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Acute Allograft Rejection (acute + allograft_rejection)
Selected AbstractsDetection of urinary biomarkers for early diagnosis of acute renal allograft rejection by proteomic analysisPROTEOMICS - CLINICAL APPLICATIONS, Issue 6 2009Xiongfei Jia Abstract Acute allograft rejection has been recognized as a major impediment to improved success in renal transplantation. Timely detection and control of rejection are very important for the improvement in long-term renal allograft survival. Thus, biomarkers for early diagnosis of acute rejection are required urgently to clinical medication. This study seeks to search for such biomarker candidates by comparing patients' pre-treatment urinary protein profiling with their post-treatment urinary protein profiling. A total of 15 significantly and consistently down-regulated protein candidates were identified. Among them, alpha-1-antichymotrypsin precursor (AACT), tumor rejection antigen gp96 (GP96) and Zn-Alpha-2-Glycoprotein (ZAG) were selected for further analysis. The results indicated that Western Blot assay of AACT, GP96 and ZAG had advanced the diagnosis time of acute renal rejection by 3 days, compared with current standard clinical observation and laboratory examination. Furthermore, the double-blind detection revealed that the accuracy, sensitivity and specificity of the diagnosis of acute renal rejection of AACT, GP96 and ZAG were 66.67%/100%/60%, 83.33%/100%/80% and 66.67%/100%/60%, respectively, and 100%/100%/100% in combination. In conclusion, urinary protein AACT, GP96 and ZAG could be a set of potential biomarkers for early non-invasive diagnosis of the acute rejection after renal transplantation. [source] Monocytes in the rat: Phenotype and function during acute allograft rejectionIMMUNOLOGICAL REVIEWS, Issue 1 2001Birte Steiniger Summary: Cells of the monocyte/macrophage system originate from the bone marrow, reach the organs via the blood, immigrate through post-capillary venules and further differentiate into organ-specific tissue macrophages. In rats and other species, activated monocytes/macrophages aggravate autoimmune reactions, rejection of non-vascularized allografts and chronic allograft rejection. It is very likely that they also contribute to acute allograft destruction. So far it has been impossible to distinguish the function of monocytes from that of macrophages, because cell phenotypes and their alterations upon activation are ill-defined. We have thus begun to characterize the ex vivo phenotype and function of rat monocytes in the normal state and during renal allograft rejection. Monocytes are recovered from both the central and the marginal blood pool by perfusing either the recipient's circulation or the allograft vasculature. Rat monocytes have a unique surface phenotype. During allograft rejection or after infusion of interferon-, they up-regulate class II MHC molecules, CD161 (NKR-P1A), CD62L and CD8, while CD4 and CD43 are down-modulated. Activated perfusate monocytes exert increased in vitro cytotoxicity against tumour targets, which differs from that of NK cells. We speculate that activated monocytes contribute to kidney allograft destruction by directly damaging endothelial cells or by promoting intravascular coagulation. [source] Older age and liver transplantation: A reviewLIVER TRANSPLANTATION, Issue 8 2004Rajesh N. Keswani Patients older than 60 are undergoing transplantation with increasing frequency. Reports from several transplant centers document that overall short-term patient survival rates in seniors undergoing liver transplantation are comparable to survival rates of younger adults. However, specific subgroups of older patients may not fare as well. Seniors with far-advanced end-stage liver disease are high-risk for liver transplantation and have poor survival rates. In addition, seniors older than 65 have worse outcomes than those who are 60 to 65, and studies have shown increased mortality with increasing age as a continuous variable. On the other hand, the majority of seniors who survive liver transplantation have full or only minimally limited functional status. Preoperative evaluation of older patients for transplantation requires careful screening to exclude cardiopulmonary disease, malignancy, and other diseases of the aged. Paradoxically, seniors may benefit from a senescent immune system, which results in decreased requirements for immunosuppressive drugs, and possibly a lower rate of acute allograft rejection. Despite good overall short-term survival in the elderly, long-term survival may be worse because of an increased rate of long-term complications, such as malignancy and heart disease. In conclusion, although advanced age is a negative risk factor, advanced age alone should not exclude a patient from liver transplantation; however, it mandates thorough pretransplant evaluation and careful long-term follow-up with attention to usual health maintenance issues in the elderly. (Liver Transpl 2004;10:957,967.) [source] Induction therapy: Why, when, and which agent?PEDIATRIC TRANSPLANTATION, Issue 3 2010Leah