T-Lymphocyte-Antigen Interactions in Transplant Rejection

Department of Pediatrics, Stanford University School of Medicine, Calif.
New England Journal of Medicine (Impact Factor: 55.87). 03/1990; 322(8):510-7. DOI: 10.1056/NEJM199002223220805
Source: PubMed
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    • "Nevertheless, allograft rejection represents a common complication, affecting the long-term outcome of the transplanted organ. Many immune cells participate in acute allograft rejection but alloreactive CD4+ and/or CD8+ T lymphocytes usually play the major role [1,2]. The introduction of immunosuppressive drugs has revolutionized the field of transplantation by substantially reducing the frequency of acute rejection [3,4], but these benefits are dampened by the drugs own toxicity, and by their side effects which include opportunistic infections and virus-induced cancers that have been found to occur at an increased frequency after organ transplantation [5]. "
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    ABSTRACT: Although transplantation is the common treatment for end-stage renal failure, allograft rejection and marked morbidity from the use of immunosuppressive drugs remain important limitations. A major challenge in the field is to identify easy, reliable and noninvasive biomarkers allowing the prediction of deleterious alloreactive immune responses and the tailoring of immunosuppressive therapy in individuals according to the rejection risk. In this study, we first established that the expression of the RC isoform of the CD45 molecule (CD45RC) on CD4 and CD8 T cells from healthy individuals identifies functionally distinct alloreactive T cell subsets that behave differently in terms of proliferation and cytokine secretion. We then investigated whether the frequency of the recipients CD45RC T cell subsets before transplantation would predict acute graft rejection in a cohort of 89 patients who had undergone their first kidney transplantation. We showed that patients exhibiting more than 54.7% of CD8 CD45RC(high) T cells before transplantation had a 6 fold increased risk of acute kidney graft rejection. In contrast, the proportions of CD4 CD45RC T cells were not predictive. Thus, a higher risk of acute rejection of human kidney allografts can be predicted from the level of CD45RC expressed by the recipients' CD8 T cells.
    Full-text · Article · Jul 2013 · PLoS ONE
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    • "The ZP has been suggested to simply act as a physical barrier against the rejection of the human pre-embryo (Ewoldsen et al., 1987). However, many types of immune cells transit through similar types of physical barriers during the rejection of a foreign organ transplant (Krensky et al., 1990). Human ZP glycoproteins express N-glycans terminated with multivalent sialyl-Lewisx sequences (SLEX) that mediate sperm binding (Figure 1) (Pang et al., 2011). "
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    ABSTRACT: Like other mucosal surfaces (e.g., the gastrointestinal tract, the respiratory tract), the human female reproductive tract acts as an initial barrier to foreign antigens. In this role, the epithelial surface and subepithelial immune cells must balance protection against pathogenic insults against harmful inflammatory reactions and acceptance of particular foreign antigens. Two common examples of these acceptable foreign antigens are the fetal allograft and human semen/sperm. Both are purposely deposited into the female genital tract and appropriate immunologic response to these non-self antigens is essential to the survival of the species. In light of the weight of this task, it is not surprising that multiple, redundant and overlapping mechanisms are involved. For instance, cells at the immunologic interface between self (female reproductive tract epithelium) and non-self (placental trophoblast cells or human sperm) express glycosylation patterns that mimic those on many metastatic cancer cells and successful pathogens. The cytokine/chemokine milieu at this interface is altered through endocrine and immunologic mechanisms to favor tolerance of non-self. The "foreign" cells themselves also play an integral role in their own immunologic acceptance, since sperm and placental trophoblast cells are unusual and unique in their antigen presenting molecule expression patterns. Here, we will discuss these and other mechanisms that allow the human female reproductive tract to perform this delicate and indispensible balancing act.
    Full-text · Article · Feb 2013 · Frontiers in Immunology
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    • "Recipient CD4+ T cell recognition of alloantigen is the central and primary event that ultimately leads to the initiation of allograft rejection [1-3]. It is now well established that alloactivation of T cells occurs via two distinct pathways [4-10]. "
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    ABSTRACT: Background In the direct pathway, T cells recognize intact donor major histocompatability complexes and allogeneic peptide on the surface of donor antigen presenting cells (APCs). Indirect allorecognition results from the recognition of processed alloantigen by self MHC complexes on self APCs. In this study, we wished to evaluate the relative contribution of different intragraft cells to the alloactivation of nave and memory T cells though the direct and the indirect pathway of allorecognition. Methods The processing of membrane fragments from IFN-treated single donor endothelial cells (EC), fibroblasts or renal epithelial cells (RPTEC) was evaluated by DiOC labeling of each cell type and flow cytometry following interaction with PBMC. Direct pathway activation of nave CD45RA+ or memory CD45RO+ CD4+ T cells was evaluated following coculture with IFN-treated and MHC class II-expressing EC, fibroblasts or RPTEC. Indirect pathway activation was assessed using CD45RA+ or CD45RO+ CD4+ T cells cocultured with autologous irradiated APCs in the absence or presence of sonicates derived from IFN-treated allogeneic EC, fibroblasts or RPTEC. Activation of T cells was assessed by [3H]thymidine incorporation and by ELISpot assays. Results We find that CD14+ APCs readily acquire membrane fragments from fibroblasts and RPTEC, but fail to acquire membrane fragments from intact EC. However, APCs process membranes from EC undergoing apoptosis.There was a notable direct pathway alloproliferative response of CD45RO+ CD4+ T cells to IFN-treated EC, but not to fibroblasts or RPTEC. Also, there was a minimal direct pathway response of CD45RA+ CD4+ T cells to all cell types. In contrast, we found that both CD45RA+ and CD45RO+ CD4+ T cells proliferated following coculture with autologous APCs in the presence of sonicates derived from IFN-treated EC, fibroblasts or RPTEC. By ELISpot, we found that these T cells stimulated via the indirect pathway also produced the cytokines IFN, IL-2, IL-4 and IL-5. Conclusions Recipient APCs may readily process membrane fragments from allogeneic intragraft cells, but not from EC unless they are undergoing apoptosis. This processing is sufficient for indirect pathway alloactivation of both CD45RA+ and CD45RO+ CD4+ T cells. Only graft vascular EC mediate direct pathway reactivation of CD4+ T cells.
    Full-text · Article · Apr 2012
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