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）：骨髓增生异常综合征（MDS）是一种 进行性不可逆造血干细胞的异质群 以进行性血细胞减少为特征且无治疗方法的疾病 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淋巴细胞具有抑制作用 造血集落生长，这会导致血细胞减少。 减少淋巴细胞数量的免疫抑制治疗或 抑制其功能，如皮质类固醇、环孢素和 抗胸腺细胞球蛋白（ATG）已被证明可以逆转血细胞减少症，并且 在某些情况下可以减少骨髓中的原始细胞数量。这些淋巴细胞如何 识别其目标抗原并抑制造血前体是 未知。然而，相关造血靶抗原的鉴定 可能会为MDS带来有用的治疗方法，并提供对其他疾病的深入了解 骨髓衰竭状态，例如再生障碍性贫血，其中 T 淋巴细胞也 被认为在全血细胞减少症的发展中起关键作用。作为一项战略 寻找那些目标抗原，我们假设在骨髓增生异常中 综合征，造血祖细胞的淋巴细胞抑制是由 通过 MHC 限制性抗原克隆或寡克隆激活 T 淋巴细胞 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，然后用于进一步鉴定相关的靶抗原。 这些克隆 T 细胞可以在治疗中更有针对性地靶向 MDS 患者的研究和 T 细胞靶细胞/抗原的鉴定可能会有所帮助 确定淋巴细胞对发育的比例贡献 MDS 中的血细胞减少。我们已经证明，对 ATG 有反应的 MDS 患者 治疗激活了抑制集落形成的 CD8+ 淋巴细胞 以 MHC I 类限制方式的单位粒细胞巨噬细胞 (CFU-GM)。 存在于的显性克隆和寡克隆淋巴细胞群 一些MDS患者的外周血和骨髓后来被替代 正态多克隆分布，这与重建 ATG治疗后有效造血。拟议的研究将隔离 并表征 MDS 患者的克隆 T 细胞，确定这些 T 细胞如何 克隆抑制造血，无论 T 细胞介导的抑制 造血作用针对发育异常或正常祖细胞，以及是否 在 ATG 治疗中添加额外的 T 细胞定向免疫抑制剂可以 在一项随机临床试验中增强血细胞减少症的恢复。