Human–porcine receptor–ligand compatibility within the immune system: relevance for xenotransplantation

Warrens, Anthony N.; Simon, Andrè; Theodore, Pierre; Sykes, Megan

doi:10.1034/j.1399-3089.1999.00020.x

Cited by 35 publications

(22 citation statements)

References 17 publications

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“…The latter relies on the efficiency of donor cell-mediated central deletion of donor antigen-reactive T cells in the recipient thymus. Although cross-species incompatibilities in adhesion molecules may limit the thymic homing of donor cells in discordant xenogeneic recipients, [35][36][37][38] such defects have not been detected in a highly disparate pig-to-mouse combination. We have previously shown that long-term repopulation of host thymus with SLA class II ϩ cells can be achieved in NOD/SCID-Tg mice by porcine BMT, 20 and that the induction of porcine hematopoietic chimerism is capable of inducing T-cell tolerance to porcine hematopoietic donor antigens in mice.…”

Section: Discussionmentioning

confidence: 99%

Induction of human T-cell tolerance to porcine xenoantigens through mixed hematopoietic chimerism

Lan

Wang

Diouf

et al. 2004

Blood

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Xenotransplantation from pigs could provide a potential solution to the severe shortage of allogeneic donor organs. Because xenogeneic tissues are subject to vigorous immune rejection, tolerance induction is likely to be essential to the success of clinical xenotransplantation. Here we explore the possibility of inducing human T-cell tolerance to porcine xenografts through mixed chimerism. We previously showed that NOD/SCID-Tg mice expressing porcine cytokine transgenes permit the induction of durable porcine hematopoietic chimerism. In this study we achieved human T-cell development in these mice by engrafting human fetal thymus/liver tissues. In porcine hematopoietic chimeras, human thymus grafts were populated with porcine class II high cells in addition to human cells, and human T cells were tolerant of the porcine hematopoietic donor as measured by mixed lymphocyte reaction assay and skin grafting. This study proves the principle that porcine chimerism induces tolerance of xenoreactive human T cells. IntroductionThe severe shortage of allogeneic organ donors currently limits the number of transplantations performed. 1,2 This supply-demand disparity could be corrected by the ability to use organs from other species (xenografts). In view of the ethical issues and impracticalities associated with the use of nonhuman primates, interest has focused on other species, in particular the pig, as the most suitable organ donor species for humans. In addition to organ size and physiologic similarities to humans, the ability to rapidly breed and inbreed pigs makes them particularly amenable to genetic modifications that could improve their ability to function as organ donors to humans. [3][4][5][6][7] However, organ transplantations across discordant species barriers are subject to vigorous immunologic rejection. 1,8 One might, therefore, expect the amount of nonspecific immunosuppression that would be required to overcome xenograft rejection to be so great that recipients would succumb to infections. Thus, it would be highly desirable to eliminate the immune response to xenografts through the induction of tolerance.Mixed chimerism has been proven to be a powerful and reliable approach for tolerance induction across allogeneic and closely related xenogeneic barriers. 9-14 Our recent studies showed that this approach also induces tolerance in a pig-to-mouse, highly disparate xenogeneic combination. 15 However, the ability of mixed chimerism to induce human T-cell tolerance to porcine xenografts has yet to be explored because of the lack of a suitable model system. It has been unclear whether or not genetic incompatibilities in immune cytokines, 16,17 accessory molecules, [17][18][19] and other unknown molecules between the 2 species might impede the induction of human T-cell tolerance to porcine xenografts through mixed chimerism. To address these questions, we have developed a murine model that permits the induction of both sustained porcine hematopoietic chimerism and active human thymopoiesis. Our results demonstrate...

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Section: Discussionmentioning

confidence: 99%

Induction of human T-cell tolerance to porcine xenoantigens through mixed hematopoietic chimerism

Lan

Wang

Diouf

et al. 2004

Blood

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“…[15][16][17][18][19][20] Thus, the host thymus-homing capacity of donor cells would be an important determinant for tolerance induction by mixed chimerism across discordant xenogeneic barriers. Although cross-species incompatibilities in adhesion molecules may limit the thymic homing of donor cells in discordant xenogeneic recipients, [32][33][34][35] such defects have not been detected in the highly disparate pig-to-mouse combination. We have previously shown that long-term (Ͼ 20 weeks) repopulation of host thymus with porcine class II ϩ cells can be achieved in NOD/ SCID-Tg mouse recipients of porcine BM (without subsequent mouse BMT).…”

Section: Discussionmentioning

confidence: 99%

Mixed chimerism induces donor-specific T-cell tolerance across a highly disparate xenogeneic barrier

