Allospecific Immunoregulatory T Cells in BMT Recipients

描述（由申请人提供）： 调节性T细胞控制的生理生长和功能， 自身反应性细胞 在外周组织中。 在动物 模型，损失或 调节性T细胞的功能障碍可导致自身免疫性疾病。 我们有 鉴定了胸腺衍生的T细胞受体（TCR）+，CD 4+， 调节性T细胞在小鼠异基因骨髓移植模型中的作用 (BMT)和供体白细胞输注（DLI）治疗， 供体T细胞的GVH反应性。这些细胞可以帮助建立和 维持对宿主和供体抗原的外周耐受性。调节性TCR+ CD 4 + 不 细胞 从 DLI处理 小鼠 抑制 异体反应 在 一个 同种异体抗原体外特异性方式与过继转移后GVH病 in vivo.我们假设，类似的调节性T细胞出现在人类 但产生调节性T细胞能力减弱 细胞（由于年龄、既往化疗、放疗等）有助于 DLI治疗后GVH疾病的风险较高，并且可能导致 慢性GVH疾病。TREC的定量测量与 独特的表型标志物现在允许对 胸腺对移植后免疫的贡献的动力学和程度 在人体内重建。使用这些技术，我们建议识别和 在高表达TREC的近期胸腺中分离人调节性T细胞 移民（RTE）人口，并将其存在（或不存在）与 同种异体BMT后的临床结果（有或无DLI治疗）。的 这项R21探索性补助金的目的是在人类中生成数据， 支持了我们的假设，并验证了在 人类BMT的临床前模型。胸腺调节性T细胞可能对 没有GVH疾病的DLI治疗的成功以及成功的 通过共刺激阻断诱导耐受。我们建议确定：（a） 是否可以在RTE细胞群中检测到调节性T细胞 在HLA不同的BMT的人接受者的外周血中;（B）是否 调节性T细胞可以从外周血中离体诱导和扩增， BMT患者的血液，可能用于过继转移方案， 预防GVH疾病，和（c）是否诱导无反应性T细胞， 共刺激阻断离体诱导同种特异性调节细胞， 骨髓移植患者或捐赠者。

DESCRIPTION (provided by applicant): Distinct and identifiable populations of regulatory T cells control the physiological outgrowth and function of autoreactive cells in peripheral tissues. In animal models, loss or dysfunction of regulatory T cells can lead to autoimmune disease. We have identified a unique population of thymus-derived T cell receptor (TCR)+, CD4+ regulatory T cells in murine models of allogeneic bone marrow transplantation (BMT) and donor leukocyte infusion (DLI) therapy that specifically suppress the GVH reactivity of donor T cells. These cells may help establish and maintain peripheral tolerance to host and donor antigens. Regulatory TCR+ CD4+ T cells from DLI-treated mice suppress alloreactivity in an alloantigen-specific manner in vitro and GVH disease after adoptive transfer in vivo. We hypothesize that similar regulatory T cells emerge from the human thymus post-transplant, but that diminished capacity to generate regulatory T cells (due to age, prior chemotherapy, radiation, etc.) contributes to a higher risk of GVH disease after DLI therapy and, possibly, to the onset of chronic GVH disease. Quantitative measurements of TRECs in combination with unique phenotypic markers now allow for a definitive assessment of the kinetics and extent of the thymic contribution to post-transplant immune reconstitution in humans. Using these techniques, we propose to identify and isolate human regulatory T cells in the high TREC-expressing recent thymic emigrant (RTE) population and correlate their presence (or absence) with clinical outcome after allogeneic BMT (with or without DLI therapy). The purpose of this R21 exploratory grant is to generate data in humans that supports our hypothesis and validates the extension of observations made in preclinical models to human BMT. Thymic regulatory T cells may be critical to the success of DLI therapy without GVH disease as well as to the successful induction of tolerance by costimulatory blockade. We propose to determine: (a) whether regulatory T cells can be detected within the population of RTE cells in the peripheral blood of human recipients of HLA-disparate BMT; (b) whether regulatory T cells can be induced and expanded ex vivo from the peripheral blood of BMT patients for possible use in adoptive transfer protocols to prevent GVH disease, and (c) whether induction of anergic T cells by costimulatory blockade ex vivo induces allospecific regulatory cells in either the BMT patient or the donor.