T CELL ACTIVITIES PROMOTING GVL, GVHD, & ALLOENGRAFTMENT

促进 GVL、GVHD 的 T 细胞活动

基本信息

批准号：
2429827
负责人：
Megan Sykes
金额：
$ 17.97万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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

项目摘要

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骼应用骨髓移植在广泛的HLA屏障上。 T细胞耗竭同种异体骨髓有效地阻止了GVHD，但与白血病复发和植入失败的风险增加。我们有表明可以将促进GVHD促进活性与移植VS-分离白血病（GVL）和宿主反应T的植入效应牢房，该提案的目的是进一步探索实现这种分离。这些是：1）用A的小鼠预防 IL-2的短期移植课程在保存时抑制GVHD 供体T细胞的促进和GVL效应。 IL-2有选择地抑制CD4活性，并保留CD8+细胞的GVL效应。此外，虽然抑制CD4依赖性GVHD =介导的GVL对A II类MHC阳性促肌细胞白血病。因此，分开 CD4+ T细胞的活性可以介导GVHD或GVL效应，这些可以通过IL-2处理解离。我们将尝试区分这些活动并确定通过IL-2治疗抑制哪些活动通过评估细胞溶细胞和各种细胞因子在 CD4介导的GVHD以及CD4和CD8介导的GVL效应中的类别 II阳性前卫白血病模型； 2）CD8+ T细胞可以介导与CD4无关的GVL效应，但在很大程度上依赖于CD4 在完全兼容的应变中引起严重的急性GVHD的能力组合。实际上，当给出没有CD4+的供体CD8+细胞时细胞，针对较小的组织兼容性的GVHD的严重程度至少与针对同一未成年人的那样严重与同种异体MHC（包括I类）抗原相关的抗原。 MHC差异的这种失败增加了CD9介导的严重程度 GVHD表明给药CD8+ T细胞没有CD4+细胞可能会允许HLA不匹配的BMT执行，没有更大的发病率与HLA匹配的同胞移植物相比，GVHD的of。到评估这种方法的潜力，我们将尝试描述影响能力的遗传因素和宿主细胞群 CD8+ T细胞没有CD4+细胞引起GVHD，并将确定每个T细胞子集的要求在各种遗传差异的情况下。最后，我们将：3）评估治愈慢性淋巴细胞性白血病的可能性可以通过使用同种异体T细胞而无需消融条件即可实现注入已建立的混合嵌合体。供体T细胞给药建立的混合嵌合体，由轻度，非 - 脊髓疾病方案淋巴结腾学GVH反应不引起GVHD。这些淋巴瘤的GVH反应可能是与GVL效应相关。这种方法可能适用于老年人慢性淋巴细胞性白血病患者，不符合资格传统的BMT是因为它们的GVHD发病率很高。在一起，我们的研究可能导致新的临床策略来保护潜在的最小化GVHD的同时，MHC反应性T细胞的有效GVL效应。