Regulation of Chronic Colitis by Mesenchymal Stem Cells

间充质干细胞对慢性结肠炎的调节

• 批准号: 8848066
• 负责人: MATTHEW B GRISHAM
• 金额: $ 32.84万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8848066
• 关键词: Acute; Adoptive Transfer; Affect; Allogenic; Animal Model; Antigens; Attenuated; Autoimmunity; Bone Marrow; Cells; Chemical Injury; Chronic; Clinical; Colitis; Collagen-Induced Arthritis; Colon; Crohn' s disease; Data; Development; Disease; Disease Progression; Effector Cell; Enteral; Etiology; Experimental Autoimmune Encephalomyelitis; Future; Generations; Genetic; Histopathology; Home environment; Homing; Human; Immune; Immune response; Immune system; Immunologic Techniques; Immunosuppressive Agents; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Injury; Interleukin-10; Investigation; Laboratories; Lamina Propria; Lymphoid; Lymphoid Tissue; Major Histocompatibility Complex; Mediating; Medical; Mesenchymal Stem Cells; Mesentery; Modeling; Molecular; Mus; Nature; Operative Surgical Procedures; Oral Administration; Oral mucous membrane structure; Patients; Poison; Population; Positioning Attribute; Production; Rattus; Rectal Administration; Regulation; Regulatory T-Lymphocyte; Reporting; Small Intestines; Stem cells; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic Agents; Tissues; Treatment Efficacy; Ulcerative Colitis; Work; allograft rejection; attenuation; bone; cost; cytokine; genetic approach; in vitro activity; in vivo; lymph nodes; mouse model; novel therapeutics; prevent; public health relevance; response; trafficking

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.

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，影响着美国约 150 万人，计算出的每年医疗费用和工作损失近 40 亿美元。目前，只有少数药物可用于治疗这些使人衰弱的炎症性疾病，预计在不久的将来也只有少数新疗法可用。因此，显然需要 开发额外的治疗药物来治疗 IBD 患者。尽管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共生肠抗原的免疫反应失调引起的。最近的研究表明，骨髓间充质干细胞（MSC）在体外和体内具有有效的免疫调节活性。此外，最近的研究表明，间充质干细胞在不同的自身免疫小鼠模型中的免疫抑制活性并不局限于主要的组织相容性复合体，这表明间充质干细胞具有“免疫特权”。一些报告表明，同种异体或异种（人类）间充质干细胞的过继转移成功植入受体小鼠或大鼠体内，抑制自身免疫性脑脊髓炎、同种异体移植排斥、胶原诱导的关节炎和移植物抗宿主病动物模型中观察到的炎症。最近的一些研究报告称，小鼠或人类间充质干细胞可以减轻由口服或直肠施用有毒化学物质引起的糜烂性、自限性结肠炎。尽管令人信服，但尚未尝试评估人类或小鼠 MSC 在慢性肠道炎症动物模型中的治疗效果。 因此，我们将在特征明确的慢性结肠炎小鼠模型中评估人或小鼠骨髓来源的 MSC 的治疗效果。由于 MSC 可以在体外生长和扩增，并在体内跨越主要组织相容性复合物屏障发挥其免疫调节活性，因此我们处于独特的地位，可以在更接近地模拟人类 IBD 的动物模型中评估人类或小鼠 MSC 的治疗效果。我们假设离体产生的 MSC 归巢于肠系膜淋巴结 (MLN) 和/或结肠固有层，在那里它们通过产生有效的调节细胞因子 TGF¿1 (TGF¿) 直接预防/限制肠道炎症和/或通过诱导产生 IL-10 的调节性 T 细胞 (Treg) 的扩增间接预防/限制肠道炎症。为了检验这一假设，我们将： a) 使用小鼠慢性肠道炎症模型，在存在或不存在 MLN 或其他次级淋巴组织的情况下，评估人类或小鼠 MSC 抑制慢性肠道炎症诱导的能力； b) 确定人或小鼠 MSC 在存在或不存在 MLN 或其他次级淋巴组织的情况下逆转/减轻已有疾病的治疗功效，以及 c) 定义 MSC 用于减轻慢性肠道炎症的诱导和持续的免疫调节机制。除了更好地了解 MSC 用于抑制肠道炎症的调节机制之外，从拟议研究中获得的数据可能会确定可开发用于治疗 IBD 患者的新治疗策略。

项目成果

Use of Humanized Mice to Study the Pathogenesis of Autoimmune and Inflammatory Diseases.

• DOI: 10.1097/mib.0000000000000446
• 发表时间: 2015-07
• 期刊: Inflammatory bowel diseases
• 影响因子: 4.9
• 作者: Koboziev I;Jones-Hall Y;Valentine JF;Webb CR;Furr KL;Grisham MB
• 通讯作者: Grisham MB

Role of the enteric microbiota in intestinal homeostasis and inflammation.

肠性微生物群在肠内稳态和炎症中的作用。

• DOI: 10.1016/j.freeradbiomed.2013.11.008
• 发表时间: 2014-03
• 期刊: FREE RADICAL BIOLOGY AND MEDICINE
• 影响因子: 7.4
• 作者: Koboziev, Iurii;Webb, Cynthia Reinoso;Furr, Kathryn L.;Grisham, Matthew B.
• 通讯作者: Grisham, Matthew B.

Protective and pro-inflammatory roles of intestinal bacteria.

• DOI: 10.1016/j.pathophys.2016.02.002
• 发表时间: 2016-06
• 期刊: Pathophysiology : the official journal of the International Society for Pathophysiology
• 作者: Reinoso Webb C;Koboziev I;Furr KL;Grisham MB
• 通讯作者: Grisham MB