with isolated heart transplantation with no recurrence of amyloid in the cardiac allograft and no systemic abnormalities 5 years after heart transplantation. Abbreviations MMF mycophenolate mofetil NYHA New York Heart Association TTR transthyretin VE minute ventilation. PMID:24818650

  19. Lipidomics comparing DCD and DBD liver allografts uncovers lysophospholipids elevated in recipients undergoing early allograft dysfunction.

    PubMed

    Xu, Jin; Casas-Ferreira, Ana M; Ma, Yun; Sen, Arundhuti; Kim, Min; Proitsi, Petroula; Shkodra, Maltina; Tena, Maria; Srinivasan, Parthi; Heaton, Nigel; Jassem, Wayel; Legido-Quigley, Cristina

    2015-01-01

    Finding specific biomarkers of liver damage in clinical evaluations could increase the pool of available organs for transplantation. Lipids are key regulators in cell necrosis and hence this study hypothesised that lipid levels could be altered in organs suffering severe ischemia. Matched pre- and post-transplant biopsies from donation after circulatory death (DCD, n = 36, mean warm ischemia time = 2 min) and donation after brain death (DBD, n = 76, warm ischemia time = none) were collected. Lipidomic discovery and multivariate analysis (MVA) were applied. Afterwards, univariate analysis and clinical associations were conducted for selected lipids differentiating between these two groups. MVA grouped DCD vs. DBD (p = 6.20 × 10(-12)) and 12 phospholipids were selected for intact lipid measurements. Two lysophosphatidylcholines, LysoPC (16:0) and LysoPC (18:0), showed higher levels in DCD at pre-transplantation (q < 0.01). Lysophosphatidylcholines were associated with aspartate aminotransferase (AST) 14-day post-transplantation (q < 0.05) and were more abundant in recipients undergoing early allograft dysfunction (EAD) (p < 0.05). A receiver-operating characteristics (ROC) curve combining both lipid levels predicted EAD with 82% accuracy. These findings suggest that LysoPC (16:0) and LysoPC (18:0) might have a role in signalling liver tissue damage due to warm ischemia before transplantation. PMID:26635289

  20. Tolerability of sirolimus: a decade of experience at a single cardiac transplant center.

    PubMed

    Thibodeau, Jennifer T; Mishkin, Joseph D; Patel, Parag C; Kaiser, Patricia A; Ayers, Colby R; Mammen, Pradeep P A; Markham, David W; Ring, William Steves; Peltz, Matthias; Drazner, Mark H

    2013-01-01

    Sirolimus is used in cardiac transplant recipients to prevent rejection, progression of cardiac allograft vasculopathy, and renal dysfunction. However, sirolimus has many potential side effects and its tolerability when used outside of clinical trials is not well established. We describe a decade of experience with sirolimus in cardiac transplant recipients at our institution. We retrospectively reviewed records of all adult cardiac transplant recipients living between September 1999 and February 2010 (n = 329) and identified 67 patients (20%) who received sirolimus. The indications for sirolimus were cardiac allograft vasculopathy (67%), renal dysfunction (25%), rejection (4%), and intolerability of tacrolimus (3%). One-third of patients discontinued sirolimus at a median (25th, 75th percentiles) of 0.9 (0.2, 1.6) yr of duration. Over 70% of subjects experienced an adverse event attributed to sirolimus. Adverse events were associated with higher average sirolimus levels (9.1 ng/mL vs. 7.1 ng/mL, p = 0.004). We conclude that sirolimus is frequently used in cardiac transplant recipients (20%) and commonly causes side effects, often necessitating discontinuation. Higher average sirolimus levels were associated with adverse events, suggesting that tolerability may improve if levels are maintained within the lower end of the current therapeutic range; however, the improvement in tolerability would need to be balanced with the potential for decreased efficacy. PMID:24304376

  1. Cardiac Sarcoidosis.

    PubMed

    Birnie, David H; Nery, Pablo B; Ha, Andrew C; Beanlands, Rob S B

    2016-07-26

    Clinically manifest cardiac involvement occurs in perhaps 5% of patients with sarcoidosis. The 3 principal manifestations of cardiac sarcoidosis (CS) are conduction abnormalities, ventricular arrhythmias, and heart failure. An estimated 20% to 25% of patients with pulmonary/systemic sarcoidosis have asymptomatic cardiac involvement (clinically silent disease). In 2014, the first international guideline for the diagnosis and management of CS was published. In patients with clinically manifest CS, the extent of left ventricular dysfunction seems to be the most important predictor of prognosis. There is controversy in published reports as to the outcome of patients with clinically silent CS. Despite a paucity of data, immunosuppression therapy (primarily with corticosteroids) has been advocated for the treatment of clinically manifest CS. Device therapy, primarily with implantable cardioverter-defibrillators, is often recommended for patients with clinically manifest disease. PMID:27443438

  2. Cardiac sarcoidosis

    PubMed Central

    Smedema, J.P.; Zondervan, P.E.; van Hagen, P.; ten Cate, F.J.; Bresser, P.; Doubell, A.F.; Pattynama, P.; Hoogsteden, H.C.; Balk, A.H.M.M.

    2002-01-01

    Sarcoidosis is a multi-system granulomatous disorder of unknown aetiology. Symptomatic cardiac involvement occurs in approximately 5% of patients. The prevalence of sarcoidosis in the Netherlands is unknown, but estimated to be approximately 20 per 100,000 population (3200 patients). We report on five patients who presented with different manifestations of cardiac sarcoidosis, and give a brief review on the current management of this condition. Magnetic Resonance Imaging (MRI) can be of great help in diagnosing this condition as well as in the follow-up of the response to therapy. ImagesFigure 1Figure 2Figure 3Figure 4Figure 5Figure 6 PMID:25696121

  3. Selection of massive bone allografts using shape-matching 3-dimensional registration

    PubMed Central

    Docquier, Pierre-Louis; Cartiaux, Olivier; Cornu, Olivier; Delloye, Christian; Banse, Xavier

    2010-01-01

    Background and purpose Massive bone allografts are used when surgery causes large segmental defects. Shape-matching is the primary criterion for selection of an allograft. The current selection method, based on 2-dimensional template comparison, is inefficient for 3-dimensional complex bones. We have analyzed a 3-dimensional (3-D) registration method to match the anatomy of the allograft with that of the recipient. Methods 3-D CT-based registration was performed to match the shapes of both bones. We used the registration to align the allograft volume onto the recipient's bone. Hemipelvic allograft selection was tested in 10 virtual recipients with a panel of 10 potential allografts, including one from the recipient himself (trap graft). 4 observers were asked to visually inspect the superposition of allograft over the recipient, to classify the allografts into 4 categories according to the matching of anatomic zones, and to select the 3 best matching allografts. The results obtained using the registration method were compared with those from a previous study on the template method. Results Using the registration method, the observers systematically detected the trap graft. Selections of the 3 best matching allografts performed using registration and template methods were different. Selection of the 3 best matching allografts was improved by the registration method. Finally, reproducibility of the selection was improved when using the registration method. Interpretation 3-D CT registration provides more useful information than the template method but the final decision lies with the surgeon, who should select the optimal allograft according to his or her own preferences and the needs of the recipient. PMID:20175643

  4. Histological Study of Fresh Versus Frozen Semitendinous Muscle Tendon Allografts

    PubMed Central

    Bitar, Alexandre Carneiro; Santos, Luiz Augusto Ubirajara; Croci, Alberto Tesconi; Pereira, João Alberto Ramos Maradei; França Bisneto, Edgard N.; Giovani, Arlete Mazzini Miranda; Oliveira, Claudia Regina G. C. M.

