Opposing Roles of Interferon Gamma in Transplantation UnderCostimulation Blockade 公开
Coley, Shana M (2009)
Abstract
During the last fifty years, organ transplantation has become a favored treatment option for patients with otherwise incurable conditions. Nevertheless, the immune response to donor tissue remains the major obstacle to long-term graft survival. Prolongation of allograft survival through T cell costimulation blockade (CoB) is based on the principle that T cell receptor stimulation in the absence of costimulation leads to abortive activation or deletion of T cells. However, resistance to CoB-induced allograft survival is seen in some mouse models. CD8 T cells are necessary for this resistance, but the mechanism by which CD8 T cells mediate rejection in the absence of major costimulatory signals is poorly understood. Interferon-gamma (IFNγ) promotes CD8 T cell responses, but IFNγ-deficient mice show early graft loss despite CoB. In contrast, we found that IFNγ receptor-deficient mice show dramatically prolonged graft survival under CoB. Investigating this paradox, we addressed the effects of IFNγ on T cell alloresponses in vivo independent of the effects of IFNγ on graft survival. We found that neither IFNγ receptor-deficient recipients nor IFNγ-deficient recipients mount anti-graft CD8 T cell responses. To explain graft loss despite undetectable T cell responses in IFNγ-deficient recipients, we found that direct action of IFNγ on the graft was necessary for graft survival, as either IFNγ neutralization in IFNγ receptor-deficient recipients or the lack of the IFNγ receptor on the graft precipitated early graft loss. Furthermore, IFNγ decreased cellular infiltrates and hemorrhage and increased transcripts for tolerance-associated molecules within grafts at early time points. In contrast to other models, NK cells were dispensable but CD4+ cells were necessary for graft maintenance. At late time points, IFNγ held in check a dormant immune response, as IFNγ neutralization not only precipitated graft loss but also led to increased transcripts for cell-mediated response genes within graft-draining lymph nodes. Importantly, late-term control via IFNγ was by direct action on graft-derived cells and by indirect action on the recipient immune system. Thus, IFNγ is required both for the recipient to mount a donor-specific CD8 T cell response under CoB as well as for allografts to initiate and maintain survival after transplantation.
Table of Contents
Table of Contents
Introduction...2
Chapter One...17
Costimulation Blockade: Successes & Shortcomings in Prolonging Graft Survival Figure 1.1 Graft survival is prolonged by blockade of CD28 & CD40 signals...27 Figure 1.2 CD28 / CD40 blockade impairs the immune response to allografts...29 Figure 1.3 Synergy is found through blockade of additional costimulatory signals...31 Figure 1.4 IFN-gamma Receptor-deficient mice are similar to wild-type mice 33
Chapter Two...35
Interferon-gamma Dictates Allograft Fate via Opposing Effects on the Graft and on Recipient CD8 T Cell Responses Figure 2.1 Donor-specific dual-cytokine producing effector CD8 T cells expand during costimulation blockade-resistant rejection...54 Figure 2.2 Disruption of IFNγ or IFNγR in the recipient results in divergent effects on graft survival under costimulation blockade...56 Figure 2.3 IFNγR-deficient recipients show no CD8 breakthrough response under costimulation blockade...58 Figure 2.4 Paradoxical graft loss with no CD8 breakthrough response in IFNγ-deficient recipients under costimulation blockade...60 Figure 2.5 IFNγ is required for prolonged graft survival on IFNγR-deficient recipients under costimulation blockade...62
Chapter Three...64
Source and Activity of Interferon-gamma in Prolonging Graft Survival in Recipients Treated with Costimulation Blockade (CoB) Figure 3.1 Prolonged graft survival on GRKO recipients treated with CoB is not dependent on the presence of CD8+ cells or NK1.1+ cells or on the production of IFNγ by the graft...87 Figure 3.2 Skin grafted in the absence of IFNγ shows vessel congestion, hemorrhage and cellular infiltrates regardless of the presence of CoB...89 Figure 3.3 Exposing donor skin to recombinant IFNγ prior to transplantation is not sufficient to prolong its survival when transplanted onto WT recipient under CoB...91 Figure 3.4 IFNγ is required even at late time points for sustained graft survival on IFNγR-deficient recipients treated with CoB...93 Figure 3.5 Tolerance-associated transcripts are upregulated in skin after treatment in vitro with rIFNγ as well as in POD 7 skin grafts on IFNγR-deficient recipients under CoB...95 Figure 3.6 CD4+ cells are required for maintenance of prolonged graft survival on IFNγR-deficient recipients treated with CoB...98 Figure 3.7 Neutralization of IFNγ in IFNγR-deficient recipients of long-term surviving grafts alters transcript profiles within graft-draining lymph nodes...100
Discussion...102
References...108
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