Delayed Regulation of GVHD with Retained GVL Effect

在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使得必须采取计算的措施来减少GVHD病理学，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匹配的、次要组织相容性抗原（miHA）不同的B10.BR->CBA小鼠模型中，新鲜分离的供体CD 4 + CD 25 + T淋巴细胞（CD 4 + CD 25 + T淋巴细胞，CD 当在BMT后第10天注射时，CD 8 + T细胞有效抑制早期进行的CD 8 + T细胞介导的GVHD。重要的是，这种发展GVHD的早期调节仍然允许对宿主型髓性白血病（MM. CBA 6）攻击的有效GVL作用。本文概述的该项目的总体目标是优化介导GVHD调节的条件，同时最大化GVL效应，并确定体内消除白血病细胞所涉及的精确细胞机制和调节细胞活性的要求，以阻止发展中的GVHD反应。我们的工作假设是供体抗宿主miHA细胞毒性T淋巴细胞（CTL）在移植后早期产生，并且在它们能够介导GVHD的广泛靶细胞损伤之前容易遇到白血病细胞。在BMT后第10天添加调节细胞将抑制GVHD和GVL应答，但GVL相互作用的窗口足够大，足以预先消除白血病攻击。为了验证这一假设，我们将集中于以下具体目标：1）确定具有最长交互机会窗口的调节细胞控制GVHD反应发展的最佳条件和机制：2）确定在B10. BR-> CBA和B6 -> BALB.B模型中GVL活性伴随CD 4 + CD 25 + T细胞调节GVHD反应发展的机制;（3）确定 在发生GVHD的CD 4 + CD 25 + T细胞调节的背景下，抗CTLA-4 mAb和GVAX处理对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.