    2010-01-01

    OBJECTIVE: The purpose of this study was to histologically analyze allografts from cadaveric semitendinous muscle after cryopreservation at −80°C in comparison to a control group kept at only −4°C to test the hypothesis that the histological characteristics of the tissue are maintained when the tendons are kept at lower temperatures. METHODS: In a tissue bank, 10 semitendinous tendons from 10 cadavers were frozen at −80ºC as a storage method for tissue preservation. They were kept frozen for 40 days, and then a histological study was carried out. Another 10 tendon samples were analyzed while still “fresh”. RESULTS: There was no histological difference between the fresh and frozen samples in relation to seven variables. CONCLUSIONS: Semitendinous muscle tendon allografts can be submitted to cryopreservation at −80ºC without suffering histological modifications. PMID:20360921

  5. Emerging role of B cells in chronic allograft dysfunction

    PubMed Central

    Colvin, Robert B.; Hirohashi, Tsutomu; Farris, Alton B.; Minnei, Francesca; Collins, A. Bernard; Smith, R. Neal

    2015-01-01

    B cells have many possible mechanisms by which they can affect allograft survival, including antigen presentation, cytokine production, immune regulation, and differentiation into alloantibody-producing plasma cells. This report reviews the last mechanism, which the authors regard as most critical for the long-term survival of allografts, namely, the promotion of chronic rejection by alloantibodies. Chronic humoral rejection characteristically arises late after transplantation and causes transplant glomerulopathy, multilamination of peritubular capillary basement membranes, and C4d deposition in PTCs and glomeruli. Circulating antidonor human leukocyte antigen class II antibodies are commonly detected and may precede the development of graft injury. Prognosis is poor, especially when recognized after graft dysfunction has developed. Improved detection and treatment are critically needed for this common cause of late graft loss. PMID:21116310

  6. Massive allograft replacement of hemiarticular traumatic defects of the elbow.

    PubMed

    Breen, T; Gelberman, R H; Leffert, R; Botte, M

    1988-11-01

    Four elbow osteoarticular allografts were done for four patients as salvage procedures for unreconstructable elbow fracture malunions. With a mean follow-up of 60 months (range, 12 to 72 months) all elbows were stable, free of pain, and had mean motion of 130 degrees active flexion and 27 degrees of flexion deformity, 67 degrees pronation and 62 degrees supination (preoperative mean: 104 degrees flexion, 42 degrees flexion contracture, 20 degrees pronation, and 34 degrees supination). Complications occurred in two elbows. One had a deep infection necessitating graft removal and subsequent regrafting. The second had an olecranon osteotomy nonunion. Elbow allografting is recommended as a salvage procedure for massive posttraumatic articular defects, bone loss, or malunion when neither arthrodesis nor conventional arthroplasty is indicated. PMID:3066816

  7. Medial Meniscal Allograft Transplantation: The Bone Plug Technique.

    PubMed

    Dean, Chase S; Olivetto, Javier; Chahla, Jorge; Serra Cruz, Raphael; LaPrade, Robert F

    2016-04-01

    The medial meniscus is crucial for knee homeostasis. Treating patients who have undergone a subtotal or total meniscectomy, or equivalent irreparable tear pattern, can be extremely challenging, especially in young, active patients. The importance of meniscal preservation has been reported by several authors. Meniscal repair is now widely accepted as the first surgical option for treating medial meniscal tears. Moreover, current guidelines recommend preserving as much meniscal tissue as possible. Treating a symptomatic medial meniscectomized knee is challenging because of limited surgical options. In this context, medial meniscal allograft transplantation arises as the preferred procedure. The purpose of this article was to detail the arthroscopic medial meniscal allograft transplantation technique with the use of 2 bone plugs. PMID:27330948

  8. 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

  9. Chest wall reconstruction using iliac bone allografts and muscle flaps.

    PubMed

    Garcia-Tutor, Emilio; Yeste, Luis; Murillo, Julio; Aubá, Cristina; Sanjulian, Mikel; Torre, Wenceslao

    2004-01-01

    Technically we can divide full-thickness thoracic reconstruction into 2 parts: providing a rigid support and ensuring well-vascularized coverage. Since 1986, the authors' center has had ample experience with bone banks and the use of cryopreserved bone grafts, which led them to consider the possibility of using these grafts for full-thickness chest wall reconstruction. They describe 3 patients in whom resection of the tumor and reconstruction of the thorax were carried out using iliac bone allografts covered with muscle flaps (1 pectoralis major and 2 rectus abdominis). None of the patients experienced breathing difficulties, pain, or instability after 14 months, 18 months, and 11 years of follow-up. The result of the reconstruction was excellent in all 3 patients in terms of function and aesthetics. The advantage of allografts compared with synthetic materials is their potential integration; they can become part of the host patient's living tissue. PMID:14676700

  10. Arthroscopic Labral Reconstruction of the Hip Using Semitendinosus Allograft

    PubMed Central

    Redmond, John M.; Cregar, William M.; Martin, Timothy J.; Vemula, S. Pavan; Gupta, Asheesh; Domb, Benjamin G.

    2015-01-01

    The labrum of the hip is recognized as being important to the stability of the hip and a major cause of hip pain. Damage to the labrum may result in increased joint stress and articular damage. Labral damage is often treated through various methods, among them simple stitch repair, base refixation, and debridement. Labral reconstruction becomes necessary when the labrum is too damaged to salvage, which renders labral repair improbable and labral debridement ineffective. In contrast to other methods that have been described for this treatment, our technique uses a semitendinosus allograft as a graft source, allowing for arthroscopic hip labral reconstruction. This technique has many advantages and is easily reproducible. It has shown promising results in patients with labral damage. The purpose of this article is to detail the step-by-step surgical technique of labral reconstruction using a semitendinosus allograft, in addition to the indications, pearls, and pitfalls of the technique. PMID:26759770

  11. Proliferative glomerulonephritis with monoclonal immunoglobulin in renal allografts

    PubMed Central

    Al-Rabadi, Laith; Francis, Jean M.; Henderson, Joel; Ghai, Sandeep

    2015-01-01

    Glomerulopathy due to dysproteinemia can have a wide spectrum of pathologic and clinical features based on specific characteristics of the abnormal protein and the response induced within the parenchymal tissue. Monoclonal immunoglobulin G (IgG) deposition can manifest as a different glomerular disease. Proliferative glomerulonephritis (GN) with monoclonal IgG deposits (PGNMID) is a unique entity mimicking immune complex GN that does not conform to any of those subtypes. IgG monoclonal granular deposition in the glomeruli with a pattern similar to immune complex disease suggested by C3 and C1q deposition should prompt consideration of PGNMID. Literature is scarce in terms of recurrence of disease in renal allografts. In this article we present the clinical–pathologic features of three cases of PGNMID in the renal allograft showing the variable course and manifestation of the disease. PMID:26613031

  12. Regulatory oversight in the United States of vascularized composite allografts.

    PubMed

    Glazier, Alexandra K

    2016-06-01

    Vascularized composite allograft (VCA) transplantation is a medically acceptable treatment for the reconstruction of major tissue loss. The advent of VCA transplantation has spurred regulatory and policy development in the United States to address the multiple clinical, ethical and legal issues that must be considered for the practice of VCA donation and transplantation to develop within the existing framework of public trust and transparency vital to the success of donation and transplantation. PMID:26284312

  13. Immunomodulation of vascular endothelium: Effects of ultraviolet B irradiation on vein allograft rejection

    SciTech Connect

    Marin, M.L.; Hardy, M.A.; Gordon, R.E.; Reemtsma, K.; Benvenisty, A.I. )

    1990-01-01

    Prosthetic grafts of vein allografts are inadequate as small-diameter vessel substitutes. We have applied ultraviolet B (UVB) irradiation to modulate the immunogenicity of vein allografts to avoid immunologic injury. The veins of male ACI rats were irradiated with UVB (60 mJ/cm2) in situ and transplanted to male ACI rats (autografts) and female Lewis rats (allografts). Nonirradiated veins served as controls. At 4, 7, 14, and 28 days, all grafts were patent and were studied for morphologic changes by scanning electron microscopy and for immunogold labeling of major histocompatibility complex class II antigen expression. In autografts, scanning electron microscopy demonstrated minimal endothelial loss after grafting, regardless of UVB irradiation. Untreated allografts showed severe endothelial injury 4, 7, and 14 days after transplantation. UVB irradiation of veins protected allografts from injury to the endothelium and basement membrane. Major histocompatibility complex class II-positive endothelial cells were not seen in autografts but were seen in 40% of cells 4 days after transplantation in untreated allografts. UVB-treated allografts showed MHC class II antigen expression labeling of 20% of the endothelial cells. Barr body analysis demonstrated the donor origin of these endothelial cells. UVB irradiation of rat vein allografts prolongs endothelial survival while decreasing endothelial surface expression of class II antigens. These data suggest that modification of vein immunogenicity with UVB irradiation may permit functional survival of small-vessel allografts without chronic immunosuppression.