Abe

Sykes

et al. 2002

Blood

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Induction of tolerance is likely to be essential for successful xenotransplantation because immune responses across xenogeneic barriers are vigorous. Although mixed hematopoietic chimerism leads to stable donor-specific tolerance in allogeneic and closely related xenogeneic (eg, rat-to-mouse) combinations, the ability of this approach to induce tolerance across a highly disparate xenogeneic barrier has not yet been demonstrated. In this study, we investigated the immune responses of murine T cells that developed in mice with pre-established porcine hematopoietic chimerism. Our results show for the first time that induction of porcine hematopoietic chimerism can eliminate the development of antiporcine donor responses in a highly disparate xenogeneic species. Porcine hematopoietic chimeras showed donor-specific nonresponsiveness in the mixed lymphocyte reaction, lack of antidonor IgG antibody production, and acceptance of donor skin grafts. Thus, mixed chimerism is capable of inducing tolerance in a highly disparate xenogeneic combination and may have clinical potential to prevent xenograft rejection. ( IntroductionXenotransplantation provides a possible solution to the severe shortage of allogeneic organs, a major limiting factor in clinical organ transplantation. In view of the ethical issues and impracticalities associated with the use of nonhuman primates, interest has become focused on nonprimates, in particular the pig, as the most suitable organ donor species for humans. However, organ transplants across discordant species barriers are subject to vigorous immunologic rejection. 1-4 Transplantation of organs from pigs results in hyperacute rejection in primate recipients due to the presence of anti-Gal␣1-3Gal natural antibodies in their sera. These antibodies also mediate a delayed form of humoral rejection, acute vascular rejection, if hyperacute rejection is overcome. The cellular immune response to xenografts is also stronger than that to allografts. Thus, tolerance induction is likely to be essential for successful xenotransplantation.Induction of mixed hematopoietic chimerism by bone marrow transplantation (BMT) leads to stable donor-specific tolerance in allogeneic and closely related xenogeneic (rat-to-mouse) combinations, 5-10 but its ability to induce porcine xenograft tolerance has not been demonstrated in any discordant xenogeneic species because of the difficulty in achieving lasting porcine hematopoietic engraftment. Studies using a pig-primate combination have shown prolonged survival of porcine kidney grafts in cynomolgus monkey recipients preinfused with donor marrow cells. However, longlasting hematopoietic chimerism was not achieved in any of these animals, and all kidney grafts were eventually rejected. 11,12 Because donor hematopoietic stem cells may fail to engraft in discordant xenogeneic recipients, even in recipients in which T and B cells are absent, 13,14 the rejection of pig kidney grafts in these studies does not distinguish between the failure of donor hematopoietic cells to en...

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“…Mechanistically, a prerequisite for the capture of human NK cells from the circulation onto porcine EC are receptor±ligand interactions between adhesion molecules. While in vitro experiments using human T cell or heterogenous leukocyte populations have shown that several such interactions are intact across the human±porcine species barrier (reviewed in [20,21]), this review will focus on and summarize the current knowledge on the adhesive interactions between human NK cells and porcine EC.…”

Section: Introductionmentioning

confidence: 99%

Adhesive Interactions between Human NK Cells and Porcine Endothelial Cells

Schneider

Forte

2001

Scand J Immunol

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Human natural killer (NK) cells are able to adhere to xenogeneic porcine endothelial cells (EC) and evidence from in vitro studies as well as animal models suggests a potential role for NK cells in the cellular recognition and damage of porcine xenogeneic tissues. One possible explanation for the observed NK cellmediated xenogeneic cytotoxicity against porcine EC is the molecular incompatibility between porcine major histocompatibility complex (MHC) class I molecules and MHC-specific inhibitory receptors on human NK cells. In this review we attempt to summarize the current knowledge concerning adhesive interactions between human NK cells and porcine EC under special considerations of the cross-species receptor±ligand interactions. Methodological differences in assessing adhesion between various studies are reviewed and comparisons to the syngeneic/allogeneic adhesion mechanisms are made. Finally, the therapeutic potential of blocking antibodies and transgenic HLA expression in preventing NK-cell adhesion and xenogeneic cytotoxicity is discussed.

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Human–porcine receptor–ligand compatibility within the immune system: relevance for xenotransplantation

Cited by 35 publications

References 17 publications

Induction of human T-cell tolerance to porcine xenoantigens through mixed hematopoietic chimerism

Induction of human T-cell tolerance to porcine xenoantigens through mixed hematopoietic chimerism

Mixed chimerism induces donor-specific T-cell tolerance across a highly disparate xenogeneic barrier

Adhesive Interactions between Human NK Cells and Porcine Endothelial Cells

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