MSC as facilitators of Transplantion Tolerance

描述（由申请人提供）： 移植耐受性，或 永久承兑 的 同种异体移植物 需要 慢性 免疫抑制，在临床上仍然是难以捉摸的。 诱导策略 然而，通过淋巴造血嵌合体的产生， 在小型和大型动物模型中取得成功， 与接受者条件反射有关的毒性。宿主预处理方案 有 传统上 需 元件 到 消除 或 灭活 宿主同种异体反应性T细胞和细胞减少治疗以释放小生境 在骨髓微环境中进行同种异体移植。最近 干细胞生物学的进展已经提供了数据表明， 可以通过使用非常大剂量的HSC来克服细胞毒性治疗。 对这一现象的可能解释包括竞争的改善 供体干细胞的骨髓龛和细胞毒性的频率降低 T淋巴细胞前体细胞通过与造血干细胞的直接相互作用 细胞骨髓的一种成分，在很大程度上被忽视， 不太了解的是MSC。 这些基质元素，发生在非常低的 频率，是多能细胞，可以诱导分化为 骨、肌肉、脂肪细胞、肌细胞和脑，并且共享许多功能和 胸腺基质细胞的表型特征。 此外，他们可以 提供抑制或促进淋巴细胞和骨髓生成的调节信号， 分化和增殖，并分泌有效的分子，如 TGF-β、SDF-1、IL-7和FGF影响T细胞增殖， B细胞迁移 有趣的是， 的 移植 的 骨 片段 为 基质 微环境与造血干细胞的结合导致造血干细胞的增加， 植入和移植耐受。 我们已经证明移植 没有HSC的骨髓微环境也会导致 小鼠心脏移植物的永久接受。单独捐款 骨和MSC在这些观察中的作用是未知的。我们的初步研究 提示MSCs可抑制混合淋巴细胞中T细胞增殖 反应，延长皮肤移植存活狒狒，和家狒狒骨 骨髓隔室，从而潜在地影响宿主微环境。 这些观察结果使我们假设MSC具有免疫调节作用。 在诱导移植中起主要作用 宽容 第一个具体目标将测试小鼠MSC的能力， 移植到骨髓和胸腺微环境中，并改变宿主T 细胞库对宿主免疫系统的作用机制将是 探索以确定MSC是否直接影响宿主T细胞或是否 MSC在宿主中诱导CD 8自身调节亚群。具体目标2将测试 MSC是否可以作为HSC植入的促进剂， 辐射小鼠我们还将测试MSC是否可以消除对 高剂量HSC在最低条件小鼠中的作用。对捐助方作用的认识 MSC在同种异体移植物接受中的作用可以应用于我们的临床前研究。 狒狒模型，用于开发新的临床前细胞疗法， 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.