  14. Fresh-frozen Complete Extensor Mechanism Allograft versus Autograft Reconstruction in Rabbits

    PubMed Central

    Chen, Guanyin; Zhang, Hongtao; Ma, Qiong; Zhao, Jian; Zhang, Yinglong; Fan, Qingyu; Ma, Baoan

    2016-01-01

    Different clinical results have been reported in the repair of extensor mechanism disruption using fresh-frozen complete extensor mechanism (CEM) allograft, creating a need for a better understanding of fresh-frozen CME allograft reconstruction. Here, we perform histological and biomechanical analyses of fresh-frozen CEM allograft or autograft reconstruction in an in vivo rabbit model. Our histological results show complete incorporation of the quadriceps tendon into the host tissues, patellar survival and total integration of the allograft tibia, with relatively fewer osteocytes, into the host tibia. Vascularity and cellularity are reduced and delayed in the allograft but exhibit similar distributions to those in the autograft. The infrapatellar fat pad provides the main blood supply, and the lowest cellularity is observed in the patellar tendon close to the tibia in both the allograft and autograft. The biomechanical properties of the junction of quadriceps tendon and host tissues and those of the allograft patellar tendon are completely and considerably restored, respectively. Therefore, fresh-frozen CEM allograft reconstruction is viable, but the distal patellar tendon and the tibial block may be the weak links of the reconstruction. These findings provide new insight into the use of allograft in repairing disruption of the extensor mechanism. PMID:26911538

  15. Healing properties of allograft from alendronate-treated animal in lumbar spine interbody cage fusion.

    PubMed

    Xue, Qingyun; Li, Haisheng; Zou, Xuenong; Bünger, Mathias; Egund, Niels; Lind, Martin; Christensen, Finn Bjarke; Bünger, Cody

    2005-04-01

    This study investigated the healing potential of allograft from bisphosphonate-treated animals in anterior lumbar spine interbody fusion. Three levels of anterior lumbar interbody fusion with Brantigan cages were performed in two groups of five landrace pigs. Empty Brantigan cages or cages filled with either autograft or allograft were located randomly at different levels. The allograft materials for the treatment group were taken from the pigs that had been fed with alendronate, 10 mg daily for 3 months. The histological fusion rate was 2/5 in alendronate-treated allograft and 3/5 in non-treated allograft. The mean bone volume was 39% and 37.2% in alendronate-treated or non-treated allograft (NS), respectively. No statistical difference was found between the same grafted cage comparing two groups. The histological fusion rate was 7/10 in all autograft cage levels and 5/10 in combined allograft cage levels. No fusion was found at all in empty cage levels. With the numbers available, no statistically significant difference was found in histological fusion between autograft and allograft applications. There was a significant difference of mean bone volume between autograft (49.2%) and empty cage (27.5%) (P<0.01). In conclusion, this study did not demonstrate different healing properties of alendronate-treated and non-treated allograft for anterior lumbar interbody fusion in pigs. PMID:15248057

  16. Prolongation of segmental and pancreaticoduodenal allografts in the primate with total-lymphoid irradiation and cyclosporine

    SciTech Connect

    Du Toit, D.F.; Heydenrych, J.J.; Smit, B.; Louw, G.; Zuurmond, T.; Els, D.; Du Toit, L.B.; Weideman, A.; Davids, H.; van der Merwe, E.

    1987-09-01

    The prolongation of segmental and pancreaticoduodenal allografts (PDA) by total lymphoid irradiation (TLI) and in combination with cyclosporine (CsA) was assessed in a well established total pancreatectomy, diabetic, primate transplantation model. Pancreatic transplantation was performed in 119 pancreatectomized baboons (Papio ursinus). Of a total of 109 allografts performed, 71 were segmental allografts (open duct drainage) and 38 PDA. Of 119 graft recipients, 10 received segmental pancreatic autografts. TLI and CsA administered separately to segmental allograft recipients resulted in modest allograft survival and indefinite graft survival was not observed. 8 of 17 (47%) segmental allograft recipients that received TLI and CsA had graft survival beyond 100 days, indicating highly significant pancreatic allograft survival. All long-term segmental allograft recipients were rendered normoglycemic (plasma glucose less than 8 mmol/L) by this immunosuppressive regimen. In contrast, poor results were observed in PDA recipients treated with TLI and CsA. Mean survival in 18 treated PDA recipients was 23.8 days, 8 survived longer than 20 days (44.4%), and 1 greater than 100 days (5.5%). Despite treatment, early rejection of the duodenum in PDA recipients frequently resulted in necrosis and perforation and contributed to a high morbidity and mortality. This study indicates that, in contrast to the significant prolongation of segmental allografts by TLI and CsA, poor immunosuppression was achieved by this regimen in PDA recipients and was associated with a high morbidity and mortality caused by early rejection of the duodenum.

  17. Quantitative podocyte parameters predict human native kidney and allograft half-lives

    PubMed Central

    Cibrik, Diane; Hodgin, Jeffrey B.; Wu, Fan; Zhang, Min; Kikuchi, Masao; Wickman, Larysa; Samaniego, Milagros; Bitzer, Markus; Wiggins, Jocelyn E.; Ojo, Akinlolu; Li, Yi; Wiggins, Roger C.

    2016-01-01

    BACKGROUND Kidney function decreases with age. A potential mechanistic explanation for kidney and allograft half-life has evolved through the realization that linear reduction in glomerular podocyte density could drive progressive glomerulosclerosis to impact both native kidney and allograft half-lives. METHODS Predictions from podometrics (quantitation of podocyte parameters) were tested using independent pathologic, functional, and outcome data for native kidneys and allografts derived from published reports and large registries. RESULTS With age, native kidneys exponentially develop glomerulosclerosis, reduced renal function, and end-stage kidney disease, projecting a finite average kidney life span. The slope of allograft failure rate versus age parallels that of reduction in podocyte density versus age. Quantitative modeling projects allograft half-life at any donor age, and rate of podocyte detachment parallels the observed allograft loss rate. CONCLUSION Native kidneys are designed to have a limited average life span of about 100–140 years. Allografts undergo an accelerated aging-like process that accounts for their unexpectedly short half-life (about 15 years), the observation that older donor age is associated with shorter allograft half-life, and the fact that long-term allograft survival has not substantially improved. Podometrics provides potential readouts for these processes, thereby offering new approaches for monitoring and intervention. FUNDING National Institutes of Health. PMID:27280173

  18. Polyglutamate directed coupling of bioactive peptides for the delivery of osteoinductive signals on allograft bone

    PubMed Central

    Culpepper, Bonnie K.; Bonvallet, Paul P.; Reddy, Michael S.; Ponnazhagan, Selvarangan; Bellis, Susan L.

    2012-01-01

    Allograft bone is commonly used as an alternative to autograft, however allograft lacks many osteoinductive factors present in autologous bone due to processing. In this study, we investigated a method to reconstitute allograft with osteoregenerative factors. Specifically, an osteoinductive peptide from collagen I, DGEA, was engineered to express a heptaglutamate (E7) domain, which binds the hydroxyapatite within bone mineral. Addition of E7 to DGEA resulted in 9× greater peptide loading on allograft, and significantly greater retention after a 5-day interval with extensive washing. When factoring together greater initial loading and retention, the E7 domain directed a 45-fold enhancement of peptide density on the allograft surface. Peptide-coated allograft was also implanted subcutaneously into rats and it was found that E7DGEA was retained in vivo for at least 3 months. Interestingly, E7DGEA peptides injected intravenously accumulated within bone tissue, implicating a potential role for E7 domains in drug delivery to bone. Finally, we determined that, as with DGEA, the E7 modification enhanced coupling of a bioactive BMP2-derived peptide on allograft. These results suggest that E7 domains are useful for coupling many types of bone-regenerative molecules to the surface of allograft to reintroduce osteoinductive signals and potentially advance allograft treatments. PMID:23182349

  19. Both rejection and tolerance of allografts can occur in the absence of secondary lymphoid tissues.

    PubMed

    Kant, Cavit D; Akiyama, Yoshinobu; Tanaka, Katsunori; Shea, Susan; Yamada, Yohei; Connolly, Sarah E; Marino, Jose; Tocco, Georges; Benichou, Gilles

    2015-02-01

    In this study, we showed that aly/aly mice, which are devoid of lymph nodes and Peyer's patches, acutely rejected fully allogeneic skin and heart grafts. They mounted potent inflammatory direct alloresponses but failed to develop indirect alloreactivity after transplantation. Remarkably, skin allografts also were rejected acutely by splenectomized aly/aly (aly/aly-spl(-)) mice devoid of all secondary lymphoid organs. In these recipients, the rejection was mediated by alloreactive CD8(+) T cells presumably primed in the bone marrow. In contrast, cardiac transplants were not rejected by aly/aly-spl(-) mice. Actually, aly/aly-spl(-) mice that spontaneously accepted a heart allotransplant and displayed donor-specific tolerance also accepted skin grafts from the same, but not a third-party, donor via a mechanism involving CD4(+) regulatory T cells producing IL-10 cytokine. Therefore, direct priming of alloreactive T cells, as well as rejection and regulatory tolerance of allogeneic transplants, can occur in recipient mice lacking secondary lymphoid organs. PMID:25535285

  20. 19F MRI detection of acute allograft rejection with in vivo perfluorocarbon labeling of immune cells.