Krischock Krischock L, Marks SD. Induction therapy: Why, when, and which agent? Pediatr Transplantation 2010: 14:298,313. © 2010 John Wiley & Sons A/S. Abstract:, The long-term outcome of paediatric transplantation has improved over the last decade with an increase in the armamentarium of immunosuppressive agents. However, the battle against the hostile immune response at the time of and after transplantation continues. Induction therapy can reduce early injury, to optimize the long-term allograft survival. The goal of induction immunosuppression in paediatric transplantation is to permit the use of lower doses of maintenance immunosuppressive agents without increased rates of acute allograft rejection and chronic allograft damage. The aim of this review is to summarize the current literature relating to the use of antibody agents for induction in paediatric solid organ transplantation. [source] Increased expression of cytotoxic effector molecules: Different interpretations for steroid-based and steroid-free immunosuppressionPEDIATRIC TRANSPLANTATION, Issue 1 2003Thomas Satterwhite Abstract: Cytotoxic T lymphocyte (CTL) effector molecules have been studied as markers of acute rejection in renal allograft recipients on steroid-based immunosuppression. We hypothesized that basal CTL gene expression may vary with time post-transplantation as well as with different immunosuppression protocols (steroid-based or steroid-free). Variations in CTL gene expression may thus impact on the ability to predict acute allograft rejection. We used the non-invasive method of quantitative competitive-reverse transcription-polymerase chain reaction (QC-RT-PCR) to quantify the amounts of CTL effector molecules (granulysin, GL; perforin, P; granzyme B, GB) in serial peripheral blood lymphocyte (PBL) samples from steroid-free and steroid-based adult and pediatric renal allograft recipients. Patients on both protocols were clinically monitored by protocol biopsies at 1, 3, 6, and 12 months post-transplantation and for graft function at 1 yr post-transplantation in a separate clinical study. Steroid-free patients with stable graft function showed an increase in GL, P, and GB gene expression over time post-transplantation with the increase being seen largely by the first post-transplant month. A further increase in GL expression was noted at the end of the first post-transplant year in the absence of acute rejection, whereas GB and P levels were unchanged. At comparative time-points post-transplantation, CTL genes were found to be higher in steroid-free patients with stable graft function, compared to steroid-based recipients with either clinically stable graft function or acute rejection. This study suggests that levels of CTL gene expression, although important in a steroid-based regimen to monitor the risk of acute rejection, may not be similarly applied in patients on steroid-free immunosuppression. The early increase in levels seen in steroid-free patients appears to correlate with the total absence of steroids. As steroid-free patients seem to have a lower incidence of acute rejection and better long-term graft function at 1 yr, the early increase in CTL genes in the absence of acute rejection may suggest an early adaptive immune activation response, promoting early graft acceptance in this protocol. [source] Type I Interferons Are Not Critical for Skin Allograft Rejection or the Generation of Donor-Specific CD8+ Memory T CellsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2010M. H. Oberbarnscheidt Type I interferons (IFN-I) link innate to adaptive immunity in microbial infection, autoimmune disease and tumor immunity. It is not known whether IFN-I have an equally central role in alloimmunity. Here we tested this possibility by studying skin allograft survival and donor-specific CD8+ T-cell responses in mice that lack the IFN-I receptor (IFN-IR,/,). We found that IFN-IR,/, mice reject fully allogeneic wild-type skin grafts at the same rate as wild-type recipients. Similarly, allograft rejection was not delayed if IFN-IR,/, male skin was transplanted to syngeneic IFN-IR,/, female mice. Quantitation of the male (H-Y)-specific CD8+ T-cell response in these mice revealed normal generation of donor-specific CD8+ effector T cells but fourfold reduction in CD8+ memory T cells. Memory CD8+ T cells generated in the absence of IFN-IR had normal phenotype and recall function, assessed by ex vivo cytokine production and the ability of IFN-IR,/, mice to mount second set rejection. Finally, these memory T cells were maintained at a constant number despite their inability to respond to IFN-1. Our findings indicate that IFN-I cytokines are not critical for acute allograft rejection or for the expansion and differentiation of donor-specific CD8+ T cells into long-lived, functional memory T cells. [source] Upregulation of TNF Receptor Type 2 in Human and Experimental Renal Allograft RejectionAMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2009U. Hoffmann An important role of TNF interacting with TNFR2 has been shown in different models of ischemic, nephrotoxic and immune-mediated