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      Xenotransplantation in the 21st Century

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          Xenotransplantation, i.e. transplantation across species, is increasingly being viewed a potential solution to the problem of severe shortage of transplant donors. Clinical application of xenotransplantation is, however, limited in large part by the pre-eminent hurdle of the immune response of the recipient against the graft. This immunologic reaction is mediated initially by natural xenoreactive antibodies, complement and natural killer cells, and later by elicited humoral and cellular immune responses that ultimately lead to graft failure. Progress in understanding the cellular and molecular basis of xenograft rejection has characterized the past few years. Additional hurdles to xenotransplantation include physiologic incompatibility of the transplant and the risk of infections. The recent development of novel strategies to overcome xenograft rejection has brought about great optimism that xenotransplantation may be attainable in the near future.

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          Most cited references 12

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          Allogeneic bone marrow transplantation with co-stimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment.

           V Dong,  J Kurtz,  G Zhao (2000)
          Allogeneic bone marrow transplantation (in immunocompetent adults) has always required cytoreductive treatment of recipients with irradiation or cytotoxic drugs to achieve lasting engraftment at levels detectable by non-PCR-based techniques ('macrochimerism' or 'mixed chimerism'). Only syngeneic marrow engraftment at such levels has been achieved in unconditioned hosts. This requirement for potentially toxic myelosuppressive host pre-conditioning has precluded the clinical use of allogeneic bone marrow transplantation for many indications other than malignancies, including tolerance induction. We demonstrate here that treatment of naive mice with a high dose of fully major histocompatibility complex-mismatched allogeneic bone marrow, followed by one injection each of monoclonal antibody against CD154 and cytotoxic T-lymphocyte antigen 4 immunoglobulin, resulted in multi-lineage hematopoietic macrochimerism (of about 15%) that persisted for up to 34 weeks. Long-term chimeras developed donor-specific tolerance (donor skin graft survival of more than 145 days) and demonstrated ongoing intrathymic deletion of donor-reactive T cells. A protocol of high-dose bone marrow transplantation and co-stimulatory blockade can thus achieve allogeneic bone marrow engraftment without cytoreduction or T-cell depletion of the host, and eliminates a principal barrier to the more widespread use of allogeneic bone marrow transplantation. Although efforts have been made to minimize host pre-treatment for allogeneic bone marrow transplantation for tolerance induction, so far none have succeeded in eliminating pre-treatment completely. Our demonstration that this can be achieved provides the rationale for a safe approach for inducing robust transplantation tolerance in large animals and humans.
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            Transplantation of discordant xenografts: a review of progress.

            Hyperacute rejection, apparently initiated by natural antibodies and complement, has been viewed as an absolute barrier to the xenotransplantation of vascularized grafts between different species. Until recently, little was known about the molecular and physiological basis for this barrier nor was there evidence that the barrier might be more than transiently breached. In this paper Jeffrey Platt, Fritz Bach and colleagues describe a model of hyperacute rejection and propose that, if hyperacute rejection can be averted for a period after transplantation, prolonged xenograft survival will be possible.
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              Human complement regulatory proteins protect swine-to-primate cardiac xenografts from humoral injury.

              The susceptibility of xenografts to hyperacute rejection is postulated to reflect in part failure of complement regulatory proteins (CRPs) to control activation of heterologous complement on graft endothelium. To test this concept, transgenic swine expressing the human CRP decay accelerating factor and CD59 were developed using a novel expression system involving transfer of the proteins from erythrocytes to endothelial cells. Hearts from transgenic swine transplanted into baboons had markedly less vascular injury and functioned for prolonged periods compared to hearts from nontransgenic swine. These results indicate that expression of human CRPs in xenogeneic organs may contribute to successful xenografting and suggest that intercellular protein transfer might be a useful approach for expression of heterologous proteins in endothelial cells.

                Author and article information

                Blood Purif
                Blood Purification
                S. Karger AG
                17 January 2002
                : 20
                : 1
                : 45-54
                Department of Immunology and Clinics of Organ Transplantation, Ospedali Riuniti di Bergamo – Mario Negri Institute for Pharmacological Research, Bergamo, Italy
                46985 Blood Purif 2002;20:45–54
                © 2002 S. Karger AG, Basel

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