    PubMed

    Hitchens, T Kevin; Ye, Qing; Eytan, Danielle F; Janjic, Jelena M; Ahrens, Eric T; Ho, Chien

    2011-04-01

    Current diagnosis of organ rejection following transplantation relies on tissue biopsy, which is not ideal due to sampling limitations and risks associated with the invasive procedure.We have previously shown that cellular magnetic resonance imaging (MRI) of iron-oxide labeled immune-cell infiltration can provide a noninvasive measure of rejection status by detecting areas of hypointensity on T 2*-weighted images. In this study, we tested the feasibility of using a fluorine-based cellular tracer agent to detect macrophage accumulation in rodent models of acute allograft rejection by fluorine-19 ((19) F) MRI and magnetic resonance spectroscopy. This study used two rat models of acute rejection, including abdominal heterotopic cardiac transplant and orthotopic kidney transplant models. Following in vivo labeling of monocytes and macrophages with a commercially available agent containing perfluoro-15-crown-5-ether, we observed (19) F-signal intensity in the organs experiencing rejection by (19) F MRI, and conventional (1) H MRI was used for anatomical context. Immunofluorescence and histology confirmed macrophage labeling. These results are consistent with our previous studies and show the complementary nature of the two cellular imaging techniques. With no background signal, (19) F MRI/magnetic resonance spectroscopy can provide unambiguous detection of fluorine labeled cells, and may be a useful technique for detecting and quantifying rejection grade in patients. PMID:21305593

  1. CALORIE RESTRICTION ENHANCES T CELL MEDIATED IMMUNE RESPONSE IN OVERWEIGHT MEN AND WOMEN

    Technology Transfer Automated Retrieval System (TEKTRAN)

    It is well known that dietary energy restriction prolongs lifespan and enhances immune responsiveness in a wide range of laboratory animals. However, information on the applicability of these results to humans is limited. In this study we examined the effects of calorie restriction on T cell mediate...

  2. Genetic diversity predicts pathogen resistance and cell-mediated immunocompetence in house finches

    PubMed Central

    Hawley, Dana M; Sydenstricker, Keila V; Kollias, George V; Dhondt, André A

    2005-01-01

    Evidence is accumulating that genetic variation within individual hosts can influence their susceptibility to pathogens. However, there have been few opportunities to experimentally test this relationship, particularly within outbred populations of non-domestic vertebrates. We performed a standardized pathogen challenge in house finches (Carpodacus mexicanus) to test whether multilocus heterozygosity across 12 microsatellite loci predicts resistance to a recently emerged strain of the bacterial pathogen, Mycoplasma gallisepticum (MG). We simultaneously tested whether the relationship between heterozygosity and pathogen susceptibility is mediated by differences in cell-mediated or humoral immunocompetence. We inoculated 40 house finches with MG under identical conditions and assayed both humoral and cell-mediated components of the immune response. Heterozygous house finches developed less severe disease when infected with MG, and they mounted stronger cell-mediated immune responses to phytohaemagglutinin. Differences in cell-mediated immunocompetence may, therefore, partly explain why more heterozygous house finches show greater resistance to MG. Overall, our results underscore the importance of multilocus heterozygosity for individual pathogen resistance and immunity. PMID:17148199

  3. KERATINOCYTE CELL-MEDIATED MUTAGENESIS ASSAY: CORRELATION WITH IN VIVO TUMOR STUDIES

    EPA Science Inventory

    A murine keratinocyte cell-mediated mutagenesis assay was characterized and examined as an in vitro model system for studying the biotransformation of promutagens/procarcinogens by mouse skin. The assay used living cultured newborn SENCAR keratinocytes for the metabolic activatio...

  4. Autologous endothelial progenitor cells improve allograft survival in porcine lung transplantation with prolonged ischemia

    PubMed Central

    Yen, Yi-Ting; Roan, Jun-Neng; Fang, Shih-Yuan; Chang, Shi-Wei; Tseng, Yau-Lin

    2016-01-01

    Background As endothelial progenitor cells (EPCs) attenuated acute lung injury (ALI) in rabbit model, we hypothesized that autologous EPCs preserved lung graft function during the acute reperfusion period of lung transplantation and tested the therapeutic potential of EPCs in a porcine model of lung transplantation with prolonged graft ischemia. Methods Day-7 EPCs isolated from the recipient subjects or plain culture media were administered into the left pulmonary artery immediately before restoration of pulmonary blood flow in a porcine lung allotransplantation model, with the transplantation surgeons blinded to the content of injection. Hemodynamics and arterial blood gas were recorded, and the right pulmonary artery was occluded 30 min after reperfusion to evaluate the lung graft function. The lung grafts were sectioned for histological examination at the end of experiments. The total ischemic time for lung graft was approximately 14 h. Results All animals receiving plain medium died within 40 min after reperfusion, but 3 out of 5 (60%) piglets receiving EPCs survived up to 4 h after diversion of the entire cardiac output into the lung graft (P<0.01). The donor body weight, recipient body weight, cold ischemic time, and time for anastomosis were comparable between the EPC and control group (P=0.989, 0.822, 0.843, and 0.452, respectively). The mean aortic pressure decreased, and the cardiac output and mean pulmonary artery pressure elevated after right pulmonary artery occlusion. All these parameters were gradually compensated in the EPC group but decompensated in the control group. Better preservation of gas exchange function, reduced thrombi formation in the terminal pulmonary arterioles, and attenuated interstitial hemorrhage of the lung graft were observed in the EPC group. Conclusions We concluded autologous EPCs significantly enhanced the function of lung allograft and improved survival in a porcine model of lung transplantation with prolonged ischemia

  5. Significance of urinary proteome pattern in renal allograft recipients.

    PubMed

    Suhail, Sufi M

    2014-01-01

    Urinary proteomics is developing as a platform of urinary biomarkers of immense potential in recent years. The definition of urinary proteome in the context of renal allograft and characterization of different proteome patterns in various graft dysfunctions have led to the development of a distinct science of this noninvasive tool. Substantial numbers of studies have shown that different renal allograft disease states, both acute and chronic, could portray unique urinary proteome pattern enabling early diagnosis of graft dysfunction and proper manipulation of immunosuppressive strategy that could impact graft prognosis. The methodology of the urinary proteome is nonetheless not more complex than that of other sophisticated assays of conventional urinary protein analysis. Moreover, the need for a centralized database is also felt by the researchers as more and more studies have been presenting their results from different corners and as systems of organizing these newly emerging data being developed at international and national levels. In this context concept of urinary proteomics in renal allograft recipients would be of significant importance in clinical transplantation. PMID:24757556

  6. Clinical Course and Outcomes of Late Kidney Allograft Dysfunction

    PubMed Central

    Zakharov, Vadym; Ksenofontova, Anna; Onishchenko, Eugene; Golubova, Tatyana; Kichatyi, Sergey; Zakharova, Olga

    2016-01-01

    Background. This study is provided to increase the efficiency of the treatment of kidney transplant recipients by predicting the development of the late allotransplant dysfunction. Methods. 330 patients who have lived for more than one year with functioning kidney allograft were evaluated. To predict the subsequent duration of the well-functioning of allotransplant the prognostic significance of 15 baseline clinical and sociodemographic characteristics on the results of the survey one year after transplantation was investigated. The result was considered to be positive in constructing the regression prognostication model if recipient lived more than 3 years from the time of transplantation. Results. It was established that more late start of renal allograft dysfunction after transplantation correlates with the more time it takes till complete loss of allograft function. Creatinine and hemoglobin blood concentration and the level of proteinuria one year after transplantation within created mathematical model allow predicting the loss of kidney transplant function three years after the transplantation. Patients with kidney transplant dysfunction are advised to renew the program hemodialysis upon reaching plasma creatinine concentration 0.5–0.7 mmol/L. Conclusion. Values of creatinine, hemoglobin, and proteinuria one year after transplantation can be used for subsequent prognostication of kidney transplant function. PMID:27478631

  7. Significance of Urinary Proteome Pattern in Renal Allograft Recipients

    PubMed Central

    Suhail, Sufi M.

