Separation of GVH and GVL in Mouse Models

描述(申请人提供)：非清髓性方法的造血细胞移植(HCT)可以潜在地利用免疫治疗移植物抗肿瘤的益处，同时避免一些与传统的清髓性HCT相关的严重毒性。几项非清髓性红细胞移植的临床研究揭示了一种新的令人惊讶的现象，即供者嵌合体缺失有时与肿瘤的持续退化有关，甚至与晚期血液系统恶性肿瘤有关。我们已经开发了一个小鼠模型来评估这种现象的机制。我们已经证明，对供者抗原的同种异体反应(与自发性移植物排斥反应或通过输注非耐受性宿主类型的淋巴细胞诱导)可导致对受者髓系或淋巴系肿瘤的显著抗肿瘤反应。我们现在建议优化和确定这种现象背后的机制，这为在不增加GVHD风险的情况下实现抗肿瘤效果提供了一种新的策略。具体地说，我们的目标是：1)确定受体淋巴细胞输注(RLI)或自发丧失嵌合体后介导抗肿瘤效应的细胞的来源和表型；2)解决受体APC间接递呈同种异体抗原导致接受RLI的嵌合体产生肿瘤抗原特异性效应CTL和细胞因子产生细胞的假说；3)利用TCR转基因/模型肿瘤抗原系统直接评估RLI导致识别肿瘤抗原的CD4+和CD8+细胞失去耐受性的假说；4)确定干扰素-γ介导RLI受体的抗肿瘤效应的机制；5)评价优化RLI抗肿瘤作用的策略。这些研究的结果将有助于理解与供者骨髓排斥反应相关的肿瘤消退临床现象背后的免疫学事件。此外，他们将推进一种潜在的新策略的开发，以实现与移植物抗宿主病风险无关的抗肿瘤效果，移植物抗宿主病是目前限制非清髓性HCT临床成功的主要并发症。

DESCRIPTION (provided by applicant): Non-myeloablative approaches to hematopoietic cell transplantation (HCT) can potentially harness an immunotherapeutic graft-versus-tumor benefit while avoiding some of the severe toxicities associated with conventional, myeloablative HCT. Several clinical studies of non-myeloablative HCT have revealed a new and surprising phenomenon wherein loss of donor chimerism can sometimes be associated with sustained tumor regressions, even of advanced hematologic malignancies. We have developed a murine model in which to assess the mechanism of this phenomenon. We have demonstrated that alloresponses against donor antigens (either in association with spontaneous graft rejection or induced by infusion of non-tolerant host-type lymphocytes) lead to significant anti-tumor responses against recipient myeloid or lymphoid tumors. We now propose to optimize and determine the mechanisms underlying this phenomenon, which suggests a new strategy for achieving anti-tumor effects without augmenting the risk of GVHD. Specifically, we aim: 1) To determine the source and phenotype of cells mediating anti-tumor effects following recipient lymphocyte infusions (RLI) or spontaneous loss of chimerism; 2) To address the hypothesis that indirect presentation of alloantigens by recipient APC leads to the generation of tumor antigen-specific effector CTL and cytokine-producing cells in chimeras receiving RLI; 3) To utilize a TCR transgenic/model tumor antigen system to directly assess the hypothesis that RLI leads to a loss of tolerance among CD4+ and CD8+ cells that recognize tumor antigens; 4) To determine the mechanism by which IFN-gamma mediates anti-tumor effects in RLI recipients; 5) To evaluate strategies for optimizing the anti-tumor effect of RLI. Results of these studies will lead toward an understanding of the immunological events underlying the clinical phenomenon of tumor regression associated with rejection of donor marrow. Moreover, they will advance the development of a potential new strategy for achieving anti-tumor effects that is not associated with a risk of graft-versus-host disease, the major complication that currently limits the clinical success of non-myeloablative HCT.