P F Halloran

..Thus IFN-gamma acting on IFN-gamma receptors in allografts promotes infiltration and MHC induction but prevents early thrombosis, congestion, and necrosis...

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..We describe here some critical problems with GSEA and propose an alternative method by extending the individual-gene analysis method, Significance Analysis of Microarray (SAM), to gene-set analyses (SAM-GS)...

..This is probably a local action of IFN-gamma produced in large quantities in the allograft...

..The active injury-repair response is the strongest correlate of organ function and future progression to failure, but should always prompt a search for the initiating injury or disease...

..Thus the molecular phenotype is best described in terms of three elements: specific diseases, including rejection; the injury-repair response and the cumulative burden of injury...

..Thus TCMR is a cognate recognition-based process that creates local inflammation and epithelial dedifferentiation, stereotyped nephron responses, and tubulitis, and if untreated causes irreversible nephron loss...

..Together with previous graft survival studies, these results indicate that the granule-associated cytotoxic mechanisms of T cells are not the effectors of T-cell-mediated allograft rejection...

..Organ transplant practice will probably change considerably as these agents become available...

..Thus, the strategy of using DSASTs in the biopsy to identify mechanism-related transcripts in biopsies from patients with clinical phenotypes indicates the selective involvement of NK cells in ABMR...

..We suggest that alloimmune effector T cells mediate epithelial injury by contact-independent mechanisms related to delayed type hypersensitivity, followed by invasion of the altered epithelium to produce tubulitis...

..We propose careful assessment of de novo DSA, particularly against class II, be performed in all late kidney transplant biopsies...

..Thus any degree of microcirculation inflammation in late kidney transplant biopsies strongly indicates presence of DSA and predicts progression to graft failure...

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..Thus, in vivo, IRF-1 plays a major role in basal and induced class I expression and in induction of class II by IFN-gamma, probably via CIITA induction...

..Thus while detecting T cell-mediated inflammation, the molecular phenotype of early protocol biopsies mostly reflects the injury-repair response to implantation stresses, and has little relationship to future events and outcomes...

..The major cause of late kidney transplant failure is antibody-mediated microcirculation injury, but detection of this phenotype requires new diagnostic criteria...

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..Interpretation of lesions should reflect these associations...

..Thus CIITA-deficient kidneys have no basal and induced class II expression but display intense induction of class I expression, and evoke typical rejection lesions, although some indices of infiltration are reduced at day 21...

..We conclude that loss of renal transcripts indicates an early stage of T-cell mediated alloimmune injury that later progresses to pathologic lesions such as tubulitis...

..This prospective cohort indicates that many actual failures after indication biopsies manifest phenotypic features of antibody-mediated or mixed rejection and also underscores the major role of nonadherence...

..The renal expression of Ly-6 is similar to that of CD59 in the human kidney, supporting the suggestion that these proteins are closely related...

..Thus FOXP3 mRNA expression is a time-dependent feature of inflammatory infiltrates in renal tissue. We hypothesize that time-dependent entry of FOXP3-positive cells represents a mechanism for stabilizing inflammatory sites...

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..Although the mechanisms and causal relationships remain to be determined, high AMA transcript levels in rejecting allografts are strongly associated with and may be a consequence of parenchymal deterioration similar to ATN...

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..The dynamic range of both platforms was sufficient to detect the relevant changes in rejection...

..PBTs represent a quantitative measure of the inflammatory disturbances in organ transplants, and a new window on the mechanisms of these changes...

..The alloresponse strikingly and selectively increased the late IRITs but not the IRITs that peak early, indicating that rejection triggers parenchymal responses similar to those in ATN...

..The most important predictor of outcome is the diagnosis of a progressive disease...

..We propose that donor class Ia or Ib products are needed to trigger inhibitory receptors on effector T cells...

..Thus, the total i-score is superior to the current Banff i-score and most diagnostic Banff categories in predicting outcome and assessing the molecular phenotype of renal allografts...

..Expression of BATs and IGTs correlated with renal function, but this relationship was due to differences in early versus late biopsies: BATs and IGTs were not related to function or future function after correcting for time...

..Thus, Ifng may control T helper type 2 (Th2) cell inflammation by induction of class I products...

..Thus QCAT sets robustly measure the burden of CTL and effector memory T cells in biopsies as %CTL RNA, in a manner not achieved by measurement of individual transcripts...

..Both molecular measurements and histopathology offer opportunities for more precise assignment of these cases after clinical validation...

..Therefore, local injury was equally effective in both wild-type and GKO mice with equivalent cytokine and MHC mRNA induction, proving that local tissue injury can induce MHC expression by non-IFN-gamma factors...

..This combination of pathologic, clinical and molecular features constitutes the typical or canonical T-cell-mediated rejection...

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..We propose that in TCMR, interstitial effector T cells mediate parenchymal injury by inflammatory mechanisms that require neither the perforin-granzyme nor the Fas-Fas ligand cytotoxic mechanisms...

..CIITA induction by IFN-gamma was partially sensitive to cycloheximide, suggesting that another protein is required for CIITA induction. The data suggest that CIITA is a major regulator of basal and induced class II expression in vivo...

..Thus, in renal allografts, allorecognition by T cells occurs in perivascular sites by day 1, but alloimmune parenchymal damage begins at day 3, coinciding with the emergence of the interstitial T-cell-MMDC infiltrate...

..Scarring is associated with a distinct pattern of inflammatory molecules, including B cell/immunoglobulin but particularly mast cell-associated transcripts, which correlated with poor outcomes...

