MECHANISMS IN SUCCESSFUL THERAPY OF GVHD WITH MOAB

描述：（申请人的摘要）移植物抗宿主病（GVHD）是一种 异基因骨髓移植潜在致死性并发症 （BMT）。 一个可靠的策略，成功地治疗GVHD一旦开始， 尚未开发。 申请人已经表明，F（ab '）2片段的 同种异体骨髓移植逆转后给予小鼠的CD 3+特异性单克隆抗体 GVHD的临床效果，并导致耐受诱导。 在 然而，携带白血病的宿主，过量或不适时地施用 抗-CD 3F（ab '）2导致白血病复发。 这个的主要目标 研究的目的是确定成功治疗的机制 抗CD 3 F（ab '）2单抗对GVHD的影响。 广泛的初步数据 在GVHD的病理和调节中涉及细胞因子。 两部分 待检验的假设陈述（i）通过以下途径消耗T细胞： 抗CD 3（Fab '）2单克隆抗体激活诱导的细胞死亡（AICD或细胞凋亡） 是治疗已建立的GVHD的必要先决条件，以及（ii）抗 CD 3 F（ab '）2激活NK-1.1+ T细胞以分泌细胞因子，其导致 耐受诱导 已经开发了小鼠模型来测试这一点 假说. 提出了四个具体目标：（a）评估 AICD在成功治疗已建立的GVHD与抗CD 3 F（ab '）2单克隆抗体在体内的表达，并将T细胞死亡与T细胞活化状态相关联。 （B）为了确定NK-1.1+ T细胞或NK-1.1+ T细胞是否在体外和体内表达， CD 3+双阴性T细胞有助于抑制移植物抗宿主病， 使用表型和功能测定通过CD 3 β信号传导， （c）为了确定IL-4或其他细胞因子是否是体外细胞增殖所必需的。 使用纯合子抗CD 3 F（ab '）2治疗GVHD的机制 缺失突变小鼠（“敲除小鼠”）;和（d）检测免疫学 导致BMT后白血病复发的因素 抗CD 3 F（ab '）2单克隆抗体和供体白细胞输注的能力， 防止复发。 拟议研究的一个独特方面是 单克隆抗体治疗移植物抗白血病（GVL）的体内效果评价 使用AKR小鼠中的急性T细胞成淋巴细胞白血病作为模型， 从研究中获得的机制见解，以及生物学 确定的原则，将促进单克隆抗体的翻译应用 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.