DEVELOPMENT OF A LARGE ANIMAL TUMOR MODEL FOR ASSESSING GVL IMMUNOTHERAPY

描述（由申请人提供）：Raimon Duran-Struuck， D.V.M.在完成他的实验动物实习和T-32 NIH比较医学奖学金[2007年7月21日]之后，将作为博士后加入MGH移植生物学研究中心（TBRC）。这种独特的研究环境为造血细胞移植（HCT）和免疫学领域的专家提供了指导。他的经验和职业目标使他成为SERCA-NCRR/K01的理想候选人，这个奖项对他发展成为一名富有成效的独立调查员很有帮助。Duran博士将由David Sachs医学博士指导，Christene Huang博士共同指导。无毒同种异体HCT后供体白细胞输注（DLI）已成为多种淋巴造血恶性肿瘤、免疫缺陷和骨髓衰竭综合征的首选治疗方法。对于这些疾病，HCT的目标是用来自供体的有能力的淋巴造血系统替换受者的淋巴造血系统。该疗法的主要局限性之一是移植物抗宿主病（GVHD）。MGH mhc近交系微型猪对HCT的反应与人类相似，为移植生物学研究提供了相关的临床前模型。在高剂量单倍相同HCT后，最低限度的骨髓抑制预备方案可导致稳定的多系嵌合，而不会引起GVHD。大型动物中缺乏可移植肿瘤，限制了临床相关HCT模型中移植物抗肿瘤（GVT）效应的研究。我们的目标是开发一种猪肿瘤模型，用于体内评估HCT和DLI的移植物抗肿瘤作用。其次，初步实验表明，在非清髓猪模型中，DLI不能有效地增加供体嵌合。我们假设残留的t细胞，可能还有调节性t细胞，通过灭活供体、受体和DLI同种异体反应性t细胞，促进嵌合并阻止DLI转化为供体型。在特异性目标2中，我们将通过调节T细胞的失活来验证这一假设，目的是改善供体嵌合并增强肿瘤模型中的GVL效应（目标1）。TBRC由八个独立实验室组成。这些包括分子生物学、细胞免疫学、干细胞生物学、T细胞和抗体多样性的研究以及小动物和大动物模型的组织移植。杜兰-斯特鲁克博士将在他的项目进展中接触到所有这些学科。

DESCRIPTION (provided by applicant): Raimon Duran-Struuck, D.V.M. after completion of his combined laboratory animal residency and T-32 NIH fellowship in comparative medicine [7/21/2007], will join the Transplantation Biology Research Center (TBRC) at MGH as a post-doctoral fellow. This unique research environment provides mentorship by experts in the fields of hematopoietic cell transplantation (HCT) and immunology. His experience and career goals make him an ideal candidate for the SERCA-NCRR/K01 and this award is instrumental for his development into a productive independent investigator. Dr. Duran will be mentored by David Sachs, M.D., and co-mentored by Christene Huang, Ph.D. Non-toxic allogeneic HCT followed by donor leukocyte infusion (DLI) has emerged as the treatment of choice for a variety of lymphohematopoietic malignancies, immunodeficiencies, and marrow failure syndromes. For these diseases, the goal of HCT is the replacement of the recipients' lymphohematopoietic system, with a competent one from the donor. One of the major limitations of this therapy is graft-versus-host disease (GVHD). MGH MHC-inbred miniature swine provide a relevant pre-clinical model for studies of transplantation biology with responses to HCT resembling those of humans. Minimally myelosuppressive preparative regimen leads to stable multi-lineage chimerism following high-dose haplo-identical HCT, without causing GVHD. The lack of transplantable tumors in large animals has limited the study of the graft -versus-tumor (GVT) effects in clinically relevant HCT models. It is our goal in specific aim #1 to develop a swine tumor model for the in vivo assessment of graft-versus-tumor effects of HCT and DLI. Second, preliminary experiments demonstrated that DLI was not effective at increasing donor chimerism in a non-myeloablative swine model. We hypothesize that residual T-cells, and possibly regulatory T-cells, promote chimerism and prevent DLI conversion to donor-type by inactivating donor, recipient and DLI alloreactive T-cells. In Specific aim #2, we will test this hypothesis through the inactivation of regulatory T cells with the goal to improve donor chimerism and enhance the GVL effects in the tumor models (aim #1). The TBRC consists of eight independent laboratories. These include molecular biology, cellular immunology, stem cell biology, study of T cell and antibody diversity and tissue transplantation in small and large animal models. Dr. Duran-Struuck will be exposed to all of these disciplines as his project progresses.