CLONAL GVL/GVH REACTIONS AND ADOPTIVE IMMUNOTHERAPY

白血病骨髓移植后复发是一个重要的 临床问题 最近的临床和实验研究表明， 如果使用T细胞耗竭， 避免移植物抗宿主病（GVH）的技术。 因此，需要 提供抗白血病或 T细胞耗竭骨背景下的移植物抗白血病（GVL）反应 骨髓移植 本研究计划的目的是 研究使用克隆的细胞毒性T淋巴细胞（CTL）， 异基因骨髓移植后GVL效应得到控制。 我们 建议使用鼠模型（AKR小鼠中的T细胞白血病/淋巴瘤）， 检验有效的GVL反应可以在体内产生的假设 通过过继转移同种异体CT 1克隆， 表达的遗传上合适的（“正常”）细胞表面抗原， 白血病细胞 与GVH反应性相对的优先GVL可以是 通过选择和操作克隆赋予反应， 与有限组织分布的抗原反应（但存在于肿瘤上 细胞）或通过使用体内寿命有限的克隆。 这种方法 避免了对肿瘤特异性抗原和免疫应答的需要 携带肿瘤的宿主对这些抗原的反应。 初步研究支持 我们的假设的科学有效性，并证明了可行性 的方法。 在拟议的研究中，我们将（a）分离CTL克隆 具有对主要组织相容性抗原外编码的特异性， 组织相容性复合物（次要抗原）和MHC（H-2K和 H-2D），以及T1 a/Qa区编码的分化抗原， (b)体外表征CTL克隆的抗原特异性， 抗原驱动的增殖、IL-2产生和细胞表面表型， (c)使用体内试验来评估CTL克隆的条件， 可用于免疫抑制宿主而不引起致死性GVH疾病 或任何其他不可接受的免疫学或病理学抗宿主作用，（d） 检查体内CT 1克隆的寿命和组织分布，和 (e)评估克隆CTL在实验模型中的GV 1效应， 异基因骨髓移植和细胞减灭放化疗 用第一代或原位自发 白血病/淋巴瘤。 拟议的研究是一种系统的方法， 优化GVL效应，同时最小化克隆CTL的GVH效应。 此外，它们还将使我们能够获得重要的新见解， 克隆性GVH反应的发病机制。

Leukemia relapse after bone marrow transplantation is a significant clinical problem. Recent clinical and experimental studies have suggested that the problem may become worse with the use of T-cell depletion techniques to avoid graft-vs-host (GVH) disease. Thus, there is a need for therapeutic strategies which would provide an antileukemic or graft-vs-leukemia (GVL) reaction within the context of T-depleted bone marrow transplantation. The objective of this research proposal is to investigate the use of cloned cytotoxic T-lymphocytes (CTL) to provide a controlled GVL effect after allogeneic bone marrow transplantation. We propose to use a murine model (T-cell leukemia/lymphoma in AKR mice) to test the hypothesis that an effective GVL reaction can be produced in vivo by the adoptive transfer of allogeneic CTl clones which recognize genetically appropriate ("normal") cell surface antigens expressed on leukemia cells. Preferential GVL as opposed to GVH reactivity can be imparted to the reaction by selection and manipulation of clones which react to antigens with limited tissue distribution (but present on tumor cells) or by using clones with limited life-span in vivo. This approach obviates the requirement for tumor-specific antigens and an immune response by the tumor-bearing host to those antigens. Preliminary studies support the scientific validity of our hypothesis and demonstrate the feasibility of the approach. In the proposed research we will (a) isolate CTL clones with specificity for histocompatibility antigens encoded outside the major histocompatibility complex (minor antigens) and within the MHC (H-2K and H-2D), as well as differentiation antigens encoded in the T1a/Qa region, (b) characterize the CTL clones in vitro for antigen specificity, antigen-driven proliferation, IL-2 production and cell surface phenotype, (c) use in vivo assays to evaluate the conditions under which CTL clones can be given to immunosuppressed hosts without causing lethal GVH disease or any other unacceptable immunologic or pathologic antihost effects, (d) examine the life-span and tissue distribution of CTl clones in vivo, and (e) assess the GVl effect of cloned CTL in experimental models using allogeneic bone marrow transplantation and cytoreductive chemoradiotherapy to treat AKR mice with first-passage or in situ spontaneous leukemia/lymphoma. The proposed studies are a systematic approach to optimizing the GVL effect while minimizing the GVH effect of cloned CTL. In addition, they will enable us to gain significant new insights into the pathogenesis of clonal GVH reactions.