    2014-01-01

    Urinary proteomics is developing as a platform of urinary biomarkers of immense potential in recent years. The definition of urinary proteome in the context of renal allograft and characterization of different proteome patterns in various graft dysfunctions have led to the development of a distinct science of this noninvasive tool. Substantial numbers of studies have shown that different renal allograft disease states, both acute and chronic, could portray unique urinary proteome pattern enabling early diagnosis of graft dysfunction and proper manipulation of immunosuppressive strategy that could impact graft prognosis. The methodology of the urinary proteome is nonetheless not more complex than that of other sophisticated assays of conventional urinary protein analysis. Moreover, the need for a centralized database is also felt by the researchers as more and more studies have been presenting their results from different corners and as systems of organizing these newly emerging data being developed at international and national levels. In this context concept of urinary proteomics in renal allograft recipients would be of significant importance in clinical transplantation. PMID:24757556

  8. Cell-Mediated Immune Function and Cytokine Regulation During Space Flight

    NASA Technical Reports Server (NTRS)

    Sams, Clarence F.; Pierson, Duane L.; Paloski, W. H. (Technical Monitor)

    2000-01-01

    The changes in immune function which occur during space flight potentially expose the crews to an increased risk for development of illness. Decreased cellular immune function has been repeatedly documented after space flight and confirmed during flight by in vivo delayed-type hypersensitivity testing. However, correlation of immune changes with a clinically significant risk factor has not yet been performed. Our hypothesis is that space flight induces a decrease in cell-mediated immune function accompanied by a shift from a type 1 cytokine pattern (favoring cell-mediated immunity) to a type 2 cytokine pattern (favoring humoral immunity). We further hypothesize that reactivation of latent viruses will occur during space flight in association with the decreased cellular immunity. To test these hypotheses, we will determine the effects of space flight on cell-mediated immunity and viral reactivation. We will utilize delayed-type hypersensitivity testing as an in vivo measure of integrated cell-mediated immune function. The production of cytokines and immunoregulatory factors by lymphocytes and monocytes will be measured to determine whether changes in cytokine patterns are associated with the space flight-induced immune dysregulation. Correlation of antigen-specific immune changes with reactivation of latent herpes viruses will be determined by measuring peripheral levels of viral (CMV, VZV, EBV) antigen-specific T cells and comparing to the levels of EBV-infected B-cells by fluorescence in situ hybridization and flow cytometry. A comparison of cell-mediated immune function, cytokine regulation and viral reactivation will provide new insights into crew member health risks during flight.

  9. Use of Contrast-Enhanced Ultrasonography to Evaluate Chronic Allograft Nephropathy in Rats and Correlations between Time-Intensity Curve Parameters and Allograft Fibrosis.

    PubMed

    Zhang, Qiang; Yu, Zexing; Xu, Yue; Zeng, Song; Zhang, Zijian; Xue, Wenrui; Wang, Wei; Zhang, Xiaodong; Hu, Xiaopeng

    2016-07-01

    This study quantitatively analyzed changes in the hemodynamic characteristics of renal allografts at different stages in a rat chronic allograft nephropathy (CAN) model as well as the relationship between hemodynamic parameters and renal allograft fibrosis using contrast-enhanced ultrasonography (CEUS). The experimental group used a CAN rat model (n = 30), and the control group used an orthotopic syngeneic renal transplant model (n = 30). After surgery, creatinine clearance rates were regularly monitored every 2 wk. The checking times were set at 4, 12 and 24 wk after surgery, which represent early, middle and late stage of CAN, respectively. At different stages of CAN, eight rats from each group were randomly selected for CEUS examination. Time-intensity curve (TIC) parameters, including rise time, peak intensity, mean transit time, area under the curve, wash-in slope, time-to-peak and α-smooth muscle actin (α-SMA) expression; Vimentin expression; and chronic allograft damage index scores were evaluated by linear correlation analysis. Before the creatinine clearance rate showed significant abnormalities, the renal allografts in the experimental group had already presented pathologic changes associated with CAN. In the early stage after surgery, compared to the TIC curve of the control group, the experimental group showed increased rise time, mean transit time, area under the curve and time-to-peak, and decreased wash-in slope (p < 0.05). Chronic allograft damage index scores and the expression levels of α-SMA and Vimentin proteins in renal allografts were correlated with TIC parameters (p < 0.05). Compared to creatinine clearance rate, CEUS can detect CAN at earlier stages. The correlations between TIC-related parameters and the expression levels of α-SMA and Vimentin in renal allografts indicate that CEUS is a feasible way to assess the degree of renal allograft fibrosis quantitatively. PMID:27056611

  10. In vitro allograft irradiation prevents graft-versus-host disease in small-bowel transplantation

    SciTech Connect

    Lee, K.K.; Schraut, W.H.

    1985-04-01

    In small-bowel transplantation, the transfer of large numbers of donor lymphocytes with the intestinal allograft may provoke a lethal graft-versus-host reaction. The effectiveness of allograft irradiation in vitro as a method of preventing graft-versus-host disease (GVHD) was studied in a rat model of small-bowel transplantation, with the Lewis----Lewis X Brown Norway F1 hybrid strain combination. Cold harvested small-bowel allografts were irradiated immediately prior to heterotopic or orthotopic transplantation. Animals that had received heterotopic allografts irradiated with 0, 250, or 500 rad all died of GVHD after 14.4 +/- 3.0, 15.0 +/- 1.3, and 14.2 +/- 1.9 days, respectively. None of the animals that had received allografts treated with 1000 rad developed clinical or pathologic evidence of GVHD, however, and all survived for more than 6 months (P less than 0.001). Allograft function was studied in animals that underwent orthotopic transplantation. Recipients of nonirradiated orthotopic allografts all died of GVHD after 14.0 +/- 0.7 days, whereas recipients of allografts irradiated with 1000 rad all survived for more than 5 months (P less than 0.001). After 120 days, weight gain (51.8 +/- 11.7%), serum albumin (3.9 +/- 0.7 g/dl), serum triglycerides (67.0 +/- 24.3 mg/dl), CBC, and differential in these animals were not statistically different from those in either age-matched isograft recipients or normal animals, and when the rats were sacrificed, irradiated allografts showed no changes suggestive of radiation injury. These results indicate that irradiation of small-bowel allografts in vitro prevents development of GVHD, and that this can be achieved at a dose which does not cause injury to or malfunction of the allograft.

  11. Two Different Regulatory T Cell Populations That Promote Corneal Allograft Survival

    PubMed Central

    Cunnusamy, Khrishen; Paunicka, Kathryn; Reyes, Nancy; Yang, Wanhua; Chen, Peter W.

