MECHANISMS IN SUCCESSFUL THERAPY OF GVHD WITH MOAB

描述：(申请者摘要)移植物抗宿主病(GVHD) 异基因骨髓移植的潜在致命性并发症 (BMT)。一旦启动，成功治疗GVHD的可靠策略已经 还没有开发出来。申请人已经证明了F(ab‘)2个片段 小鼠异基因骨髓移植逆转后应用CD3 epsilon特异性单抗 GVHD的临床疗效及诱导耐受性。在……里面 然而，携带白血病的宿主过量或不及时地服用 抗CD3F(ab‘)2抗体可导致白血病复发。这样做的主要目标是 研究是为了找出成功治疗的机制 用抗CD3 F(ab‘)2单抗体内接种GVHD。广泛的初步数据 细胞因子参与移植物抗宿主病的病理和调控。两部分 有待检验的假设表明：(I)T细胞通过 抗CD3(Fab‘)2单抗激活诱导细胞死亡(AICD或凋亡) 是治疗已确诊的移植物抗宿主病的必要前提 CD3 F(ab‘)2激活NK-1.1+T细胞分泌细胞因子 耐受性诱导。已经开发了小鼠模型来测试这一点 假设。提出了四个具体目标：(A)评估 AICD在抗CD3抗体成功治疗GVHD中的作用 F(ab‘)2Moab在体内的表达及其与T细胞死亡和活化状态的关系 (B)测定NK-1.1+T细胞或 CD3+双阴性T细胞对GVHD的抑制作用 用表型和功能分析研究CD3-epsilon信号转导 (C)确定IL-4或其他细胞因子是否对 抗CD3 F(ab‘)2纯合子治疗移植物抗宿主病的机制 缺失突变小鼠(“基因敲除小鼠”)；和(D)检查免疫学 骨髓移植后白血病复发的相关因素分析 抗CD3 F(ab‘)2单抗及供者白细胞输注对小鼠免疫功能的影响 防止复发。拟议研究的一个独特方面是平行 单抗体内治疗移植物抗白血病(GVL)的疗效评价 以AKR小鼠急性T淋巴细胞白血病为模型。 从研究中获得的机械论见解，以及生物学 确定的原则，将促进摩押的翻译应用 到临床骨髓移植。

DESCRIPTION: (Applicant's Abstract) Graft-vs-host disease (GVHD) is a potentially lethal complication of allogenic bone marrow transplantation (BMT). A reliable strategy to successfully treat GVHD once initiated has not yet been developed. The applicant has shown that F(ab')2 fragments of CD3 epsilon specific MoAb administered to mice after allogeneic BMT reverses the clinical effects of GVHD and leads to tolerance induction. In leukemia-bearing hosts, however, excessive or ill-timed administration of anti-CD3 F(ab')2 leads to leukemia relapse. The primary goal of this research is to identify mechanisms responsible for the successful treatment of GVHD with anti-CD3 F(ab')2 MoAb in vivo. Extensive preliminary data implicated cytokines in the pathology and regulation of GVHD. The two-part hypothesis to be tested states that (i) depletion of T-cells through activation-induced cell death (AICD or apoptosis) by anti-CD3 (Fab')2 MoAb is an essential prerequisite for treatment of established GVHD and (ii) anti CD3 F(ab')2 activates NK-1.1+ T-cells to secrete cytokines which lead to tolerance induction. Murine models have been developed to test this hypothesis. Four specific aims are proposed: (a) To assess the importance of AICD in the successful treatment of established GVHD with anti-CD3 F(ab')2 MoAb in vivo and correlate T-cell death with activation state of the T-cells in vitro and in vivo; (b) To determine whether NK-1.1+ T-cells or CD3+ double-negative T-cells contribute to suppression of GVHD after signaling through CD3 epsilon using phenotypic and functional assays in vitro; (c) To ascertain whether IL-4 or other cytokines are essential to the mechanism involved in therapy of GVHD with anti-CD3 F(ab')2 using homozygous deletion mutant mice ("knockout mice"); and (d) To examine immunological factors that contribute to post-BMT leukemia relapse after treatment with anti CD3 F(ab')2 MoAb and the ability of donor leukocyte infusions to prevent relapse. A unique aspect of the proposed studies is the parallel evaluation of the effects of MoAb therapy in vivo on graft-vs-leukemia (GVL) reactivity using acute T-cell lymphoblastic leukemia in AKR mice as a model. Mechanistic insights gained from the studies, together with the biological principles identified, will facilitate the translational application of MoAb to clinical BMT.