Delayed Regulation of GVHD with Retained GVL Effect

异基因血液和骨髓移植(BMT)后，移植物抗宿主病(GVHD)和白血病复发之间的高度负相关性要求采取有计划的措施来减少GVHD的病理，同时保留移植物抗白血病(GVL)效应。在这方面，我们最近发现，在MHC相合的次要组织相容性抗原(MIHA)完全不同的B10.BR-&GT；CBA小鼠模型中，新鲜分离的供体CD4 CD25 T 当骨髓移植后第10天注射细胞时，细胞在抑制早期进行的CD8 T细胞介导的GVHD方面是有效的。重要的是，这种对GVHD发生的早期调节仍然允许针对宿主型髓系白血病(MM.CBA6)的挑战产生强大的GVL效应。该项目的总体目标是在最大化GVL效应的同时优化调节GVHD的条件，并确定体内消除白血病细胞所涉及的确切细胞机制以及为了阻止GVHD反应而调节细胞活动的要求。我们的工作假设是供者抗宿主MIHA细胞毒性T淋巴细胞(CTL)是在移植后早期产生的，在它们能够介导GVHD广泛的靶细胞损伤之前，很容易与白血病细胞接触。在骨髓移植后第10天加入调节细胞将同时抑制GVHD和GVL反应，但GVL相互作用的窗口足够大，可以优先消除白血病挑战。为了验证这一假说，我们将集中于以下具体目标：1)确定以最长的交互机会窗口调控GVHD反应的调节细胞的最佳条件和机制；2)在B10.BR-&GT；CBA和B6-&GT；BALB.B模型中，确定GVL活动伴随着CD4 CD25 T细胞调节GVHD反应的机制；以及3)确定 抗CTLA-4单抗和GVAX治疗在CD4CD25T细胞调节GVHD发展中对GVL活性的影响。

Following allogeneic blood and marrow transplantation (BMT), the high inverse correlation between graft-versus-host disease (GVHD) and leukemic relapse necessitates that calculated measures be taken to reduce GVHD pathology while retaining a graft-versus-leukemia (GVL) effect. In this regard, we have recently found that in the MHC-matched, minor histocompatibility antigen (miHA) disparate B10.BR->CBA murine model, freshly isolated donor CD4+CD25+ T cells were effective at suppressing early-ongoing CD8+ T cell-mediated GVHD when injected as late as day 10 post-BMT. Of importance, this early regulation of developing GVHD still permitted a potent GVL effect against a host-type myeloid leukemia (MM.CBA6) challenge. The overall goal of the project outlined here is to optimize the conditions for mediating GVHD regulation while maximizing the GVL effect, and to determine the precise cellular mechanisms involved in the elimination of the leukemia cells in vivo and the requirements for regulatory cell activity in order to stop the developing GVHD response. Our working hypothesis is that donor anti-host miHA cytotoxic T lymphocytes (CTL) are generated early after transplantation and readily encounter leukemia cells before they are able to mediate extensive target cell injury of GVHD. The addition of regulatory cells at day 10 post-BMT would then suppress both the GVHD and GVL responses, but the window for GVL interaction was large enough for prior elimination of the leukemic challenge. To test this hypothesis, we will focus on the following specific aims: 1) To determine the optimum conditions and mechanism for regulatory cell control over developing GVHD responses with the longest window of interactive opportunity; 2) To determine the mechanism of the GVL activity concomitant with CD4+CD25+ T cell regulation of developing GVHD responses in the B10.BR -> CBA and B6 -> BALB.B models; and 3) To determine the effect of anti-CTLA-4 mAb and GVAX treatments on GVL activity in the context of CD4+CD25+ T cell regulation of developing GVHD.