THE ROLE OF TNF-ALPHA IN LYMPHOCYTE DEVELOPMENT IN NOD MICE

肿瘤坏死因子-α是一种促炎细胞因子 这对多种组织都有多效性。的作用 肿瘤坏死因子-α在胰岛素依赖型糖尿病(IDDM)中的作用 有争议的问题。先前的研究表明，在体外，肿瘤坏死因子- 阿尔法与IL-1等其他细胞因子相结合，对 成人体内应用肿瘤坏死因子-α时的胰岛β细胞 非肥胖糖尿病(NOD)小鼠可以预防糖尿病。最近，它已经 研究表明，肿瘤坏死因子-α是在胸腺早期产生的 发展和给予抗肿瘤坏死因子-α抗体可以阻断 小鼠胸腺发育正常。有趣的是，我们最新的研究 已经证明在新生的NOD小鼠中注射肿瘤坏死因子-α， 与成年小鼠的结果相反，它会加速疾病 在抗肿瘤坏死因子-α治疗期间发病并完全抑制胰岛素炎 预防糖尿病。这些数据表明，肿瘤坏死因子-α可能在 在淋巴细胞发育中的关键作用，特别是在 产生对胰岛β细胞的自身免疫。我们建议的研究 将集中在肿瘤坏死因子-α通过细胞和分子机制 可以同时影响胸腺中未成熟淋巴细胞的发育和 成熟的辅助性T细胞和效应细胞毒性淋巴细胞的功能。 将使用的方法将包括：(1)治疗新生NOD小鼠 用肿瘤坏死因子-α或抗肿瘤坏死因子-α的单抗； 肿瘤坏死因子-α对正常淋巴细胞发育和阴性淋巴细胞的影响 选择；(3)确定肿瘤坏死因子-α在调节中的作用 自身抗原特异性Th1与Th2反应的比较；(4)肿瘤坏死因子- Alpha介导的胰岛β特异性细胞毒活性 以及(4)评估肿瘤坏死因子-α对细胞的潜在影响。 淋巴细胞归巢至胰岛。这些研究可能会导致 进一步了解IDDM的免疫发病机制。一个推论 这项工作的一项工作是可能开发新的方法来 胰岛素依赖型糖尿病的细胞因子免疫治疗。

Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine that has pleiotropic effects on a wide variety of tissues. The role of TNF-alpha in insulin-dependent diabetes mellitus (IDDM) has been a controversial issue. Previous studies have shown that in vitro, TNF- alpha in combination with other cytokines such as IL-1 is cytotoxic to pancreatic beta cells while administration of TNF-alpha in vivo in adult non-obese diabetic (NOD) mice can prevent diabetes. Recently, it has been shown that TNF-alpha is produced very early during thymic development and that administration of anti-TNF-alpha antibody can block normal thymic development in mice. Interestingly, our most recent study has demonstrated that administration of TNF-alpha in newborn NOD mice, in contrast to the result obtained with adult mice, accelerates disease onset while anti-TNF-alpha treatment inhibits insulitis and completely prevents diabetes. These data indicate that TNF-alpha may play a critical role in lymphocyte development and particularly in the generation of autoimmunity to pancreatic beta cells. Our proposed study will focus on the cellular and molecular mechanisms by which TNF-alpha can effect both the development of immature lymphocytes in the thymus and the function of mature T helper cells and effector cytotoxic lymphocytes. The approaches to be used will include: (1) treatment of newborn NOD mice with TNF-alpha or monoclonal anti-TNF-alpha antibody; (2) examination of TNF-alpha's effect on normal lymphocyte development, and on negative selection; (3) determination of the role of TNF-alpha in the regulation of autoantigen-specific Th1 vs. Th2 responses; (4) measurement of TNF- alpha mediated specific cytotoxic activity specific for pancreatic beta cells; and (4) assessment of the potential effect of TNF-alpha on lymphocyte homing to the pancreatic islets. These studies may lead to a further understanding of the immunopathogenesis of IDDM. A corollary of this work is the possible development of novel approaches for cytokine-based immunotherapy of IDDM.