    2010-01-01

    Purpose. To compare and contrast the T regulatory cells (Tregs) induced by anterior chamber (AC) injection of antigen with those induced by orthotopic corneal allografts. Methods. Anterior chamber–associated immune deviation (ACAID) Tregs were induced by injecting C57BL/6 spleen cells into the AC of BALB/c mice. Delayed-type hypersensitivity responses to C57BL/6 alloantigens were evaluated by a conventional ear swelling assay. Corneal allograft Tregs were induced by applying orthotopic C57BL/6 corneal allografts onto BALB/c hosts. The effects of anti-CD25, anti-CD8, anti-interferon-γ (IFN-γ), anti-IL-17A, or cyclophosphamide treatments on corneal allograft survival and ACAID were evaluated. Results. Administration of either anti-CD25 or anti-IFN-γ antibodies prevented the expression of ACAID and abolished the immune privilege of corneal allografts. By contrast, in vivo treatment with anti-CD8 antibody abrogated ACAID but had no effect on corneal allograft survival. Further discordance between ACAID and corneal allograft survival emerged in experiments in which the induction of allergic conjunctivitis or the administration of anti-IL-17A abolished the immune privilege of corneal allografts but had no effect on the induction or expression of ACAID. Conclusions. Although orthotopic corneal allografts are strategically located for the induction of ACAID by the sloughing of corneal cells into the AC, the results reported here indicate that the Tregs induced by orthotopic corneal allografts are remarkably different from the Tregs that are induced by AC injection of alloantigen. Although both of these Treg populations promote corneal allograft survival, they display distinctly different phenotypes. PMID:20702818

  12. Prevention of Allogeneic Cardiac Graft Rejection by Transfer of Ex Vivo Expanded Antigen-Specific Regulatory T-Cells

    PubMed Central

    Takasato, Fumika; Morita, Rimpei; Schichita, Takashi; Sekiya, Takashi; Morikawa, Yasuhide; Kuroda, Tatsuo; Niimi, Masanori; Yoshimura, Akihiko

    2014-01-01

    The rate of graft survival has dramatically increased using calcineurin inhibitors, however chronic graft rejection and risk of infection are difficult to manage. Induction of allograft-specific regulatory T-cells (Tregs) is considered an ideal way to achieve long-term tolerance for allografts. However, efficient in vitro methods for developing allograft-specific Tregs which is applicable to MHC full-mismatched cardiac transplant models have not been established. We compared antigen-nonspecific polyclonal-induced Tregs (iTregs) as well as antigen-specific iTregs and thymus-derived Tregs (nTregs) that were expanded via direct and indirect pathways. We found that iTregs induced via the indirect pathway had the greatest ability to prolong graft survival and suppress angiitis. Antigen-specific iTregs generated ex vivo via both direct and indirect pathways using dendritic cells from F1 mice also induced long-term engraftment without using MHC peptides. In antigen-specific Treg transferred models, activation of dendritic cells and allograft-specific CTL generation were suppressed. The present study demonstrated the potential of ex vivo antigen-specific Treg expansion for clinical cell-based therapeutic approaches to induce lifelong immunological tolerance for allogeneic cardiac transplants. PMID:24498362

  13. Cardiac optogenetics

    PubMed Central

    2013-01-01

    Optogenetics is an emerging technology for optical interrogation and control of biological function with high specificity and high spatiotemporal resolution. Mammalian cells and tissues can be sensitized to respond to light by a relatively simple and well-tolerated genetic modification using microbial opsins (light-gated ion channels and pumps). These can achieve fast and specific excitatory or inhibitory response, offering distinct advantages over traditional pharmacological or electrical means of perturbation. Since the first demonstrations of utility in mammalian cells (neurons) in 2005, optogenetics has spurred immense research activity and has inspired numerous applications for dissection of neural circuitry and understanding of brain function in health and disease, applications ranging from in vitro to work in behaving animals. Only recently (since 2010), the field has extended to cardiac applications with less than a dozen publications to date. In consideration of the early phase of work on cardiac optogenetics and the impact of the technique in understanding another excitable tissue, the brain, this review is largely a perspective of possibilities in the heart. It covers the basic principles of operation of light-sensitive ion channels and pumps, the available tools and ongoing efforts in optimizing them, overview of neuroscience use, as well as cardiac-specific questions of implementation and ideas for best use of this emerging technology in the heart. PMID:23457014

  14. Cardiac Surgery

    PubMed Central

    Weisse, Allen B.

    2011-01-01

    Well into the first decades of the 20th century, medical opinion held that any surgical attempts to treat heart disease were not only misguided, but unethical. Despite such reservations, innovative surgeons showed that heart wounds could be successfully repaired. Then, extracardiac procedures were performed to correct patent ductus arteriosus, coarctation of the aorta, and tetralogy of Fallot. Direct surgery on the heart was accomplished with closed commissurotomy for mitral stenosis. The introduction of the heart-lung machine and cardiopulmonary bypass enabled the surgical treatment of other congenital and acquired heart diseases. Advances in aortic surgery paralleled these successes. The development of coronary artery bypass grafting greatly aided the treatment of coronary heart disease. Cardiac transplantation, attempts to use the total artificial heart, and the application of ventricular assist devices have brought us to the present day. Although progress in the field of cardiovascular surgery appears to have slowed when compared with the halcyon times of the past, substantial challenges still face cardiac surgeons. It can only be hoped that sufficient resources and incentive can carry the triumphs of the 20th century into the 21st. This review covers past developments and future opportunities in cardiac surgery. PMID:22163121

  15. CT Lesion Model-Based Structural Allografts: Custom Fabrication and Clinical Experience

    PubMed Central

    Brune, Jan Claas; Hesselbarth, Uwe; Seifert, Philipp; Nowack, Dimitri; von Versen, Rüdiger; Smith, Mark David; Seifert, Dirk

    2012-01-01

    Summary Background Patients requiring knee and hip revision arthroplasty often present with difficult anatomical situations that limit options for surgery. Customised mega-implants may be one of few remaining treatment options. However, extensive damage to residual bone stock may also be present, and in such cases even customised prosthetics may be difficult to implant. Small quantities of lost bone can be replaced with standard allografts or autologous bone. Larger defects may require structural macro-allografts, sometimes in combination with implants (allograft-prosthesis composites). Methods Herein, we describe a process for manufacturing lesion-specific large structural allografts according to a 3D, full-scale, lithographically generated defect model. These macro-allografts deliver the volume and the mechanical stability necessary for certain complex revisions. They are patient-and implant-matched, negate some requirements for additional implants and biomaterials and save time in the operating theatre by eliminating the requirement for intra-operative sizing and shaping of standard allografts. Conclusion While a robust data set from long-term follow-up of patients receiving customised macro-allografts is not yet available, initial clinical experience and results suggest that lesion-matched macro-allografts can be an important component of revision joint surgery. PMID:23800856

  16. Storage conditions do not have detrimental effect on allograft collagen or scaffold performance.

    PubMed

    Abreu, E L; Palmer, M P; Murray, M M

    2009-11-01

    Musculoskeletal allografts are a valuable alternative to autograft tissue in orthopaedic surgeries. However, the effects of the allografts' storage history on the collagen and subsequent allograft scaffold properties are unknown. In this study, we hypothesized that freezing and refrigeration of allografts for 1 week would alter the biologic performance and mechanical properties of the allograft collagen. Allograft collagen was characterized by SDS-PAGE migration pattern, amino acid profile and measured denaturation. Scaffolds made from allograft collagen were evaluated for fibroblast proliferation, platelet activation and scaffold retraction. Collagen gelation kinetics (elastic and inelastic moduli and the viscous-elastic transition point) were also evaluated. Fibroblast proliferation, platelet activation and scaffold retraction results showed only minor, though statistically significant, differences between the storage groups. In addition, there were no significant differences in rheological properties or collagen biochemistry. In conclusion, this study suggests that freezing or refrigeration for 1 week does not appear to have any detrimental effect on the mechanical properties and biologic performance of the collagen within allografts. PMID:19507051

  17. Meniscal replacement using a cryopreserved allograft. An experimental study in the dog.

    PubMed

    Arnoczky, S P; Warren, R F; McDevitt, C A

    1990-03-01

    The medial menisci of 14 adult dogs were replaced using a cryopreserved meniscal allograft. The morphology and metabolic activity of the transplanted allografts were then evaluated using routine histology, a vascular-injection (Spalteholz) technique, and autoroentgenography (Na2(35)SO4 incorporation) at various intervals, from two weeks to six months postoperatively. After transplantation, the allografts retained their normal gross appearance and healed to the capsular tissues of the host by fibrovascular scar tissue. Histologically, the grafts demonstrated a decrease in the number of metabolically active cells after transplantation but had a normal cellular distribution and Na2(35)SO4 uptake by three months. The allografts appeared to function normally after transplantation. Although some degenerative changes were noted in the tibial articular cartilage not covered by the meniscus, the cartilage beneath the allograft appeared normal. PMID:2302876

  18. Endocrine function after immunosuppression of pancreatic allograft by ionizing irradiation in the primate

    SciTech Connect

    Du Toit, D.F.; Heydenrych, J.J.; Smit, B.; Louw, G.; Zuurmond, T.; Laker, L.; Els, D.; Weideman, A.; Wolfe-Coote, S.; Du Toit, L.B.

