RESUMEN
Ischemia-reperfusion injury (IRI) evokes intragraft inflammatory responses, which markedly augment alloimmune responses against the graft. Understanding the mechanisms underlying these responses is fundamental to develop therapeutic regimens to prevent/ameliorate organ IRI. Here, we demonstrate that IRI results in a marked increase in mitochondrial damage and autophagy in dendritic cells (DCs). While autophagy is a survival mechanism for ischemic DCs, it also augments their production of interleukin (IL)-6. Allograft-derived dendritic cells (ADDCs) lacking autophagy-related gene 5 (Atg5) showed higher death rates posttransplantation. Transplanted ischemic hearts from CD11cCre/Atg5 conditional knockout mice showed marked reduction in intragraft expression of IL-6 compared with controls. To antagonize the effect of IL-6 locally in the heart, we synthesized novel anti-IL-6 nanoparticles with capacity for controlled release of anti-IL-6 over time. Compared with systemic delivery of anti-IL-6, localized delivery of anti-IL-6 significantly reduced chronic rejection with a markedly lower amount administered. Despite improved allograft histology, there were no changes to splenic T cell populations, illustrating the importance of local IL-6 in driving chronic rejection after IRI. These data carry potential clinical significance by identifying an innovative, targeted strategy to manipulate organs before transplantation to diminish inflammation, leading to improved long-term outcomes.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Sistemas de Liberación de Medicamentos , Rechazo de Injerto/prevención & control , Trasplante de Corazón/efectos adversos , Interleucina-6/antagonistas & inhibidores , Nanopartículas/administración & dosificación , Daño por Reperfusión/prevención & control , Animales , Proteína 5 Relacionada con la Autofagia/fisiología , Células Cultivadas , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Rechazo de Injerto/etiología , Rechazo de Injerto/metabolismo , Supervivencia de Injerto/efectos de los fármacos , Supervivencia de Injerto/inmunología , Inflamación/etiología , Inflamación/metabolismo , Inflamación/prevención & control , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Nanopartículas/química , Daño por Reperfusión/etiología , Daño por Reperfusión/metabolismoRESUMEN
Over the past several years, the field of transplantation has witnessed significant progress on several fronts; in particular, achievements have been made in devising novel immunosuppressive strategies. An under-explored area that may hold great potential to improve transplantation outcomes is the design of novel strategies to apply specifically to organs to reduce intra-graft inflammation. A growing body of evidence indicates a key role of intra-graft inflammatory cascade in potently instigating the alloimmune response. Indeed, controlling the activation of innate immunity/inflammatory responses has been shown to be a promising strategy to increase the graft acceptance and survival. In this minireview, we provide an overview of emerging targeted strategies, which can be directly applied to grafts to down-regulate intra-graft inflammation prior to transplantation.
Asunto(s)
Antiinflamatorios/uso terapéutico , Inflamación/etiología , Inflamación/prevención & control , Trasplante de Órganos/efectos adversos , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Humanos , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/fisiología , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Inflamación/inmunología , ARN Interferente Pequeño/farmacología , ARN Interferente Pequeño/uso terapéutico , Transducción de Señal/efectos de los fármacosRESUMEN
The clonal expansion of effector T cells and subsequent generation of memory T cells are critical in determining the outcome of transplantation. While cytotoxic T lymphocytes induce direct cytolysis of target cells through secretion of Granzyme-B (GrB), they also express cytoplasmic serine protease inhibitor-6 (Spi6) to protect themselves from GrB that has leaked from granules. Here, we studied the role of GrB/Spi6 axis in determining clonal expansion of alloreactive CD8-T cells and subsequent generation of memory CD8-T cells in transplantation. CD8-T cells from Spi6(-/-) mice underwent more GrB mediated apoptosis upon alloantigen stimulation in vitro and in vivo following adoptive transfer into an allogeneic host. Interestingly, while OT1.Spi6(-/-) CD8 T cells showed significantly lower clonal expansion following skin transplants from OVA mice, there was no difference in the size of the effector memory CD8-T cells long after transplantation. Furthermore, lack of Spi6 resulted in a decrease of short-lived-effector-CD8-cells but did not impact the pool of memory-precursor-effector-CD8-cells. Similar results were found in heart transplant models. Our findings suggest that the final alloreactive CD8-memory-pool-size is independent from the initial clonal-proliferation as memory precursors express low levels of GrB and therefore are independent of Spi6 for survival. These data advance our understanding of memory T cells generation in transplantation and provide basis for Spi6 based strategies to target effector T cells.