renal injury. To systematically evaluate the expression of TNFR2 in renal allograft rejection, we investigated human renal allograft biopsies and, in addition, established an experimental transplantation model in rats to verify the human data under standardized conditions. The expression of TNFR2 was analyzed in 96 human renal allograft biopsies with different disease entities. In a 6-day and a 28-day experimental protocol, TNFR2 was examined in kidney specimens and in the urine of control, uni-nephrectomized and transplanted rats ± cyclosporine treatment (n = 114). In human biopsies and in rat allografts on day 6 with acute allograft rejection, significantly elevated expression of TNFR2 was observed in tubular epithelial cells, podocytes, B cells and monocytes/macrophages. The expression level was associated with renal function. The TNFR2 expression level at day 28 was significantly lower compared to day 6. TNFR2 is markedly upregulated both in human and experimental acute renal allograft rejection. Our data are robust and consistent between different species, suggesting a role for TNFR2 in the early course of rejection. [source] Preferential Priming of Alloreactive T Cells with Indirect ReactivityAMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2009T. V. Brennan The relative contributions of the direct and indirect pathways in alloimmune responses have not been fully elucidated. We report a novel murine TCR transgenic system that can simultaneously track the CD4-direct (CD4-d), CD4-indirect (CD4-i) and CD8-direct (CD8-d) pathways after transplantation. Using this system, we have observed a profoundly greater proliferation of CD4-i T cells relative to CD4-d and CD8-d T cells after transplantation. Furthermore, a much larger proportion of CD4-i T cells attain an effector phenotype. We also analyzed endogenous, wild-type T cells using enzyme-linked immunospot analysis. In naïve mice, T cells with indirect reactivity were undetectable, but T cells with direct reactivity were abundant. However, 10 days after skin or heterotopic heart transplantation, CD4-i T cells comprised approximately 10% of the CD4+ response. Consistent with increased priming of the CD4-i pathway, we observed that the CD4-i T cells were further enriched in the effector cells migrating to the allograft and in memory-like T cells persisting after rejection. Thus, priming of the CD4-i pathway is favored after transplantation, allowing a rare population to rapidly become a major component of the CD4+ T-cell response in acute allograft rejection. The generalizability of this observation to other models remains to be determined. [source] Aging Augments IL-17 T-Cell Alloimmune ResponsesAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2009B. M. Tesar As increasing numbers of elderly patients require solid organ transplantation, the need to better understand how aging modifies alloimmune responses increases. Here, we examined whether aged mice exhibit augmented, donor-specific memory responses prior to transplantation. We found that elevated donor-specific IL-17, but not IFN-,, responses were observed in aged mice compared to young mice prior to transplantation. Further characterization of the heightened IL-17 alloimmune response with aging demonstrated that memory CD4+ T cells were required. Reduced IL-2 alloimmune responses with age contributed to the elevated IL-17 phenotype in vitro, and treatment with an anti-IL-17 antibody delayed the onset of acute allograft rejection. In conclusion, aging leads to augmented, donor-specific IL-17 immune responses that are important for the timing of acute allograft rejection in aged recipients. IL-17 targeting therapies may be useful for averting transplant rejection responses in older transplant recipients. [source] Role of Natural Killer Cell Subsets in Cardiac Allograft RejectionAMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2006M. E. McNerney To achieve donor-specific immune tolerance to allogeneic organ transplants, it is imperative to understand the cell types involved in acute allograft rejection. In wild-type mice, CD4+ T cells are necessary and sufficient for acute rejection of cardiac allografts. However, when T-cell responses are suboptimal, such as in mice treated with costimulation-targeting agents or in CD28-deficient mice, and perhaps in transplanted patients taking immunosuppressive drugs, the participation of other lymphocytes such as CD8+ T cells and NK1.1+ cells becomes apparent. We found that host NK but not NKT cells were required for cardiac rejection. Ly49G2+ NK cells suppressed rejection, whereas a subset of NK cells lacking inhibitory Ly49 receptors for donor MHC class I molecules was sufficient to promote rejection. Notably, rejection was independent of the activating receptors Ly49D and NKG2D. Finally, our experiments supported a mechanism by which NK cells promote expansion and effector function of alloreactive T cells. Thus, therapies aimed at specific subsets of NK cells may facilitate transplantation tolerance in settings of impaired T-cell function. [source] Blockade of Macrophage Colony-Stimulating