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Excerpt
Bartholomew AM, Powelson J, Sachs DH, Bailin M, Boskovic S, Colvin R, Hong HZ, Johnson M, Kimikawa M, LeGuern A, Meehan S, Sablinski T, Wee SL, and Cosimi AB.
The article by Bartholomew et al. is the most recent update on the mechanisms required to achieve xenograft tolerance and is based on many years of efforts by the Boston group to achieve allograft tolerance (1).
Using a complex conditioning regime consisting of antithymocyte globulin, non-lethal total body irradiation, thymic irradiation, a splenectomy followed by simultaneous bone marrow and renal transplants, and a 1-month course of cyclosporin A, mixed lymphohematopoietic chimerism and renal allograft tolerance has been achieved. Although this form of therapy is not currently clinically applicable in human allotransplantation, it has provided major insights into the mechanisms of allograft rejection, and it highlights the extent to which the immune system needs to be manipulated to achieve long term transplant survival. The potential benefits of this system are greatly reducing the long term mortality and morbidity associated with immunosuppressive therapy and reducing the cost to the healthcare system.
Using the established regime for achieving allograft tolerance, Bartholomew et al. pose the question of whether tolerance can be achieved using the same preconditioning methods in a concordant primate xenograft model. The answer clearly is no. The study immediately dispels several assumptions regarding xenotransplantation between concordant species combinations. First, concordant species combinations, which by definition do not have preformed xenoreactive antibodies, will be met with a cell-mediated form of rejection similar to allograft rejection. Second, the currently available immunosuppressive agents will prevent cell-mediated concordant xenograft rejection and prevent the emergence of specific anti-graft antibodies by inhibiting T-cell activation.
What then are the differences between allografts and concordant xenografts that permit tolerance induction between allografts but not xenografts? In allografts, the difference between donor and recipient resides largely in MHC allelic variation between the immune system of the recipient and the MHC status of the donor organ. The ensuing rejection response is mediated by antigen specific T-cells directed toward MHC antigens. Furthermore, in highly sensitized allograft recipients, the preformed antibodies are most commonly directed toward MHC antigens. The number of differences encountered after xenotransplants is much greater and extends beyond the MHC locus.
Transplanting organs between species has identified an ever expanding list of incompatibilities that may explain some of the differences between allograft and xenograft rejection. These differences result from structural variation between species of molecules, such as cytokines, cytokine receptors, and adhesion molecules, which play an integral role in the rejection response (2). These molecular incompatibilities, in addition to influencing the evolution of an immune response, may also add to the large pool of additional antigens encountered after transplantation across species.
Work by Auchincloss (3) and others has recently highlighted the relative importance of direct pathways of antigen recognition compared with indirect antigen recognition in xenotransplantation, and this may be the key to understanding the mechanisms of concordant xenograft rejection. Bartholomew et al. have demonstrated that the addition of deoxyspergualin (DSG) to the standard conditioning regime for the first 2 weeks significantly extended transplant survival. DSG is a potent immunosuppressive agent with only limited use in allotransplantation. Unlike cyclosporin A, which acts only on T-cells, DSG inhibits T-cells, monocytes/macrophages, and antibody generation (4). The function of DSG as an inhibitor of antigen presentation and monocyte activation may explain the prolongation in organ transplant survival observed in this model.
