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Allograft Transplantation (allograft + transplantation)
Selected AbstractsAn Immunomodulatory Role for Follistatin-Like 1 in Heart Allograft TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 11 2008J. B. Le Luduec Donor-specific tolerance to heart allografts in the rat can be achieved by donor-specific blood transfusions (DST) before transplantation. We have previously reported that this tolerance is associated with strong leukocyte infiltration, and that host CD8+ T cells and TGF, are required. In order to identify new molecules involved in the induction phase of tolerance, we compared tolerated and rejected heart allografts (suppressive subtractive hybridization) 5 days after transplantation. We identified overexpression of Follistatin-like 1 (FSTL1) transcript in tolerated allografts compared to rejected allografts or syngeneic grafts. We show that FSTL1 is overexpressed during both the induction and maintenance phase of tolerance, and appears to be specific to the tolerance model induced by DST. Analysis of graft-infiltrating cells revealed predominant expression of FSTL1 in CD8+ T cells from tolerated grafts, and depletion of these cells prior to transplantation abrogated FSTL1 expression and heart allograft survival. Moreover, overexpression of FSTL1 by adenovirus gene transfer in vivo significantly prolonged allograft survival in association with inhibition of the proinflammatory cytokines, IL6, IL17 A and IFN,. Taken together, these results suggest that FSTL1 could be an active component of the mechanisms mediating heart allograft tolerance. [source] A Case of Human Intramuscular Adrenal Gland Transplantation as a Cure for Chronic Adrenal InsufficiencyAMERICAN JOURNAL OF TRANSPLANTATION, Issue 2 2010E. Grodstein Intramuscular endocrine gland transplantation has been well described as it pertains to parathyroid autotransplantation; however, transplantation of the adrenal gland is less well characterized. While adrenal autotransplantation in the setting of Cushing's disease has been described, intramuscular adrenal allotransplantation as a cure for adrenal insufficiency to our knowledge has not been previously carried out. Current treatment for adrenal insufficiency leaves patients without diurnal variation in cortisol release and susceptible to the detrimental effects of chronic hypercortisolism. We describe here the case of a 5-year-old girl with renal failure who had adrenal insufficiency following fulminant meningococcemia that led to requirements for both stress-dose steroid and mineralocorticoid replacement. Ten months after the onset of her disease, she received a simultaneous renal and adrenal gland transplant from her mother. The adrenal gland allograft was morselized into 1 mm3 segments and implanted into three 2 cm pockets created in her rectus abdominis muscle. Three years after surgery, her allograft remains fully functional, responding well to adrenocorticotropin hormone stimulation and the patient does not require any steroid or mineralcorticoid supplementation. We believe this case represents the first description of successful functional intramuscular adrenal allograft transplantation with long-term follow up as a cure for adrenal insufficiency. [source] Purified Eicosapentaenoic Acid Induces Prolonged Survival of Cardiac Allografts and Generates Regulatory T CellsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 6 2009D. Iwami Fish oil, which is rich in eicosapentaenoic acid (EPA), has been found to have immunomodulatory effects. We examined whether administration of purified EPA affected survival of fully mismatched murine cardiac allografts. Hearts from C57BL/10 (H-2b) mice were transplanted into CBA (H-2k) recipients treated with one intraperitoneal dose of purified EPA the day of transplantation. Untreated CBA recipients and recipients given 0.1 g/kg of EPA rejected C57BL/10 hearts (median survival time [MST], 8 and 13 days, respectively). With a 1.0 g/kg dose of EPA, graft survival was markedly prolonged (MST >100 days). To determine whether regulatory cells were generated, naïve mice (secondary recipients) underwent adoptive transfer of splenocytes from EPA-treated primary recipients and cardiac allograft transplantation. Adoptive transfer of whole, CD4+ and CD4+CD25+ splenocytes from EPA-treated recipients induced indefinite survival in secondary recipients. Flow cytometry showed that the CD4+CD25+ cells were Foxp3+. In reverse transcriptase-polymerase chain reaction (RT-PCR) studies, the expression of peroxisome proliferator-activated receptor , (PPAR,) mRNA was upregulated by EPA treatment. A PPAR, antagonist abrogated the prolongation of graft survival induced by EPA treatment (MST, 13 days). Thus, in our model, purified EPA induced prolonged survival of fully mismatched cardiac allografts and generated regulatory T cells dependent on PPAR, activation. [source] Disruption of Murine Cardiac Allograft Acceptance by Latent CytomegalovirusAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2009C. H. Cook 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-, 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. [source] Risk of diarrhoea in a long-term cohort of renal transplant patients given mycophenolate mofetil: the significant role of the UGT1A8*2 variant alleleBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2010Jean-Baptiste Woillard WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Mycophenolate mofetil (MMF), the most widely used drug in allograft transplantation, is subject to hepatic and intestinal glucuronidation and entero-hepatic cycling. , Diarrhoea is its most frequent adverse event leading to non-compliance, treatment interruption and ultimately to an increased rate of acute rejection. , Cyclosporin reduces the biliary excretion of mycophenolate metabolites, presumably by inhibiting the efflux transporter MRP2. , When combined with MMF, cyclosporin reduces the incidence of diarrhoea, suggesting the role played by biliary excretion of mycophenolate glucuronides in this adverse event. WHAT THIS STUDY ADDS , In a long-term cohort of renal transplant patients on MMF, the two factors significantly associated with a reduced incidence of diarrhoea were the co-medication with cyclosporin (as opposed to tacrolimus or sirolimus) and the *2 variant allele of the intestinal UGT1A8. , Polymorphisms in the other UDP-glucuronosyl-transferases and MRP2 were not significant. AIM In renal transplant patients given mycophenolate mofetil (MMF), we investigated the relationship between the digestive adverse events and polymorphisms in the UGT genes involved in mycophenolic acid (MPA) intestinal metabolism and biliary excretion of its phase II metabolites. METHODS Clinical data and DNA from 256 patients transplanted between 1996 and 2006 and given MMF with cyclosporin (CsA, n = 185), tacrolimus (TAC, n = 49) or sirolimus (SIR, n = 22), were retrospectively analysed. The relationships between diarrhoea and polymorphisms in UGT1A8 (*2; 518C>G, *3; 830G>A), UGT1A7 (622C>T), UGT1A9 (,275T>A), UGT2B7 (,840G>A) and ABCC2 (,24C>T, 3972C>T) or the co-administered immunosuppressant were investigated using the Cox proportional hazard model. RESULTS Multivariate analysis showed that patients on TAC or SIR had a 2.8 higher risk of diarrhoea than patients on CsA (HR = 2.809; 95%CI (1.730, 4.545); P < 0.0001) and that non-carriers of the UGT1A8*2 allele (CC518 genotype) had a higher risk of diarrhoea than carriers (C518G and 518GG genotypes) (HR = 1.876; 95%CI (1.109, 3.175); P = 0.0192). When patients were divided according to the immunosuppressive co-treatment, a significant effect of UGT1A8*2 was found in those co-treated with CsA (HR = 2.414; 95%CI (1.089, 5.354); P = 0.0301) but not TAC or SIR (P = 0.4331). CONCLUSION These results suggest that a possible inhibition of biliary excretion of MPA metabolites by CsA and a decreased intestinal production of these metabolites in UGT1A8*2 carriers may be protective factors against MMF-induced diarrhoea. [source] Rationale and timeliness for IL-1,-targeted therapy to reduce allogeneic organ injury at procurement and to diminish risk of rejection after transplantationCLINICAL TRANSPLANTATION, Issue 3 2010Alan A. Wanderer Wanderer AA. Rationale and timeliness for IL-1,-targeted therapy to reduce allogeneic organ injury at procurement and to diminish risk of rejection after transplantation. Clin Transplant 2010: 24: 307,311. © 2010 John Wiley & Sons A/S. Abstract:, Ischemia-reperfusion injury (IRI) involving allograft transplantation and procured organs may in part be induced by stimulation of a newly described innate pro-inflammatory immune system (i.e., NALP-3-inflammasome), which can cause secretion of IL-1, and subsequent neutrophilic inflammation. Ischemia and/or hypoxia/anoxia can induce anaerobic metabolism with metabolic acidosis and subsequent development of danger signals known to stimulate IL-1, secretion from the NALP-3 inflammasome. Observations from IRI studies and hereditary auto-inflammatory syndromes with NALP-3 inflammasome mutations suggest that IL-1, secretion can induce robust neutrophilic inflammation that is responsive to IL-1, targeted therapy. Based on these observations and data from transplantation studies, it may be timely to consider commercially available IL-1, targeted biologic therapy to improve allograft tolerance and viability of procured organs. [source] | ||||||||||