    1986-05-01

    The object of this preliminary study was to evaluate the endocrine function after heterotopic intraperitoneal segmental pancreatic allotransplantation with unligated duct in irradiated, totally pancreatectomized primates. All allograft recipients received, pre- and peroperative donor-specific blood transfusions and peroperative external irradiation from a linear accelerator; 200 rads was administered weekly and increased to a total dose of 1,500 rads. Pancreatic transplantation was performed between 2 and 6 weeks after completion of irradiation and preoperative blood transfusions. As previously reported, only minimal pancreatic allograft survival was achieved following preoperative irradiation. One recipient remained normoglycaemic for greater than 100 days after transplantation, the longest surviving pancreatic allograft recipient reported from this laboratory. Intravenous glucose tolerance test results in this recipient revealed normoglycaemia, reduced K-value, hypoinsulinaemia, normal glucagon response, reduced C-peptide values, and moderate glucose intolerance. Aortography and electron-microscopic examination of allograft biopsy tissue confirmed the presence of a functioning allograft.

  19. Rat Cytomegalovirus Vaccine Prevents Accelerated Chronic Rejection in CMV-Naïve Recipients of Infected Donor Allograft Hearts.

    PubMed

    Streblow, D N; Hwee, Y K; Kreklywich, C N; Andoh, T; Denton, M; Smith, P; Hart, E; Broekel, R; Pallett, C; Rogers, K; Streblow, A D; Chuop, M; Perry, A; Slifka, M; Messaoudi, I; Orloff, S L

    2015-07-01

    Cytomegalovirus accelerates transplant vascular sclerosis (TVS) and chronic rejection (CR) in solid organ transplants; however, the mechanisms involved are unclear. We determined the efficacy of a CMV vaccine in preventing CMV-accelerated rat cardiac allograft rejection in naïve recipients of CMV+ donor hearts. F344 donor rats were infected with RCMV 5 days prior to heterotopic cardiac transplantation into CMV-naïve or H2 O2 -inactivated RCMV-vaccinated Lewis recipients. Recipients of RCMV-infected donor hearts rejected at POD59, whereas vaccinated recipients exhibited a significantly prolonged time to rejection-POD97, similar to recipients of uninfected donor hearts (POD108). Although all of the donor hearts were preinfected, the vaccinated recipients had lower graft and PBMC viral loads at POD 7 compared to unvaccinated controls. Adoptive T cell and passive antibody transfers from vaccinated Lewis rats into naïve recipients demonstrate that both T-cell and B-cell arms of the adaptive immune response provide protection against CMV-accelerated rejection. Similar findings were obtained when testing three different adjuvants in passive transfer experiments. We have determined that the timing of the vaccine prior to transplantation and the specific adjuvant play critical roles in mediating anti-viral responses and promoting graft survival. CMV vaccination prior to transplantation may effectively increase graft survival. PMID:25766876

  20. Effect of disodium cromoglycate on mast cell-mediated immediate-type allergic reactions.

    PubMed

    Shin, Hye-Young; Kim, Jung-Sook; An, Nyeon-Hyoung; Park, Rae-Kil; Kim, Hyung-Min

    2004-04-23

    We investigated the effect of disodium cromoglycate (DSCG) on mast cell-mediated immediate-type hypersensitivity. DSCG inhibited systemic allergic reaction induced by compound 48/80 dose-dependently. Passive cutaneous anaphylaxis was inhibited by 71.6% by oral administration of DSCG (1 g/kg). When DSCG was pretreated at concentration rang from 0.01-1000 g/kg, the serum histamine levels were reduced in a dose dependent manner. DSCG also significantly inhibited histamine release from rat peritoneal mast cell (RPMC) by compound 48/80. We confirmed that DSCG inhibited compound 48/80-induced degranulation of RPMC by alcian blue/nuclear fast red staining. In addition, DSCG showed a significant inhibitory effect on anti-dinitrophenyl IgE-mediated tumor necrosis factor-alpha production. These results indicate that DSCG inhibits mast cell-mediated immediate-type allergic reaction. PMID:15050425

  1. Effect of microencapsulated ampicillin on cell-mediated immune responses in mice.

    PubMed

    Barsoum, I S; Kopydlowski, K M; Burge, J R; Setterstrom, J A

    1997-11-01

    The effects of free ampicillin, microencapsulated ampicillin anhydrate (MEAA) and antibiotic-free microspheres on the cell-mediated immune response in Balb/c mice were measured by lymphoproliferation assay, delayed-type hypersensitivity (DTH) and cytokine production. Injection into mice for seven consecutive days with equivalent subcutaneous doses of ampicillin, MEAA or placebo microspheres did not produce any consistent change in lymphocyte proliferation nor did it affect DTH responses or interleukin-2 production. Although the production of interleukin-4 in mice treated with ampicillin or MEAA increased compared with the control mice, this increase was not statistically significant. These results indicate that ampicillin and MEAA have similar effects on cell-mediated immunity in mice. PMID:9421323

  2. Challenges and Opportunities for T-Cell-Mediated Strategies to Eliminate HIV Reservoirs

    PubMed Central

    Brockman, Mark A.; Jones, R. Brad; Brumme, Zabrina L.

    2015-01-01

    HIV’s ability to establish latent reservoirs of reactivation-competent virus is the major barrier to cure. “Shock and kill” methods consisting of latency-reversing agents (LRAs) followed by elimination of reactivating cells through cytopathic effects are under active development. However, the clinical efficacy of LRAs remains to be established. Moreover, recent studies indicate that reservoirs may not be reduced efficiently by either viral cytopathic or CD8+ T-cell-mediated mechanisms. In this perspective, we highlight challenges to T-cell-mediated elimination of HIV reservoirs, including characteristics of responding T cells, aspects of the cellular reservoirs, and properties of the latent virus itself. We also discuss potential strategies to overcome these challenges by targeting the antiviral activity of T cells toward appropriate viral antigens following latency. PMID:26483795

  3. Triple drug immunosuppression significantly reduces immune activation and allograft arteriosclerosis in cytomegalovirus-infected rat aortic allografts and induces early latency of viral infection.

    PubMed Central

    Lemström, K. B.; Bruning, J. H.; Bruggeman, C. A.; Lautenschlager, I. T.; Häyry, P. J.

    1994-01-01

    The effect of triple drug immunosuppression (cyclosporine A 10 mg/kg/day+methylprednisolone 0.5 mg/kg/day+azathioprine 2 mg/kg/day) on rat cytomegalovirus (RCMV)-enhanced allograft arteriosclerosis was investigated applying WF (AG-B2, RT1v) recipients of DA (AG-B4, RT1a) aortic allografts. The recipients were inoculated intraperitoneally with 10(5) plaque-forming units of RCMV 1 day after transplantation or left noninfected. The grafts were removed on 7 and 14 days, and at 1, 3, and 6 months after transplantation. The presence of viral infection was demonstrated by plaque assays, cell proliferation by [3H]thymidine autoradiography, and vascular wall alterations by quantitative histology and immunohistochemistry. Triple drug immunosuppression reduced the presence of infectious virus in plaque assays and induced early latency of viral infection. It significantly reduced the peak adventitial inflammatory response (P < 0.05) and reduced and delayed intimal nuclear intensity and intimal thickening (P < 0.05) in RCMV-infected allografts. The proliferative response of smooth muscle cells was reduced by triple drug immunosuppression to 50% of that observed in nonimmunosuppressed RCMV-infected allografts, but still the proliferative peak response was seen at 1 month. Only low level immune activation, ie, the expression of interleukin-2 receptor (P < 0.05) and MHC class II, was observed under triple drug immunosuppression in the adventitia of RCMV-infected allografts, whereas there was no substantial change in the phenotypic distribution of inflammatory cells. In conclusion, although RCMV infection significantly enhances allograft arteriosclerosis also in immunosuppressed allografts, triple drug immunosuppression has no additional detrimental effect but rather a protective one on vascular wall histology. These results further suggest that RCMV-enhanced allograft arteriosclerosis may be an immunopathological condition linked to the host immune response toward the graft and

  4. Results of 32 Allograft-prosthesis Composite Reconstructions of the Proximal Femur

    PubMed Central

    Larousserie, Frédérique; Thévenin, Fabrice; Piperno-Neumann, Sophie; Anract, Philippe

    2009-01-01

    The use of allograft-prosthesis composites for reconstruction after bone tumor resection at the proximal femur has generated considerable interest since the mid1980s on the basis that their use would improve function and survival, and restore bone stock. Although functional improvement has been documented, it is unknown whether these composites survive long periods and whether they restore bone stock. We therefore determined long-term allograft-prosthesis composite survival, identified major complications that led to revision, and determined whether allograft bone stock could be spared at the time of revision. We also compared the radiographic appearance of allografts sterilized by gamma radiation and fresh-frozen allografts. We retrospectively reviewed 32 patients with bone malignancy in the proximal femur who underwent reconstruction with a cemented allograft-prosthesis composite. The allograft-prosthesis composite was a primary reconstruction for 23 patients and a revision procedure for nine. The minimum followup was 2 months (median, 68 months; range, 2–232 months). The cumulative incidence of revision for any reason was 14% at 5 years (95% confidence interval, 1%–28%) and 19% at 10 years (95% confidence interval, 3%–34%). Nine patients (28%) had revision of the reconstruction during followup; four of these patients had revision surgery for infection. Allografts sterilized by gamma radiation showed worse resorption than fresh-frozen allografts. Based on reported results, allograft-composite prostheses do not appear to improve survival compared with megaprostheses. Level of Evidence: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID:19851817

  5. [Production of a dialysable transfer factor of cell mediated immunity by lymphoblastoid cells in continuous proliferation].

