CXCL9 influences effector T cell priming to cardiac allografts

描述（由申请人提供）：尽管侵入性和非侵入性治疗策略取得了进展，心脏移植仍然是几种心血管疾病的最终治疗选择。尽管急性和慢性移植排斥反应涉及一系列体液和细胞免疫反应，但移植界的主要目标是预防T细胞介导的急性排斥反应。目前的治疗旨在抑制或阻断效应T细胞产生的干扰素(IFN)-v，最终导致免疫反应的其他部分的激活和随后的移植器官的排斥反应。我们实验室最近的工作表明，IFN-?诱导的趋化因子CXCL9/单因子（MIG）在效应CD4和CD8 T细胞向IFN-？第表现型。我推测，在血管化的心脏同种异体移植后，脾脏中MIG的产生与启动期间T细胞上CXCR3的上调有关，并且时机合适，可以驱动幼稚T细胞产生ifn -v效应表型。此外，我认为尽管CXCR3在CD8和CD4 T细胞上表达，但MIG并不是促进移植物中效应物浸润的关键或决定性因素。本提案概述了我将使用的方法，以测试在同种异体反应性T细胞启动部位产生的MIG如何与幼稚T细胞分化相关，从而导致主要产生ifn -v的表型。特异性目标1将测试MIG在启动位点的来源和时间产生，因为它与T细胞增殖和效应表型的产生相关。特异性Aim 2将直接测试MIG驱动效应细胞浸润同种异体移植物的要求，以及浸润效应细胞是否必须表达CXCR3。更全面地了解暴露于同种异体抗原后T细胞如何发展为产生ifn -v的表型，以及它们如何迁移到移植的实体器官，将有助于在预防移植排斥的竞争中产生更合适和更有效的治疗干预靶点。

DESCRIPTION (provided by applicant): Despite advances in invasive and non-invasive therapeutic strategies, cardiac transplantation remains the final treatment option for several cardiovascular pathologies. Although acute and chronic graft rejection, involve a repertoire of humoral and cellular immunological responses, a predominant goal in the transplantation community is the prevention of T cell-mediated acute rejection. Current treatments aim at suppression or blockade of interferon (IFN)-v produced by effector T cells which ultimately lead to activation of the other arms of the immune response and subsequent rejection of the grafted organ. Recent work in our laboratory indicates that the chemokine CXCL9/Monokine Induced by IFN-? (MIG) plays a role in the polarization of effector CD4 and CD8 T cells to an IFN-?-producing phenotype. I hypothesize that, following vascularized cardiac allografting, MIG production in the spleen is correlated with upregulation of CXCR3 on T cells during priming, and that the timing is appropriate to drive naive T cells to an IFN-v-producing effector phenotype. Additionally, I believe that MIG is not a crucial or determinate factor in promoting effector infiltration into the graft despite expression of CXCR3 on CD8 and CD4 T cells. This proposal outlines the methods I will use to test how MIG production at the site of alloreactive T cell priming correlates to the differentiation of naive T cells resulting in a predominantly IFN-v-producing phenotype. Specific Aim 1 will test the source and temporal production of MIG at the site of priming as it correlates to T cell proliferation and generation of effector phenotype. Specific Aim 2 will directly test the requirement for MIG to drive effector cell infiltration into allografts, and whether infiltrating effectors must express CXCR3. A more complete understanding of how T cells develop to an IFN-v-producing phenotype following exposure to alloantigen and how they migrate to a transplanted solid organ will aid in generating more appropriate and more effective targets for therapeutic intervention in the race to prevent graft rejection.