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The Hematopathology Molecular Genetics subcommittee presents recommendations for molecular diagnostic testing in acute myeloid leukemia, myeloproliferative neoplasms, myelodysplastic syndrome, and lymphomas and for the development of an interfacility consultation service.
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BACKGROUND: Acute allograft rejection is dependent on adaptive immunity, but it is unclear whether the same is true for chronic rejection. Here we asked whether innate immunity alone is sufficient for causing chronic rejection of mouse cardiac allografts. METHODS: We transplanted primarily vascularized cardiac grafts to recombinase activating gene-knockout (RAG(-/-)) mice that lack T and B cells but have an intact innate immune system. Recipients were left unmanipulated, received adjuvants that stimulate innate immunity, or were reconstituted with B-1 lymphocytes to generate natural IgM antibodies. In a second model, we transplanted cardiac allografts to mice that lack secondary lymphoid tissues (splenectomized aly/aly recipients) and studied the effect of NK cell inactivation on T cell-mediated chronic rejection. RESULTS: Acute cardiac allograft rejection was not observed in any of the recipients. Histological analysis of allografts harvested 50 to 90 days after transplantation to RAG(-/-) mice failed to identify chronic vascular or parenchymal changes beyond those observed in control syngeneic grafts. Chronic rejection of cardiac allografts parked in splenectomized aly/aly mice was observed only after the transfer of exogenously activated T cells. NK inactivation throughout the experiment, or during the parking period alone, reduced the severity of T cell-dependent chronic rejection. CONCLUSIONS: The innate immune system alone is not sufficient for causing chronic rejection. NK cells predispose healed allografts to T cell-dependent chronic rejection and may contribute to chronic allograft pathology.
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Rechazo de Injerto/inmunología , Trasplante de Corazón/inmunología , Inmunidad Innata , Activación de Linfocitos , Linfocitos T/inmunología , Animales , Subgrupos de Linfocitos B/inmunología , Células Asesinas Naturales/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Trasplante HomólogoRESUMEN
Lymphoid neogenesis is the process by which ectopic lymphoid accumulations that resemble lymph nodes arise in nonlymphoid tissues. Such lymphoid accumulations, known as tertiary lymphoid organs (TLO), are observed in chronic autoimmunity and they propagate immune pathology by setting up local antigen presenting sites. Whether lymphoid neogenesis occurs in transplanted organs and contributes to rejection is not well understood. To begin to address this question, we retrospectively analyzed 319 murine cardiac allografts for microscopic evidence of lymph-node-like structures. We found 78 allografts that had either classical TLO, characterized by discrete T- and B-cell zones and high endothelial venules (HEV) expressing peripheral node addressin (PNAd) (n = 34), or PNAd(+) HEV without organized lymphoid accumulations (n = 44). These changes were present in both short- and long-lived allografts and were invariably associated with rejection. Importantly, they occurred in 78% of allografts undergoing chronic rejection (n = 85) but in only 7% of allografts undergoing primarily acute rejection (n = 184). These findings indicate that, like autoimmunity, alloimmunity is associated with lymphoid neogenesis in the target organ and suggest a role for local T-cell activation in chronic allograft rejection.
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Rechazo de Injerto/patología , Trasplante de Corazón , Tejido Linfoide/anomalías , Miocardio/patología , Animales , Enfermedad Crónica , Tejido Linfoide/crecimiento & desarrollo , Ratones , Trasplante HomólogoRESUMEN
The allospecifc T cell population responding to a transplanted organ consists of both naive and memory lymphocytes. Although it is established that naive T cells are activated by antigen within the organized structures of secondary lymphoid organs (the spleen, lymph nodes, and mucosal lymphoid tissues), it is not clear whether memory T cell activation and propagation depend on homing to these organs. To answer this question, we investigated whether allospecific naive or memory T cells can mediate acute cardiac allograft rejection in mutant mice that lack all of their secondary lymphoid tissues. The results of our experiments demonstrated that antigen-experienced memory T cells have two advantages over naive T cells: (i) memory T cells mount a vigorous immune response that leads to allograft rejection independent of secondary lymphoid organs; and (ii) memory T cells generate more memory T cells without homing to secondary lymphoid organs. These unique properties of memory T cells were further confirmed by showing that memory-like T cells that arise from the homeostatic proliferation of naive T cells in the absence of antigenic stimulation are suboptimal at rejecting allografts and do not generate memory T cells in mice devoid of secondary lymphoid tissues.
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Memoria Inmunológica , Ganglios Linfáticos/inmunología , Membrana Mucosa/inmunología , Bazo/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Trasplante de Células , Citometría de Flujo , Inmunofenotipificación , Ratones , Ratones Endogámicos BALB C , Mutación , Recombinación Genética , Linfocitos T Citotóxicos/metabolismoRESUMEN
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.
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Presentación de Antígeno/inmunología , Tejido Linfoide/inmunología , Trasplante Heterólogo/inmunología , Animales , Formación de Anticuerpos/genética , Presentación de Antígeno/genética , Antígenos Heterófilos/administración & dosificación , Antígenos Heterófilos/inmunología , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , División Celular/genética , División Celular/inmunología , Rechazo de Injerto/inmunología , Rechazo de Injerto/patología , Rechazo de Injerto/prevención & control , Inmunidad Innata/genética , Memoria Inmunológica/genética , Inyecciones Intraperitoneales , Interfase/genética , Interfase/inmunología , Células Asesinas Naturales/inmunología , Tejido Linfoide/anomalías , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Mutantes , Ratones SCID , Ratas , Ratas Sprague-Dawley , Transducción de Señal/genética , Transducción de Señal/inmunología , Trasplante de Piel/inmunología , Trasplante de Piel/patología , Bazo/citología , Bazo/inmunología , Bazo/trasplante , Esplenectomía , Porcinos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/trasplante , Trasplante Heterólogo/métodos , Trasplante Heterólogo/patologíaRESUMEN
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.