    PubMed

    Goust, J M; Viza, D; Moulias, R; Trejdosiewicz, L; Lesourd, B; Marescot, M R; Prévot, A

    1975-01-20

    Four lymphoblastoid cell lines tested in this work contain normally a dialysable moiety having by ultraviolet spectroscopy, column chromatography (Biogel P 10) and chemically the same properties than human dialysable Transfer Factor (TFd), but unable to transfer cell mediated immune response against common antigens. Two of them are able to do so after incubation with minimal amounts of TFd. Production of a molecule identical to human TFd is possible in some lymphoblastoid cell lines after induction with TFd. PMID:808340

  6. Urine Metabolite Profiles Predictive of Human Kidney Allograft Status.

    PubMed

    Suhre, Karsten; Schwartz, Joseph E; Sharma, Vijay K; Chen, Qiuying; Lee, John R; Muthukumar, Thangamani; Dadhania, Darshana M; Ding, Ruchuang; Ikle, David N; Bridges, Nancy D; Williams, Nikki M; Kastenmüller, Gabi; Karoly, Edward D; Mohney, Robert P; Abecassis, Michael; Friedewald, John; Knechtle, Stuart J; Becker, Yolanda T; Samstein, Benjamin; Shaked, Abraham; Gross, Steven S; Suthanthiran, Manikkam

    2016-02-01

    Noninvasive diagnosis and prognostication of acute cellular rejection in the kidney allograft may help realize the full benefits of kidney transplantation. To investigate whether urine metabolites predict kidney allograft status, we determined levels of 749 metabolites in 1516 urine samples from 241 kidney graft recipients enrolled in the prospective multicenter Clinical Trials in Organ Transplantation-04 study. A metabolite signature of the ratio of 3-sialyllactose to xanthosine in biopsy specimen-matched urine supernatants best discriminated acute cellular rejection biopsy specimens from specimens without rejection. For clinical application, we developed a high-throughput mass spectrometry-based assay that enabled absolute and rapid quantification of the 3-sialyllactose-to-xanthosine ratio in urine samples. A composite signature of ratios of 3-sialyllactose to xanthosine and quinolinate to X-16397 and our previously reported urinary cell mRNA signature of 18S ribosomal RNA, CD3ε mRNA, and interferon-inducible protein-10 mRNA outperformed the metabolite signatures and the mRNA signature. The area under the receiver operating characteristics curve for the composite metabolite-mRNA signature was 0.93, and the signature was diagnostic of acute cellular rejection with a specificity of 84% and a sensitivity of 90%. The composite signature, developed using solely biopsy specimen-matched urine samples, predicted future acute cellular rejection when applied to pristine samples taken days to weeks before biopsy. We conclude that metabolite profiling of urine offers a noninvasive means of diagnosing and prognosticating acute cellular rejection in the human kidney allograft, and that the combined metabolite and mRNA signature is diagnostic and prognostic of acute cellular rejection with very high accuracy. PMID:26047788

  7. Injury-induced allograft rejection: A rendezvous with evolution.

    PubMed

    Land, Walter G

    2013-01-01

    Modern immunology, in many ways, is based on three major paradigms: the clonal selection theory, the pattern recognition theory, and the danger/injury theory. The last theory holds that any cell stress and tissue injury, including allograft injury, via induction of damage-associated molecular patterns, induces immunity, including alloimmunity, leading to allograft rejection. On the other hand, the concept precludes that non-self per se induces immunity as proposed by the two former theories. Recently, the danger/injury model has gained considerable acceptance by immunologists, in particular as promoted by new insights into the function of the mammalian gut microbiota, representing a huge assemblage of non-self. Harboring microbiota by hosts is characterized by the fact that harmless noninjurious commensal microbes are protected by innate immunity-based tolerance, whereas intestinal injury-causing pathogenic microbes are immunologically attacked. Plausibility and validity of the danger/injury concept is stringently supported by observations of similar phenomena across the tree of life: the ability of the immune system to discriminate between harmful life-threatening non-self to induce immunity and harmless beneficial non-self to induce tolerance has apparently emerged during evolution. Immune defense responses to injuring/injured non-self (e.g., as reflected by plant resistance to biotic and abiotic stresses on one hand, and allograft rejection on the other hand) as well as immunity-controlled protection of beneficial non-self (e.g., as reflected by microbiota and the fetus of placental mammals) are processes in the interest of evolution and, thus, evolved under pressure across the phylogenetic tree. PMID:25095509

  8. Until they have faces: the ethics of facial allograft transplantation.

    PubMed

    Agich, G J; Siemionow, M

    2005-12-01

    The ethical discussion of facial allograft transplantation (FAT) for severe facial deformity, popularly known as facial transplantation, has been one sided and sensationalistic. It is based on film and fiction rather than science and clinical experience. Based on our experience in developing the first IRB approved protocol for FAT, we critically discuss the problems with this discussion, which overlooks the plight of individuals with severe facial deformities. We discuss why FAT for facial deformity is ethically and surgically justified despite its negative portrayal in the media. PMID:16319234

  9. Renal allograft transplant recipient with ruptured hydatid native kidney.

    PubMed

    Bhat, Riyaz Ahmad; Wani, Imtiyaz; Khan, Imran; Wani, Muzaffar

    2014-07-01

    Echinococcosis of the kidneys in a renal transplant recipient is extremely rare and its occurrence being related to immunosuppression is a possibility which needs further characterisation. Ruptured renal hydatid in a renal transplant recipient is not reported so far to our best knowledge. We present a 42-year-old renal allograft receipient who presented one year after transplant with left flank pain, palpable left lumbar mass and gross hydatiduria. Investigations revealed a ruptured native hydatid kidney. Patient was managed with a combination of chemotherapy and left native nephrectomy and discharged in a satisfactory condition. PMID:25125908

  10. Activation of cell-mediated immunity by Morinda citrifolia fruit extract and its constituents.

    PubMed

    Murata, Kazuya; Abe, Yumi; Futamura-Masudaa, Megumi; Uwaya, Akemi; Isami, Fumiyuki; Matsuda, Hideaki

    2014-04-01

    Morinda citrifolia, commonly known as noni, is a traditional natural medicine in French Polynesia and Hawaii. Functional foods derived from M. citrifolia fruit have been marketed to help prevent diseases and promote good health. The objective of this study was to assess the effects of M. citrifolia fruit on cell-mediated immunity. In the picryl chloride-induced contact dermatitis test, M. citrifolia fruit extract (Noni-ext) inhibited the suppression of cell-mediated immunity by immunosuppressive substances isolated from freeze-dried ascites of Ehrlich carcinoma-bearing mice (EC-sup). In addition, Noni-ext inhibited reduction of IL-2 production in EC-sup-treated mice and activated natural killer cells in normal mice. These results suggest that Noni-ext has multiple effects on the recovery of cell-mediated immunity. Furthermore, we investigated the active principles of Noni-ext and identified an iridoid glycoside, deacetylasperulosidic acid. Oral administration of deacetylasperulosidic acid inhibited the reduction of ear swelling, and also cancelled the suppression of IL-2 production along with the activation of natural killer cells in the same manner as that of Noni-ext. PMID:24868850