Mesenchymal Stem Cel-Transplantion Tolerance Facilitator

描述(由申请人提供)：移植耐受性，或 永久接受同种异体移植物，不需要慢性 免疫抑制，在临床上仍然难以捉摸。诱因的策略 通过产生淋巴造血嵌合体而产生的耐受性 在小动物和大动物模型上的成功，一直受到 接受者的条件反射所涉及的毒性。宿主调理疗法 具有传统上需要消除或停用的元素 宿主-同种异体反应性T细胞和细胞还原治疗以释放利基 在骨髓微环境中进行同种异体植入。近期 干细胞生物学的进展已经提供了数据表明这一要求 对于细胞毒性治疗，可以通过使用非常大剂量的造血干细胞来克服。 对这一观察结果的可能解释包括竞争的改善 供者干细胞用于骨髓微环境和减少细胞毒作用的频率 T淋巴细胞前体与造血干细胞的直接相互作用 细胞。骨髓中的一种成分，它在很大程度上被忽视了， 鲜为人知的是MSC。这些基质元素，出现在非常低的位置 频率，是可以被诱导分化为 骨、肌肉、脂肪细胞、肌细胞和脑，并共享许多功能和 胸腺基质细胞的表型特征。此外，他们还可以 提供抑制或促进淋巴和骨髓生成的调节信号， 分化、增殖和分泌强有力的分子，如 转化生长因子-β、SDF-1、IL-7和成纤维细胞生长因子影响T、B细胞迁移。 有趣的是，将骨碎片移植到基质中 微环境与造血干细胞共同作用导致造血量增加 植入和移植耐受。我们已经证明了移植 没有造血干细胞的骨髓微环境也会导致 小鼠同种异体心脏移植的永久性接受。不同的捐款 骨和间充质干细胞在这些观察中的比例尚不清楚。我们的初步研究 提示MSCs可抑制混合淋巴细胞中T细胞的增殖 这种反应延长了狒狒的皮肤移植存活时间，也是狒狒骨骼的来源 骨髓室，从而潜在地影响宿主微环境。 这些观察使我们假设间充质干细胞具有免疫调节作用。 性质，并在诱导移植中起主要作用 宽容。第一个特定目标将测试小鼠骨髓间充质干细胞 骨髓和胸腺微环境中的移植和改变宿主T细胞 细胞谱系。对宿主免疫系统的影响机制将是 探索确定MSCs是否直接影响宿主T细胞或 MSCs在宿主体内诱导CD8自身调节亚群。《特定目标2》将进行测试 骨髓间充质干细胞能否在致死性移植中发挥促进剂作用 受过辐射的小鼠。我们还将测试MSCs是否可以消除对 最低条件下小鼠的高剂量肝星状细胞。关于捐赠者角色的见解 骨髓间充质干细胞在同种异体移植接受中的作用然后可能被应用于我们的临床前 用于开发新的临床前细胞疗法的恒河猴模型 移植耐受。

DESCRIPTION (provided by applicant): Transplantation tolerance, or the permanent acceptance of an allograft without the need for chronic immunosuppression, has remained clinically elusive. Strategies to induce tolerance through the production of lymphohematopoietic chimerism, though successful in small and large animal models, have been hampered by the toxicities involved in conditioning the recipient. Host conditioning regimens have traditionally required elements to eliminate or inactivate host-alloreactive T cells and cytoreductive treatment to liberate niches within the bone marrow microenvironment for allogeneic engraftment. Recent advances in stem cell biology have provided data indicating the requirement for cytotoxic therapy can be overcome by using very large doses of HSCs. Possible explanations of this observation have included improved competition of donor stem cells for marrow niches and diminished frequencies of cytotoxic T lymphocyte precursors by the direct interaction with hematopoietic stem cells. A component of the bone marrow that has largely been ignored and is poorly understood, is the MSC. These stromal elements, occurring in very low frequency, are multipotential cells that can be induced to differentiate into bone, muscle, adipocytes, myocytes, and brain and share many functional and phenotypical characteristics of thymic stromal cells. Further, they can provide regulatory signals that inhibit or promote lympho- and myelopoiesis, differentiation, and proliferation and secrete potent molecules, such as TGF-beta, SDF-1, IL-7, and FGF that affect T and B cell migration. Interestingly, the transplantation of bone fragments for stromal microenvironment in conjunction with HSCs has led to increased hematopoietic engraftment and transplantation tolerance. We have shown that transplantation of the bone marrow microenvironment without HSCs can also lead to the permanent acceptance of murine cardiac allografts. The separate contributions of bone and MSCs in these observations are unknown. Our preliminary studies suggest that MSCs can inhibit T cell proliferation in the mixed lymphocyte reaction, prolong skin graft survival in baboons, and home to the baboon bone marrow compartment, thereby potentially influencing the host microenvironment. These observations have led us to hypothesize that MSCs have immunomodulatory properties and play a major role in the induction of transplantation tolerance. The first specific aim will test the ability of mouse MSCs to engraft in the bone marrow and thymic microenvironments and to alter host T cell repertoire. The mechanism of effect on the host immune system will be explored to determine whether MSCs directly affect host T cells or whether MSCs induce a CD8 autoregulatory subset in the host. Specific aim 2 will test whether MSCs can function as facilitators of HSC engraftment in lethally irradiated mice. We will also test whether MSCs can eliminate the need for high dose HSC in minimally conditioned mice. Insights gained on the role donor MSCs play in allograft acceptance may then be applied to our pre-clinical baboon model for development of novel pre-clinical cellular therapies in transplantation tolerance.