New Insights Into Mechanisms of Allograft Rejection
Understanding of the molecular basis of organ allograft rejection has increased tremendously in the past decade. Insight into the nature of the alloantigen and the mechanisms underlying T cell recognition, activation, and differentiation provide novel targets for immunotherapy. Appreciation of the role that peptides present in the human leukocyte antigen groove play in allorecognition provides a new target for synthetic peptide therapy. Elucidation of signal transduction pathways downstream from the T-cell receptor helps to explain the mechanism of action of immunosuppressive agents and impacts the design of new drugs. An understanding of the role of costimulatory molecules, such as CD28, has given rise to new therapies, such as CTLA4-Ig. Information about the mechanisms of cytotoxicity, chemoattraction, and vascular biology similarly has provided new targets for rational drug design. This article highlights new insights into the mechanism of allograft rejection relevant to the design of new immunotherapies.
Available from: Jason H Huang
- "The idea that MHC antigen expressing cells, such as Schwann cells, are the immunogenic components that cause this conduit rejection has been proposed before . We are also attributing our results to the acute immune response involved with MHC antigens and the resulting lymphocyte immune response described by Pattison et al . "
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ABSTRACT: A major problem hindering the development of autograft alternatives for repairing peripheral nerve injuries is immunogenicity. We have previously shown successful regeneration in transected rat sciatic nerves using conduits filled with allogeneic dorsal root ganglion (DRG) cells without any immunosuppression. In this study, we re-examined the immunogenicity of our DRG neuron implanted conduits as a potential strategy to overcome transplant rejection. A biodegradable NeuraGen® tube was infused with pure DRG neurons or Schwann cells cultured from a rat strain differing from the host rats and used to repair 8 mm gaps in the sciatic nerve. We observed enhanced regeneration with allogeneic cells compared to empty conduits 16 weeks post-surgery, but morphological analyses suggest recovery comparable to the healthy nerves was not achieved. The degree of regeneration was indistinguishable between DRG and Schwann cell allografts although immunogenicity assessments revealed substantially increased presence of Interferon gamma (IFN-γ) in Schwann cell allografts compared to the DRG allografts by two weeks post-surgery. Macrophage infiltration of the regenerated nerve graft in the DRG group 16 weeks post-surgery was below the level of the empty conduit (0.56 fold change from NG; p<0.05) while the Schwann cell group revealed significantly higher counts (1.29 fold change from NG; p<0.001). Major histocompatibility complex I (MHC I) molecules were present in significantly increased levels in the DRG and Schwann cell allograft groups compared to the hollow NG conduit and the Sham healthy nerve. Our results confirmed previous studies that have reported Schwann cells as being immunogenic, likely due to MHC I expression. Nerve gap injuries are difficult to repair; our data suggest that DRG neurons are superior medium to implant inside conduit tubes due to reduced immunogenicity and represent a potential treatment strategy that could be preferable to the current gold standard of autologous nerve transplant.
Available from: Andreas H Wagner
- "Acute rejection episodes are known to predispose for development of chronic rejection and chronic allograft dysfunction    and, therefore, also have a major impact on long-term results after solid organ transplantation. Mechanistically, acute allograft rejection is the result of an allogeneic, primarily T-cell-dependent response of the recipient's immune system towards the graft   . "
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ABSTRACT: Acute myocardial rejection is a cell-mediated process characterized by increased leukocyte recruitment into the graft myocardial tissue. Transcription factors like STAT-1 and AP-1 are critically involved in this process by regulating vascular adhesion molecule expression. The aim of our study was to investigate the effect of decoy oligodeoxynucleotide (dODN) treatment targeting transcription factors AP-1 and STAT-1 on acute cardiac allograft rejection in a rat transplant model.
Wistar-Furth (WF) cardiac allografts were transplanted into Lewis (LEW) rats after perfusion with STAT-1 or AP-1 dODN solution (5 micromol/l), buffer or the corresponding mutant control ODNs. Grafts were harvested and processed for histologic and immunohistochemical evaluation.
As demonstrated by fluorescence dye-labelled dODN, exposure of the grafts to the dODNs during 45 min of warm ischemia resulted in a dominant uptake of naked DNA by the graft endothelium. Treatment with AP-1 and STAT-1 dODNs, but not with vehicle or the control dODNs, significantly prolonged cardiac allograft survival by approximately 40% from 5.6+/-0.5 days to 7.8+/-1.3 days and 7.4+/-0.5 days, respectively (mean+/-S.D., p<0.01, n=5 in each group). Immunohistochemical examination on days 1, 3 and 6 revealed a marked reduction of infiltrating leukocytes (AP-1 dODN: 85%, STAT-1 dODN: 50%), namely T-cells, in the dODN-perfused grafts at day 3 post transplantation. In addition, as demonstrated by immunohistochemical analysis, endothelial expression of ICAM-1 and VCAM-1 was found to be markedly reduced in dODN-treated grafts.
Both AP-1 and STAT-1 dODN treatments suppress graft endothelial adhesion molecule expression, reduce graft infiltration and in turn significantly delay acute rejection. The utilization of dODNs in the cardioplegic solution might be a novel strategy to protect transplanted organs from early damage during transplantation, to preserve organ function and bridge the critical phase after transplantation when standard immunosuppression is not yet completely effective.
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ABSTRACT: Renal transplantation is the treatment of choice in children with end stage renal disease. Advances in organ retrieval and preservation, improved surgical techniques and postsurgical care, newer immunosuppressive drugs and prevention and treatment of infections have significantly improved survival of the renal allograft. The absolute requirements for a transplant are compatible blood group and a negative cytotoxic crossmatch. HLA identical grafts have a longer half-life than those that are less well matched. The immunosuppressive drugs most often used are cyclosporin A (or tacrolimus), azathioprine (or mycophenolate mofetil) and prednisone. Complications following transplantation include episodes of acute rejection, serious bacterial and viral infections, hypertension and recurrence of primary disease in the allograft. Each centre must have standard protocols for pre-transplant evaluation, and monitoring during surgery and in the post-operative period. Socio-economic factors should be evaluated before offering renal transplantation to children in developing countries.
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