CXCL9 influences effector T cell priming to cardiac allografts

描述(由申请人提供)：尽管在侵入性和非侵入性治疗策略方面取得了进展，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物排斥反应涉及一系列体液和细胞免疫反应，但移植社区的主要目标是预防T细胞介导的急性排斥反应。目前的治疗目标是抑制或阻断效应T细胞产生的干扰素-v，最终导致免疫反应的其他臂被激活，并随后导致移植器官的排斥反应。本实验室最近的工作表明，干扰素-？(MiG)在效应器CD4和CD8T细胞向产生干扰素的表型的极化中起作用。我假设，在带血管的同种异体心脏移植后，脾中MIG的产生与启动过程中T细胞上CXCR3的上调有关，并且时机合适，将初始T细胞驱动到产生干扰素-v的效应表型。此外，尽管CD8和CD4T细胞上表达CXCR3，但我认为MIG不是促进效应器渗透到移植物中的关键或决定性因素。这份提案概述了我将使用的方法来测试同种异体反应性T细胞启动部位的MIG产生如何与初始T细胞的分化相关，从而导致主要产生干扰素-v的表型。具体目标1将测试MIG的来源和时间，因为它与T细胞增殖和效应器表型的产生有关。特殊目的2将直接测试MIG驱动效应细胞渗透到同种异体移植物中的要求，以及渗透的效应细胞是否必须表达CXCR3。更全面地了解T细胞在暴露于同种异体抗原后如何发展为产生干扰素-v的表型，以及它们如何迁移到移植的实体器官，将有助于在防止移植排斥反应的竞赛中产生更合适和更有效的靶点进行治疗干预。

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.