ADULT LEUKEMIA RESEARCH CENTER

成人白血病研究中心

• 批准号: 3805837
• 负责人: JOHN A HANSEN
• 金额: --
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3805837
• 关键词: MHC class II antigen; T lymphocyte; acyclovir; antileukocyte isoantibody; autologous transplantation; bone marrow transplantation; cell differentiation; cell mediated lymphocytolysis test; clinical trials; clone cells; corticosteroids; cryopreservation; cyclosporines; genetic markers; graft versus host disease; histocompatibility; histocompatibility gene; histocompatibility typing; homologous transplantation; human genetic material tag; human population genetics; human subject; leukemia; leukocyte activation /transformation; leukocyte antigen typing; major histocompatibility complex; methotrexate; minor histocompatibility loci; mixed lymphocyte reaction test; monoclonal antibody; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; radiation immunosuppression; serology /serodiagnosis; serotyping; surface antigens; tissue donors; transplantation resource /registry /referral center; whole body irradiation effect

The long-range goal of this study is to develop the capability of providing allogeneic marrow transplantation to patients who lack an HLA genotypically identical sibling donor. Both "partially matched" related and phenotypically matched unrelated individuals will be considered as alternative donors and the feasibility and efficacy of transplantation in this setting will be evaluated. Although successful HLA incompatible transplants have been performed, it is not clear whether disparity for any given HLA antigen will cause a significant allograft reaction. For this reason, we will continue to analyze the role of HLA in marrow transplantation and will attempt to define the minimal degree of HLA class I and class II compatibility required to reduce the incidence of graft rejection and graft-versus-host disease (GVHD). Further elucidation of the most relevant genetic factors will be especially important in helping to establish practical matching criteria for selecting volunteer unrelated marrow donors. Pilot clinical trials will be undertaken to determine whether additional immunosuppressive therapy, including total lymphoid irradiation (TLI) and monoclonal antibodies, can reduce the risk of rejection. This objective must be successfully addressed before T cell depletion of donor marrow can be safely used for the prevention of GVHD in mismatched transplants. The laboratory components of this project will address three transplanted-related questions. First, we will study T cell reactivity immediately following transplantation by cloning and limiting dilution methods to determine whether variants of conventionally-defined HLA alleles or undetected HLA determinants can induce specific T cell reactivity. Second, we will determine the frequency of recombination within the HLA-D region, and study whether such recombination in putative identical siblings might increase the risk of GVHD. Third, we will study the suppressor T cells that regulate autoreactive and non- HLA-reactive effector cells, and the role that these suppressors play in preventing anti-host responses and induction of tolerance in HLA identical transplants.

本研究的长期目标是培养以下能力： 为缺乏骨髓移植的患者提供同种异体骨髓移植 HLA 基因型相同的兄弟供体。 两者都“部分 匹配”相关和表型匹配无关 个人将被视为替代捐助者，并且 在这种情况下移植的可行性和有效性将 评价。 尽管HLA不相容移植取得了成功 已执行，尚不清楚是否存在任何差异 给予HLA抗原会引起明显的同种异体移植反应。 为了 为此，我们将继续分析HLA在其中的作用 骨髓移植，并将尝试确定最低限度 降低 HLA I 类和 II 类相容性程度 移植物排斥和移植物抗宿主病的发生率 （移植物抗宿主病）。 进一步阐明最相关的遗传因素 对于帮助建立切实可行的 选择志愿者无关骨髓的匹配标准 捐助者。 将进行试点临床试验以确定 是否需要额外的免疫抑制治疗，包括总免疫抑制治疗 淋巴照射（TLI）和单克隆抗体，可以减少 被拒绝的风险。 这个目标必须成功 在可以安全地耗尽供体骨髓的 T 细胞之前解决 用于预防不匹配移植物中的 GVHD。 这 该项目的实验室部分将解决三个问题 移植相关问题。 首先，我们要研究T细胞 克隆移植后立即具有反应性 有限稀释方法来确定是否存在变体 传统定义的 HLA 等位基因或未检测到的 HLA 决定簇可以诱导特异性 T 细胞反应。 第二，我们 将决定 HLA-D 内重组的频率 区域，并研究这种重组是否在假定的 同卵兄弟姐妹可能会增加 GVHD 的风险。 第三，我们将 研究调节自身反应性和非反应性的抑制性 T 细胞 HLA 反应性效应细胞，以及这些抑制因子的作用 在防止抗宿主反应和诱导耐受中发挥作用 在 HLA 相同移植物中。