IMMUNOTHERAPY OF LOW RISK MYELODYSPLASTIC SYNDROME

低风险骨髓增生异常综合征的免疫治疗

• 批准号: 6892850
• 负责人: JEFFREY J MOLLDREM
• 金额: $ 21.79万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6892850
• 关键词: CD95 molecule; T cell receptor; T lymphocyte; apoptosis; blood disorder chemotherapy; clinical trials; combination therapy; cyclosporines; dyserythropoietic anemia; flow cytometry; fludarabine; gamma globulin; hematopoiesis; human subject; human therapy evaluation; immunotherapy; interferon gamma; interleukin 2; interleukin 4; outcomes research; patient oriented research; prognosis; single strand conformation polymorphism; tumor necrosis factor alpha; tumor necrosis factor beta

DESCRIPTION (Provided by applicant): Myelodysplastic syndrome (MDS) is a heterogeneous group of progressive, irreversible, hematopoietic stem cell disorders characterized by progressive cytopenia and for which there are no effective therapies. Experimental and clinical evidence indicates that lymphocytes from patients with MDS exert an inhibitory effect on autologous hematopoietic colony growth, and that this contributes to cytopenia. Immunosuppressive treatments that decrease the number of lymphocytes or suppress their function such as corticosteroids, cyclosporine, and antithymocyte globulin (ATG) have been shown to reverse that cytopenia, and in some cases to reduce the number of blasts in the marrow. How these lymphocytes recognize their target antigens and inhibit hematopoietic precursors is unknown. Identification of relevant hematopoietic target antigens, however, might lead to useful therapies for MDS, and would provide insight into other bone marrow failure states such as aplastic anemia where T lymphocytes are also thought to play a key role in the development of pancytopenia. As a strategy to search for those target antigens, we hypothesize that in myelodysplastic syndrome, lymphocyte inhibition of hematopoietic progenitors is mediated by clonal or oligoclonal activated T lymphocytes through MHC-restricted antigen recognition. The long-term goal of this project is to investigate whether clonal T cells associated with inhibition of marrow progenitors can be isolated from MDS patients and then used to further identify relevant target antigens. These clonal T cells could then be more specifically targeted in the treatment of MDS patients and identification of T cell target cells/antigens could help determine the proportional contribution of lymphocytes to the development of cytopenia in MDS. We have shown that patients with MDS who respond to ATG treatment have activated CD8+ lymphocytes that inhibit colony forming unit-granulocyte macrophage (CFU-GM) in a MHC class I-restricted manner. Dominant clonal and oligoclonal lymphocyte populations that are present in peripheral blood and bone marrow in some MDS patients are later replaced by a normal polyclonal distribution, which coincides with reestablishment of effective hematopoiesis after ATG treatment. The proposed studies will isolate and characterize clonal T cells from MDS patients, determine how these T cell clones suppress hematopoiesis, whether T cell-mediated inhibition of hematopoiesis is directed against dysplastic or normal progenitors, and whether additional T-cell-directed immunosuppressive agents added to ATG treatment can enhance recovery from cytopenia in a randomized clinical trial.

描述（由申请人提供）：骨髓增生综合征（MDS）是 异构性，不可逆的造血干细胞的异质群 以进行性细胞质的特征的疾病，没有 有效的疗法。实验和临床证据表明 MDS患者的淋巴细胞对自体产生抑制作用 造血菌落生长，这有助于细胞质。 减少淋巴细胞数量的免疫抑制作用或 抑制它们的功能，例如皮质类固醇，环孢菌素和 抗猜测细胞球蛋白（ATG）已证明可以逆转那种细胞减少症，在 某些情况是减少骨髓中爆炸的数量。这些淋巴细胞如何 识别其靶抗原和抑制造血前体是 未知。但是，鉴定相关的造血靶抗原 可能会导致MD有用的疗法，并将提供对其他的见解 骨髓衰竭状态，例如性贫血，T淋巴细胞也是 被认为在全年多年症的发展中起着关键作用。作为策略 搜索那些靶抗原，我们假设在骨髓塑料中 综合征，淋巴细胞抑制造血祖细胞是由 克隆或寡克隆活化的T淋巴细胞通过MHC限制抗原 认出。该项目的长期目标是调查是否 可以分离与抑制骨髓祖细胞相关的克隆T细胞 来自MDS患者，然后用于进一步识别相关的靶抗原。 然后，这些克隆T细胞可以更具体地针对治疗 MDS患者和T细胞靶细胞/抗原的鉴定可能有助于 确定淋巴细胞对发展的比例贡献 MDS中的细胞质减少症。我们已经表明，有反应ATG的MD的患者 治疗激活了抑制菌落形成的CD8+淋巴细胞 MHC I类限制方式的单位颗粒细胞巨噬细胞（CFU-GM）。 主要的克隆和寡克隆淋巴细胞种群存在于 一些MDS患者的外周血和骨髓后来被A取代 正常的多克隆分布，与重新建立一致 ATG治疗后有效造血。拟议的研究将隔离 并表征来自MDS患者的克隆T细胞，确定这些T细胞如何 克隆抑制造血，是否t细胞介导的抑制 造血针对发育不良或正常祖细胞，以及是 添加到ATG治疗中的其他T细胞指导的免疫抑制剂可以 在一项随机临床试验中，增强了细胞减少症的恢复。