RESUMO
The location of immune activation is controversial during acute allograft rejection and unknown in xenotransplantation. To determine where immune activation to a xenograft occurs, we examined whether splenectomized alymphoplastic mice that possess no secondary lymphoid organs can reject porcine skin xenografts. Our results show that these mice rejected their xenografts, in a T cell-dependent fashion, at the same tempo as wild-type recipients, demonstrating that xenograft rejection is not critically dependent on secondary lymphoid organs. Furthermore, we provide evidence that immune activation in the bone marrow did not take place during xenograft rejection. Importantly, immunity to xenoantigens was only induced after xenotransplantation and not by immunization with porcine spleen cells, as xenografted mutant mice developed an effector response, whereas mutant mice immunized by porcine spleen cells via i.p. injection failed to do so. Moreover, we provide evidence that antixenograft immunity occurred via direct and indirect Ag presentation, as recipient T cells could be stimulated by either donor spleen cells or recipient APCs. Thus, our data provide evidence that direct and indirect Ag presentation by a xenograft induces immunity in the absence of secondary lymphoid organs. These results have important implications for developing relevant xenotransplantation protocols.
Assuntos
Apresentação de Antígeno/imunologia , Tecido Linfoide/imunologia , Transplante Heterólogo/imunologia , Animais , Formação de Anticorpos/genética , Apresentação de Antígeno/genética , Antígenos Heterófilos/administração & dosagem , Antígenos Heterófilos/imunologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Divisão Celular/genética , Divisão Celular/imunologia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Rejeição de Enxerto/prevenção & controle , Imunidade Inata/genética , Memória Imunológica/genética , Injeções Intraperitoneais , Interfase/genética , Interfase/imunologia , Células Matadoras Naturais/imunologia , Tecido Linfoide/anormalidades , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos SCID , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Transplante de Pele/imunologia , Transplante de Pele/patologia , Baço/citologia , Baço/imunologia , Baço/transplante , Esplenectomia , Suínos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/transplante , Transplante Heterólogo/métodos , Transplante Heterólogo/patologiaRESUMO
Transplanted organs fail due to either acute or chronic rejection. The prevailing view is that the nature or magnitude of the recipient's immune response to donor Ags determines the type of rejection. In variance with this view, we show in this study that the status of the graft itself plays a dominant role in defining the type of rejection even in the face of an established alloimmune response. Using adoptive transfer mouse models in which the graft is exposed to a constant number of effector lymphocytes, we found that newly transplanted heart allografts are rejected acutely, while healed-in allografts undergo chronic rejection. Acute rejection of healed-in allografts was largely recapitulated by subjecting the grafts to ischemia-reperfusion injury similar to that present in newly transplanted organs. Ischemia-Reperfusion injury altered the outcome of rejection by enhancing the accumulation of effector T cells within the graft. The accumulation of effector T cells in the graft was dependent on the presence of both ischemia-reperfusion injury (inflammation) and alloantigens. These findings demonstrate that the graft plays a dominant role in shaping the outcome of rejection by controlling the trafficking of effector T cells.
