Regulation of Chronic Colitis by Mesenchymal Stem Cells

描述（由申请人提供）：炎症性肠病（IBD;克罗恩病;溃疡性结肠炎）是小肠和/或结肠的慢性炎症性疾病，在美国影响约150万人，计算的医疗费用和工作损失的年成本接近40亿美元。目前，只有少数医学治疗可用于治疗这些使人衰弱的炎症性疾病，预计在不久的将来只有少数新疗法可用。因此，显然需要 开发治疗IBD患者的其他治疗剂。虽然克罗恩病和溃疡性结肠炎的病因尚未完全阐明，但越来越多的临床和实验证据表明，慢性肠道炎症是由对肠道抗原的免疫应答失调引起的。骨髓间充质干细胞（MSCs）在体内外均具有较强的免疫调节活性。此外，最近的研究表明，MSC在不同的小鼠自身免疫模型中的免疫抑制活性并不限于主要组织相容性复合物，这表明MSC是“免疫特权”的。几个报告表明，同种异体或异种（人）MSC的过继转移成功地植入受体小鼠或大鼠中，在那里它们抑制在自身免疫性脑脊髓炎、同种异体移植物排斥、胶原诱导的关节炎和移植物抗宿主病的动物模型中观察到的炎症。最近的一项研究报道，小鼠或人MSC减轻了由口服或直肠给予有毒化学物质诱导的糜烂性、自限性结肠炎。尽管令人信服，但尚未尝试评估人或小鼠MSC在慢性肠道炎症动物模型中的治疗功效。 因此，我们将评估人或小鼠骨髓来源的MSC在充分表征的慢性结肠炎小鼠模型中的治疗功效。由于间充质干细胞可以在体外生长和扩增，并在体内发挥其免疫调节活性，跨越主要组织相容性复合物屏障，我们处于独特的地位，以评估人类或小鼠间充质干细胞在动物模型中的治疗效果，更密切地模仿人类IBD。我们假设离体产生的MSC归巢到肠系膜淋巴结（MLN）和/或结肠固有层，在那里它们直接通过产生有效的调节细胞因子TGF？1（TGF？）和/或间接通过诱导产生IL-10的调节性T细胞（TGF？）的扩增来预防/限制肠道炎症。a）使用慢性肠道炎症的小鼠模型，在存在或不存在MLN或其它次级淋巴组织的情况下，评价人或小鼠MSC抑制慢性肠道炎症诱导的能力; B）确定人或小鼠MSC在逆转/抑制细胞增殖中的治疗功效。在存在或不存在MLN或其他次级淋巴组织的情况下减弱预先存在的疾病，和c）定义MSC用于减弱慢性肠道炎症的诱导和持续的免疫调节机制。除了更好地理解MSC用于抑制肠道炎症的调节机制外，从拟议研究中获得的数据可能会确定可用于治疗IBD患者的新治疗策略。

DESCRIPTION (provided by applicant): The inflammatory bowel diseases (IBD; Crohn's disease; ulcerative colitis) are chronic inflammatory disorders of the small bowel and/or colon that affect approximately 1.5 million people in the US with a calculated annual cost for both medical expenses and work loss of almost $4 billion dollars. Currently, there are only a handful of medical treatments available for treating these debilitating inflammatory disorders with only a few new therapies projected to be available in the near future. Thus, there is a clear need for the development of additional therapeutic agents to treat patients with IBD. Although the etiologies of Crohn's disease and ulcerative colitis have yet to be fully elucidated, there is growing clinica and experimental evidence to suggest that chronic gut inflammation results from a dysregulated immune response to commensal enteric antigens. Recent studies demonstrate that bone marrow-derived mesenchymal stem cells (MSCs) have potent immunoregulatory activity in vitro and in vivo. In addition, recent investigations show that the immunosuppressive activity of MSCs in different mouse models of autoimmunity is not restricted to the major histocompatibility complex suggesting that MSCs are "immune-privileged". Several reports demonstrate that adoptive transfer of allogeneic or xenogeneic (human) MSCs successfully engraft in recipient mice or rats where they suppress the inflammation observed in animal models of autoimmune encephalomyelitis, allograft rejection, collagen-induced arthritis and graft vs. host disease. A fe recent studies have reported that mouse or human MSCs attenuate the erosive, self-limiting colitis induced by the oral or rectal administration of toxic chemicals. Although compelling, no attempt has been made to evaluate the therapeutic efficacy of human or mouse MSCs in an animal model of chronic gut inflammation. Therefore, we will evaluate the therapeutic efficacy of human or mouse bone marrow-derived MSCs in a well-characterized, mouse model of chronic colitis. Because MSCs can be grown and expanded in vitro and exert their immunoregulatory activity across major histocompatibility complex barriers in vivo, we are in the unique position to evaluate the therapeutic efficacy of human or mouse MSCs in an animal model that more closely mimics human IBD. We hypothesize that ex vivo-generated MSCs home to the mesenteric lymph nodes (MLNs) and/or colonic lamina propria where they prevent/limit gut inflammation directly via their production of the potent regulatory cytokine TGF¿1 (TGF¿) and/or indirectly by inducing the expansion of IL-10-producing regulatory T-cells (Tregs). In order to test this hypothesis we will: a) Evaluate the ability of human or mouse MSCs to suppress the induction of chronic gut inflammation in the presence or absence of MLNs or other secondary lymphoid tissue using mouse models of chronic intestinal inflammation; b) Determine the therapeutic efficacy of human or mouse MSCs in reversing/attenuating preexisting disease in the presence or absence of MLNs or other secondary lymphoid tissue and c) Define the immunoregulatory mechanisms utilized by MSCs to attenuate the induction and perpetuation of chronic gut inflammation. In addition to better understanding the regulatory mechanisms used by MSCs to suppress intestinal inflammation, data obtained from the proposed studies may identify new therapeutic strategies that could be developed to treat patients with IBD.