..Results are expected to be presented at the 12th Banff meeting to be held in 2013 in Brazil. No change to the Banff classification occurred in 2011...

..Participation of B cells in allograft rejection and genomics markers of rejection were also major subjects addressed by the conference...

..The remaining 27%, mostly BD, may be a different disease or a stage in which A and C are undetectable...

..This study serves as a foundation for the interpretation of CATs in rejecting allografts and highlights the extensive sharing of CATs among CD4(+) CTL, CD8(+) CTL and effector memory T cells...

..The fact that MHC class I is induced in endothelium may be useful therapeutically for reduction of immune recognition in transplantation...

..03) but not with clinical or histopathologic scores. The transcriptome reflects kidney quality and susceptibility to DGF better than available clinical and histopathological scoring systems...

..The local increase in MHC class I and II in parenchymal cells in response to injury reflects both IFN-gamma and a non-IFN-gamma factor. Systemic MHC class I and II induction is almost exclusively due to IFN-gamma...

..Thus, the reduction of CN activity observed in CsA-treated patients is accompanied by a similar degree of reduction in lymphocyte gene activation, and accounts for the immunosuppression observed...

..The threat is the degree to which the renal transplant community will participate in and support this process...

..Expression of CATs was established before diagnostic lesions and remained remarkably consistent through day 42 despite massive alterations in the pathology, and probably reflects T cells recruited to the graft...

..Thus each cyclosporine dose produces rapid and wide-spread inhibition of calcineurin in tissues, with differences in total susceptibility of each tissue...

..The most important recent advance has been the emergence of potent immunosuppressive drug combinations that have greatly reduced rejection...

..Transplant glomerulopathy has a serious prognosis but is less frequent in patients on newer immunosuppression, unlike recurrent IgAN...

..The findings suggest a role for somatic cell senescence mechanisms in progression of GD...

..94%) than C4d. The results were validated in independent set of 82 kidneys. High renal endothelial transcript expression in patients with alloantibody is indicator of active antibody-mediated allograft damage and poor graft outcome...

..The molecular basis of renal aging is not completely understood...

..This article reviews recent molecular studies in kidney allograft tissues that decipher molecular burden and mechanisms of ABMR, leading to discovery of a new phenotype: 'C4d-negative ABMR'...

..Thus in rejecting kidney transplants, IRF-1 in the graft mediates MHC induction, but it also mediates resistance to necrosis, an effect that could be crucial to permit success in interventions against rejection...

..Thus, in biopsies performed for clinical reasons, functional disturbances are reflected in transcriptome changes representing tissue injury and dedifferentiation but not the inflammatory burden...

..In an independent validation set, the molecular risk score was the only predictor of graft loss. Thus, the molecular risk score reflects active injury and is superior to either scarring or function in predicting graft failure...

..Thus, aging, injury and disease may share common pathways involving somatic cell senescence...

..These findings support a model in which the TEC damage induces loss of epithelial features and expression of fibroblast features, as a common pathway of deterioration by either immunologic or nonimmunologic processes...

..Thus, measurement of injury-induced transcripts at the time of implantation improves the prediction of early kidney dysfunction, but risk prediction may fail when old kidneys are transplanted into old recipients...

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..These results suggest that the product of this transcript may be functionally relevant...

..Thus IFN-gamma has diverse and potentially contradictory effects on organ allograft survival, acting both on the immune system and on the graft itself, the net effect depending on the graft type and the time post-transplant...

..We previously showed that human kidney cortex displays telomere shortening with age. In this study, we compared the structural and functional changes in rat kidney with age to phenomena associated with cellular senescence in vitro...

..The diagnosis of late ongoing AMR raises the possibility of treatment to suppress the alloantibody, but efficacy of the available treatments requires further study...

..Thus IFN-gamma mediates a direct effect on rejecting liver allografts that reduces hemorrhage and necrosis, induces MHC expression, and is absolutely required for spontaneous acceptance...

..Despite continued calcineurin inhibitor use, late improvement in function now occurs in many cadaver kidney transplants, suggesting a previously unappreciated capacity for functional adaptation...

..In contrast, rejection affects survival and function, but it is not primarily determined by the characteristics of the donor tissue. Graft survival reflects both of these influences...

..In the present study, we evaluated the relationship between renal age in humans and a number of phenomena associated with cellular senescence in vitro...

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..Immunosuppressive regimens with the fewest possible toxic effects are desirable for transplant recipients. This study evaluated the efficacy and relative toxic effects of four immunosuppressive regimens...

..Belatacept may preserve the glomerular filtration rate and reduce the rate of chronic allograft nephropathy...

..Future meetings are planned for 2005 (Edmonton), 2007 and 2009, with active ongoing Internet discussion between meetings...

..78 (0.64-0.95), p = 0.0110 during 1999-2002 (compared to 1984-1989). We conclude that the rate of decline in allograft function after kidney transplantation has improved, suggesting that stable, long-term function may be achievable...

..The level of function and the slope of the loss of function should be separately determined. This approach can be applied both in research and in clinical practice, and can be adapted to other organ transplants...

..This supports the concept that restoration of cardiac normoxia by mechanical unloading, particularly in the subendocardium, may be in part responsible for the phenomenon of 'reverse remodelling'...

..This creates a feedback loop in which effectors produce IFN-gamma that limits IL-2 production which in turn limits CTL generation...

..This classification represents a working formulation, to be revisited as additional data accumulate in this important area of renal transplantation...