IMMUNOTHERAPY OF LOW RISK MYELODYSPLASTIC SYNDROME

描述(申请人提供)：骨髓增生异常综合征是一种 不同种类的渐进性、不可逆性造血干细胞 以进行性细胞减少为特征的疾病，没有治疗方法 有效的治疗方法。实验和临床证据表明， MDS患者淋巴细胞对自体淋巴细胞的抑制作用 造血细胞集落生长，这有助于细胞减少。 免疫抑制治疗，减少淋巴细胞数量或 抑制它们的功能，如皮质类固醇、环孢素和 抗胸腺细胞球蛋白(ATG)已被证明可以逆转这种细胞减少，而且在 在某些情况下可以减少骨髓中的原始细胞数量。这些淋巴细胞是如何 识别其靶抗原并抑制其造血祖细胞 未知。然而，相关的造血靶抗原的鉴定， 可能会为MDS带来有用的治疗方法，并将为其他 骨髓衰竭状态，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中 综合征，造血祖细胞的淋巴细胞抑制是通过 MHC限制性抗原激活的克隆性或寡克隆性T细胞 承认。这个项目的长期目标是调查 可以分离出与抑制骨髓祖细胞相关的克隆性T细胞 然后用于进一步鉴定相关的靶抗原。 然后，这些克隆性T细胞就可以在治疗中更具特异性 对MDS患者和识别T细胞靶细胞/抗原可能有帮助 确定淋巴细胞在人的发育过程中的比例贡献 MDS患者细胞减少。我们已经证明，对ATG有反应的MDS患者 治疗激活了CD8淋巴细胞，抑制了克隆形成 单位粒细胞巨噬细胞(CFU-GM)以MHC-I类限制性方式表达。 主要克隆性和寡克隆性淋巴细胞群体存在于 一些MDS患者的外周血和骨髓后来被一种 正态多克隆分布，这与重建 ATG治疗后有效的造血功能。拟议的研究将分离出 并鉴定MDS患者的克隆性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 造血针对的是发育不良或正常的祖细胞，以及 在ATG治疗中添加额外的T细胞导向免疫抑制剂可以 在一项随机临床试验中促进细胞减少症的恢复。

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.