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.在完成了他的实验室动物住院医师和T-32 NIH比较医学奖学金[7/21/2007]后，他将加入MGH的移植生物学研究中心（TBRC）担任博士后研究员。这种独特的研究环境提供了造血细胞移植（HCT）和免疫学领域的专家指导。他的经验和职业目标使他成为SERCA-NCRR/K 01的理想候选人，该奖项有助于他发展成为一名富有成效的独立调查员。杜兰博士将由医学博士大卫萨克斯指导，并由Christene Huang博士共同指导。无毒异基因HCT后供体白细胞输注（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治疗选择。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体的淋巴造血系统。这种疗法的主要局限性之一是移植物抗宿主病（GVHD）。MGH MHC近交系小型猪提供了一个相关的临床前模型，用于研究对HCT的反应类似于人类的移植生物学。最低限度的骨髓抑制准备方案在高剂量单倍相合HCT后导致稳定的多谱系嵌合体，而不引起GVHD。在大型动物中缺乏可移植肿瘤限制了在临床相关HCT模型中研究移植物抗肿瘤（GVT）效应。我们的具体目标1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。第二，初步实验表明，DLI在非清髓性猪模型中不能有效增加供体嵌合体。我们假设，残留的T细胞，可能是调节性T细胞，促进嵌合体和防止DLI转化为供体型失活供体，受体和DLI同种异体反应性T细胞。在具体目标#2中，我们将通过调节性T细胞的失活来检验这一假设，目的是改善供体嵌合状态并增强肿瘤模型中的GVL效应（目标#1）。TBRC由8个独立的实验室组成。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和组织移植在小型和大型动物模型。Duran-Struuck博士将随着项目的进展接触所有这些学科。

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.