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.，在完成他的联合实验动物住院医生和T-32 NIH比较医学奖学金[7/21/2007]后，将作为博士后研究员加入MGH移植生物学研究中心。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，这一奖项有助于他发展成为一名富有成效的独立调查员。杜兰博士将由David Sachs医学博士指导，并由Christene Huang博士共同指导。无毒异基因HCT和供者白细胞输注(DLI)已成为各种淋巴造血系统恶性肿瘤、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的目标是用供者的合格淋巴造血系统取代受者的淋巴造血系统。这种疗法的主要局限性之一是移植物抗宿主病(GVHD)。MGH-MHC近交系小型猪为移植生物学研究提供了一个相关的临床前模型，其对HCT的反应与人类相似。在大剂量单倍体相合的HCT后，最小限度的骨髓抑制准备方案可导致稳定的多系嵌合体，而不会引起GVHD。在大型动物身上缺乏可移植的肿瘤限制了在临床相关的HCT模型中移植物抗肿瘤(GVT)效应的研究。我们在具体目标#1中的目标是开发一种猪肿瘤模型，用于体内评估HCT和DLI的移植物抗肿瘤效应。其次，初步实验表明，在非清髓猪模型中，DLI在增加供体嵌合体方面并不有效。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，促进嵌合体的形成，防止DLI向供体类型的转化。在特定的目标#2中，我们将通过灭活调节性T细胞来检验这一假说，目的是改善供体嵌合体并增强肿瘤模型中的GVL效应(目标#1)。TBRC由八个独立的实验室组成。这些领域包括分子生物学、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大小动物模型中的组织移植。随着项目的进展，杜兰-斯特鲁克博士将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.