T CELL ACTIVITIES PROMOTING GVL, GVHD, & ALLOENGRAFTMENT

促进 GVL、GVHD 的 T 细胞活动

• 批准号: 2107652
• 负责人: Megan Sykes
• 金额: $ 17.93万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-12 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2107652
• 关键词: MHC class II antigen; T lymphocyte; acute monocytic leukemia; bone marrow transplantation; cell mediated lymphocytolysis test; cell population study; cell sorting; chronic lymphocytic leukemia; clone cells; cytokine; cytolysis; cytotoxic T lymphocyte; disease /disorder model; enzyme linked immunosorbent assay; graft versus host disease; helper T lymphocyte; homologous transplantation; hybridomas; interleukin 2; laboratory mouse; leukemia; lymphokine activated killer cell; monoclonal antibody; polymerase chain reaction

The complication of GVHD currently prohibits the application of bone marrow transplantation across extensive HLA barriers. T cell depletion of allogeneic marrow effectively prevents GVHD, but is associated with increased risks of leukemic relapse and of engraftment failure. We have shown that GVHD-promoting activity can be separated from the graft-vs- leukemia (GVL) and engraftment-promoting effects of host-reactive T cells, and the goal of this proposal is to further explore strategies for achieving this separation. These are: 1) Prophylaxis of mice with a short peri-transplant course of IL-2 inhibits GVHD while preserving engraftment-promoting and GVL effects of donor T cells. IL-2 selectively inhibits CD4 activity, and preserves GVL effects of CD8+ cells. Furthermore, while inhibiting CD4-dependent GVHD=mediated GVL against a class II MHC-positive pro-monocytic leukemia. Therefore, separate activities of CD4+ T cells can mediate GVHD or GVL effects, and these can be dissociated by IL-2 treatment. We will attempt to distinguish these activities and to determine which ones are inhibited by IL-2 treatment by evaluating the role of cytolytic cells and of various cytokines in CD4-mediated GVHD and in CD4- and CD8-mediated GVL effects in the class II-positive promonocytic leukemia model; 2) CD8+ T cells can mediate CD4-independent GVL effects, but are largely CD4-dependent for their capacity to cause severe acute GVHD in fully histoincompatible strain combinations. In fact, when donor CD8+ cells are given without CD4+ cells, the severity of GVHD directed against minor histoincompatibilities alone is at least as severe as that directed against the same minor antigens in association with allogeneic MHC (including class I) antigens. This failure of MHC disparity to increase the severity of CD9-mediated GVHD suggests that administration of CD8+ T cells without CD4+ cells might permit HLA-mismatched BMT to be performed with no greater incidence of GVHD than is observed for HLA-matched sibling transplants. To evaluate the potential of this approach, we will attempt to delineate the genetic factors and host cell populations that influence the capacity of CD8+ T cells given without CD4+ cells to cause GVHD, and will determine the requirement for each T cell subset to achieve optimal alloengraftment in the setting of various genetic disparities. Finally, we will: 3) evaluate the possibility that cure of chronic lymphocytic leukemia could be achieved without ablative conditioning by using allogeneic T cell infusion to established mixed chimeras. Donor T cells administered to established mixed allogeneic chimeras prepared with a mild, non- myeloablative conditioning regimen lymphohematopoietic GVH reactions without causing GVHD. These lymphohematopoietic GVH reactions might be associated with GVL effects. This approach could be applicable in elderly patients with chronic lymphocytic leukemia, who are not eligible for conventional BMT because of their high incidence of GVHD. Together, our studies may lead to new clinical strategies for preserving potentially potent GVL effects of MHC-reactive T cells while minimizing GVHD.

GVHD的并发症目前禁止骨移植的应用 骨髓移植跨越广泛的 HLA 屏障。 T细胞耗竭 同种异体骨髓可有效预防 GVHD，但与 白血病复发和植入失败的风险增加。 我们有 表明 GVHD 促进活性可以与移植物抗 白血病 (GVL) 和宿主反应性 T 的植入促进作用 细胞，该提案的目标是进一步探索策略 实现这种分离。 这些是： 1) 对患有以下疾病的小鼠进行预防 IL-2 的围移植期短疗程可抑制 GVHD，同时保留 供体 T 细胞的植入促进和 GVL 作用。 选择性IL-2 抑制 CD4 活性，并保留 CD8+ 细胞的 GVL 效应。 此外，在抑制 CD4 依赖性 GVHD=介导的 GVL 的同时， II 类 MHC 阳性前单核细胞白血病。 因此，分开 CD4+ T 细胞的活性可以介导 GVHD 或 GVL 效应，并且这些可以 通过IL-2处理解离。 我们将尝试区分这些 活性并确定哪些活性受到 IL-2 治疗的抑制 通过评估溶细胞细胞和各种细胞因子的作用 CD4介导的GVHD以及CD4和CD8介导的GVL效应中的类 II阳性早幼粒细胞白血病模型； 2）CD8+T细胞可以介导 不依赖 CD4 的 GVL 效应，但很大程度上依赖于 CD4 在完全组织不相容的菌株中引起严重急性 GVHD 的能力 组合。 事实上，当供体 CD8+ 细胞不含 CD4+ 时 细胞，针对轻微组织不相容性的 GVHD 严重程度 单独的行为至少与针对同一未成年人的行为一样严重 与同种异体 MHC（包括 I 类）抗原相关的抗原。 MHC 差异未能增加 CD9 介导的严重性 GVHD 表明只给予 CD8+ T 细胞而不给予 CD4+ 细胞 可能允许在不增加发生率的情况下进行 HLA 不匹配的 BMT GVHD 的发生率高于 HLA 匹配的同胞移植物。 到 评估这种方法的潜力，我们将尝试描绘 影响能力的遗传因素和宿主细胞群 不给予 CD4+ 细胞的 CD8+ T 细胞会引起 GVHD，并将确定 每个 T 细胞亚群实现最佳同种异体移植的要求 在各种遗传差异的背景下。 最后，我们将：3) 评估治愈慢性淋巴细胞白血病的可能性 通过使用同种异体 T 细胞无需消融调理即可实现 输注至已建立的混合嵌合体。 供体 T 细胞施用至 建立了混合同种异体嵌合体，用温和的、非 清髓性预处理方案 淋巴造血 GVH 反应 而不引起GVHD。 这些淋巴造血 GVH 反应可能是 与 GVL 效应有关。这个方法可能适用于老年人 患有慢性淋巴细胞白血病且不符合治疗条件的患者 传统的 BMT 因其 GVHD 的发生率较高。 在一起，我们的 研究可能会带来新的临床策略，以保留潜在的 MHC 反应性 T 细胞的有效 GVL 效应，同时最大限度地减少 GVHD。