CLONAL CVL/GVH REACTIONS AND ADOPTIVE IMMUNOTHERAPY

骨髓移植后白血病复发是一个重要的因素 临床问题。最近的临床和实验研究表明 这个问题可能会随着T细胞耗尽的使用而变得更糟 避免移植物抗宿主(GVH)疾病的技术。因此，有必要 治疗策略将提供抗白血病或 T耗竭骨骼中的移植物抗白血病(GVL)反应 骨髓移植。这项研究提案的目的是 研究克隆的细胞毒性T淋巴细胞(CTL)的用途 控制异基因骨髓移植后的GVL效应。我们 建议使用小鼠模型(AKR小鼠中的T细胞白血病/淋巴瘤)来 检验体内可产生有效GVL反应的假设 通过同种异体CTL克隆的过继转移 基因上合适的(“正常”)细胞表面抗原表达于 白血病细胞。相对于GVH反应性，优先的GVL可以 通过选择和操纵克隆而赋予反应的 对组织分布有限(但存在于肿瘤上)的抗原发生反应 细胞)或使用体内寿命有限的克隆。这种方法 消除了对肿瘤特异性抗原和免疫反应的要求 这些抗原的荷瘤宿主。初步研究支持 验证了我们假设的科学正确性，并论证了其可行性 这种方法的重要性。在拟议的研究中，我们将(A)分离CTL克隆 具有组织相容性抗原的特异性编码在主要 组织相容性复合体(次要抗原)和MHC内(H-2K和 H-2D)，以及编码在T1a/Qa区的分化抗原， (B)体外鉴定CTL克隆的抗原特异性， 抗原驱动的增殖、IL-2的产生和细胞表面表型， (C)使用体内试验评估CTL克隆的条件 可以给免疫抑制的宿主服用，而不会导致致命性GVH疾病 或任何其他不可接受的免疫或病理抗宿主作用，(D) 体内检测CTL克隆的寿命和组织分布，以及 (E)评估克隆的CTL在实验模型中的GVL效应 异基因骨髓移植与细胞减量放化疗 首次传代或原位自发传代治疗AKR小鼠 白血病/淋巴瘤。拟议的研究是一种系统的方法，以 优化GVL效应，同时最小化克隆CTL的GVH效应。 此外，它们将使我们能够获得对 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.