IMMUNOTHERAPY OF LOW RISK MYELODYSPLASTIC SYNDROME

描述（由申请人提供）：骨髓增生异常综合征（MDS）是一种 进行性、不可逆造血干细胞异质群 以进行性血细胞减少为特征的疾病， 有效的治疗。实验和临床证据表明 骨髓增生异常综合症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，这有助于血细胞减少。 减少淋巴细胞数量的免疫抑制治疗，或 抑制它们功能，如皮质类固醇、环孢菌素， 抗胸腺细胞球蛋白（ATG）已显示可逆转血细胞减少， 在某些情况下，以减少骨髓中的原始细胞数量。这些淋巴细胞 识别它们的靶抗原并抑制造血前体， 未知然而，相关造血靶抗原的鉴定， 可能会导致有用的治疗MDS，并将提供深入了解其他 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。作为一种战略， 寻找这些靶抗原，我们假设在骨髓增生异常 综合征，造血祖细胞的淋巴细胞抑制是由 通过MHC限制性抗原激活的克隆或寡克隆T淋巴细胞 识别.该项目的长期目标是调查是否 可以分离与骨髓祖细胞抑制相关的克隆T细胞 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特异地靶向 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中的血细胞减少。我们已经证明，对ATG有反应的MDS患者 治疗具有抑制集落形成的活化的CD 8+淋巴细胞 单位-粒细胞巨噬细胞（CFU-GM）以MHC I类限制性方式。 优势克隆和寡克隆淋巴细胞群体，存在于 一些MDS患者的外周血和骨髓后来被 正常的多克隆分布，这与 ATG治疗后有效造血。这些研究将隔离 并表征MDS患者的克隆T细胞，确定这些T细胞 克隆抑制造血，无论是T细胞介导的抑制 造血是针对发育不良或正常的祖细胞，以及是否 加入到ATG治疗中的另外的T细胞定向的免疫抑制剂可 在随机临床试验中提高血细胞减少的恢复。

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.