Factor Reduces Macrophage Proliferation and Accumulation in Renal Allograft RejectionAMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2003Matthew D. Jose Macrophage accumulation within an acutely rejecting allograft occurs by recruitment and local proliferation. To determine the importance of M-CSF in driving macrophage proliferation during acute rejection, we blocked the M-CSF receptor, c-fms, in a mouse model of acute renal allograft rejection. C57BL/6 mouse kidneys (allografts, n = 20) or BALB/c kidneys (isografts, n = 5) were transplanted into BALB/c mice. Anti-c-fms antibody (AFS98) or control Ig (50 mg/kg/day, i.p.) was given daily to allografts from days 0,5. All mice were killed day 6 postoperatively. Expression of the M-CSF receptor, c-fms, was restricted to infiltrating CD68+ macrophages. Blockade of c-fms reduced proliferating (CD68+/BrdU+) macrophages by 82% (1.1 v 6.2%, p < 0.001), interstitial CD68+ macrophage accumulation by 53% (595 v 1270/mm2, p < 0.001), and glomerular CD68+ macrophage accumulation by 71% (0.73 V 2.48 CD68+ cells per glomerulus, p < 0.001). Parameters of T-cell involvement (intragraft CD4+, CD8+ and CD25+ lymphocyte numbers) were not affected. The severity of tubulointerstitial rejection was reduced in the treatment group as shown by decreased tubulitis and tubular cell proliferation. Macrophage proliferation during acute allograft rejection is dependent on the interaction of M-CSF with its receptor c-fms. This pathway plays a significant and specific role in the accumulation of macrophages within a rejecting renal allograft. [source] Successful rescue and maintenance of long-term remission of anti-HLA antibody-mediated acute allograft rejection by rituximab-containing therapy: case reportCLINICAL TRANSPLANTATION, Issue 2008Yasuo Takeuchi Abstract:, A 38-yr-old man with chronic renal failure received a second kidney transplantation from a cadaveric donor. Complement-dependent cytotoxicity cross-match (CDC) was negative against T cells, but positive with the B-cell warm test. Human leukocyte antigen (HLA)-typing showed a one haplo-identical match. The blood type was compatible. He was treated with tacrolimus, mycophenolate mofetil (MMF), methylpredonisolone (MP), and basiliximab as immunosuppressive therapy. A clinical episode graft biopsy and Flow-PRA on post-operative day (POD) 19 showed anti-HLA antibody-mediated acute rejection (AHR). The patient was treated with plasmapheresis (PP). Renal biopsy performed on POD 65 because of re-rise of serum creatinine level showed worsening of renal injury. The patient was treated with rituximab (100 mg/body) with PP and MP pulse therapy, followed by tacrolimus and MMF. Graft function thereafter improved. A renal allograft biopsy specimen on POD 300 and Flow-PRA showed the remission of AHR within one-yr after transplantation. [source] The kinetics of CD154 (CD40L) expression in peripheral blood mononuclear cells of healthy subjects in liver allograft recipients and X-linked hyper-IgM syndromeCLINICAL TRANSPLANTATION, Issue 6 2000A Bartlett The costimulatory pathways play a key role in T cell activation during allograft rejection (AR). Inhibition of the T cell costimulatory molecule CD154 (CD40 ligand) has been effective in producing long-term allograft survival in rodents and non-human primates. The role of the CD40-CD154 pathway in human orthotopic liver transplantation (OLT) has not been examined. Aim: To describe the patterns of CD154, CD69 and CD152 (CTLA4) expression in OLT recipients and to determine their temporal relationship to AR. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from 15 OLT allograft recipients just prior to and for seven consecutive days postoperatively. Gene and protein expression of CD154, CD69 and CD154 were examined by reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry (FC), respectively. Results: FC failed to demonstrate an up-regulation of CD154 and CD152 protein expression during the first postoperative week. Intracellular FC did not increase the sensitivity. There was an increased level of CD3+CD8+ T cells expressing CD69 at the time of rejection compared to that on day 0. RT-PCR demonstrated a sporadic expression of CD154 and CD69 mRNA, with no correlation to episodes of acute cellular rejection. In vitro stimulation of PBMCs revealed an impaired up-regulation of CD154 in patients receiving conventional immunosuppression compared to healthy controls. The assays were validated using positive and negative controls, including a family with X-linked hyper-IgM syndrome. Conclusion: We found no evidence of spontaneous CD154 gene or protein expression in PBMCs associated with acute rejection episodes following OLT. Immunosuppression resulted in impaired responses to ex vivo stimulation. Lymphocyte costimulatory pathways play a critical role in mediating acute allograft rejection. However, we found no evidence of spontaneous CD154 gene or protein expression in PBMCs associated with acute rejection episodes following OLT. Furthermore, stimulation in vitro resulted in less up-regulation of CD154 than for healthy controls. [source] | ||||||||||