MARROW TRANSPLANT IN CANCER THERAPY T CELL RECOVERY

这项研究的长期目标是开发免疫疗法，以预防异基因骨髓移植受者中的病毒感染。相合的非亲缘供者和不匹配的亲缘供者骨髓移植的使用增加了移植物抗宿主病(GVHD)的风险，在GVHD中，供者的T细胞对受者的人类白细胞抗原(HL A)产生反应。这种同种异体移植通常会耗尽成熟的T细胞来预防GVHD，使受者在T细胞反应重建之前容易受到病毒感染。如果供者外周血单个核细胞(PBMC)中的记忆T细胞能够安全地转移到骨髓移植接受者，病毒感染和疾病就可以预防。以前的资金已经使一种新的耗尽策略得以开发，在这种策略中，对宿主人类白细胞抗原有反应的T细胞被选择性地从供者PBMC中移除。供体细胞与宿主来源的抗原提呈细胞在体外共培养，根据细胞大小和表型去除对这种刺激反应的供体细胞。荧光激活的细胞分选严格耗尽宿主反应性T细胞，包括那些仅微弱表达激活抗原的T细胞。这里提出的研究验证了这样的假设，即同种异体供体T细胞可以在保持病毒特异性活性的同时消除GVHD潜力。验证这一假说的具体目的是：1.将宿主特异性T细胞耗竭(HSTD)技术应用于临床。2.确定向异基因骨髓移植受者注射剂量递增的HSTD细胞的安全性。3.检测输注HSTD后骨髓移植受者的T细胞功能。安全输送具有广泛抗病毒特异性的成熟T细胞可能会保护异基因骨髓移植受者免受病毒感染的发病率和死亡率的影响。最终，无GVHD潜能的供者T细胞的临床可获得性可能会提高骨髓移植的成功率和适用性。在圣犹大儿童研究医院(SJCRH)，PI和共同PI已经证明了他们将基础实验室研究转化为可测试的临床假设的能力，预测了拟议研究的成功实施。

The long-term objective of this research is to develop immunotherapies for preventing viral infections among recipients of allogeneic bone marrow transplants. The growing use of matched unrelated-donor and mismatched related-donor bone marrow transplantation has increased the risk of graft-versus-host disease (GVHD), in which the donor T cells respond to recipient human leukocyte antigens (HLA). Such allogeneic grafts are routinely depleted of mature T cells to prevent GVHD, rendering recipients vulnerable to viral infections until the T-cell response has been reconstituted. Viral infections and disease could be prevented if memory T cells from donor peripheral blood mononuclear cells (PBMC) could be made safe for transfer to BMT recipients. Previous funding has allowed the development of a novel depletion strategy in which T cells responsive to host HLA are selectively removed from donor PBMC. Donor cells are co-cultivated in vitro with host-derived antigen presenting cells, and donor cells responding to this stimulation are removed based on cell size and phenotype. Fluorescence-activated cell sorting stringently depletes host-reactive T cells, including those that express activation antigens only weakly. Studies proposed here test the hypothesis that allogeneic donor T cells can be depleted of GVHD potential while preserving virus-specific activity. Specific aims to test this hypothesis are to: 1. Implement host-specific T-cell depletion (HSTD) technology for clinical application. 2. Determine the safety of administering escalating doses of HSTD cells to allogeneic bone marrow transplant recipients. 3. Characterize T cell function transferred to BMT recipients following HSTD infusions. Safe delivery of mature T cells with broad anti-viral specificities may protect recipients of allogeneic BMT from the morbidity and mortality of viral infections. Ultimately, clinical availability of donor T cells free of GVHD potential may enhance the success and applicability of bone marrow transplantation. The PI and co-PI have demonstrated their ability to translate basic laboratory studies into testable clinical hypotheses at St. Jude Children's Research Hospital (SJCRH), predicting successful implementation of the proposed studies.