Cytokines And Growth Factors In Autoimmune Diseases

细胞因子和生长因子在免疫功能的正常内稳态中起着关键作用。转化生长因子-β1是炎症反应的主要调节因子。我们早先建立了转化生长因子-1-/-小鼠，表现出与白细胞与内皮细胞黏附增加相关的多灶性炎症，MHC-I和-II类抗原的异常表达，以及类似于干燥综合征的自身免疫表现。此外，去除CD8细胞改善了转化生长因子-1基因缺失小鼠的健康状况。为了阐明转化生长因子-1在MHC异常表达中的作用，在MHC-I和MHC-II缺乏的背景下产生了转化生长因子-1缺失的小鼠。转化生长因子-1X MHC-I缺失小鼠的寿命延长，炎症减轻，自身免疫表现减少，骨髓生成显著增加。尽管转化生长因子-1X MHC-II小鼠缺乏炎症和自身免疫反应，但它们的新生儿死亡率与增加的骨髓生成和化生有关。这些结果表明，转化生长因子-β1在白细胞成熟和功能中起主导作用。 为了评估循环中活性转化生长因子-1水平的治疗潜力，我们通过将转化生长因子-1(+/-)小鼠与转基因小鼠(TG)杂交，在转化生长因子-1缺失背景(转化生长因子-1(-/-/TG)的背景下产生内分泌表达活性转化生长因子-1的小鼠(-/-/TG)，转基因小鼠(TG)在肝脏中特异性表达重组转化生长因子-1并在血液中分泌。转化生长因子-1(-/-/TG)小鼠的存活曲线与转化生长因子-1(-/-)小鼠相似，表明未能挽救致死表型。然而，转化生长因子-β1(-/-/TG)组小鼠的血清转化生长因子-β1水平恢复到正常水平，在所有组织中都有表达，尤其是在肾脏和脾组织。组织病理学显示，所有靶组织的炎症反应都有所减轻，特别是心脏。有趣的是，与转化生长因子β(-/-)小鼠不同的是，转化生长因子-1(-/-/甘油三酯)小鼠的肾脏中的肾小球肾炎与转基因小鼠相似。因此，动物模型的表型提示了循环活性的转化生长因子-1在减轻炎症中的潜在作用，但它不能挽救转化生长因子-1缺失的小鼠的致死性，表明自分泌转化生长因子-1的关键作用。

Cytokines and growth factors play critical roles in normal homeostasis of immune functions. TGF-?1 is the dominant regulator of inflammatory responses. We have earlier generated TGF-?1-/- mice that exhibit multifocal inflammation associated with increased adhesion of leukocytes to endothelium, aberrant expression of MHC class-I and -II antigens, and autoimmune manifestations similar to Sjogren syndrome. Moreover, depletion of CD8 cells ameliorated health status of TGF-?1 null mice. To delineate role of TGF-?1 in aberrant MHC expression, TGF-?1 null mice were generated in the MHC-I and MHC-II deficient backgrounds. TGF-?1 X MHC-I null mice exhibit increased longevity associated with reduced inflammation, diminished autoimmune manifestations and significantly elevated myelopoiesis. Although the TGF-?1 X MHC-II mice exhibited lack of inflammation and autoimmune response, they showed neonatal mortality associated with increased myelopoiesis and metaplasia. These results indicate a dominant role of TGF-?1 in leukocyte maturation and function. To assess the therapeutic potential of circulating levels of active TGF-?1, we generated mice with endocrine expression of active TGF-?1 on a TGF-?1 null background (TGF-?1(-/-/TG)) by crossing TGF-?1(+/-) mice with transgenic mice (TG) that express recombinant TGF-?1 specifically in the liver and secrete it in the blood. The TGF-_1(-/-/TG) mice exhibit a survival profile similar to the TGF-?1 (-/-) mice indicating a failure to rescue the lethal phenotype. However, serum TGF-?1 levels in theTGF-?1 (-/-/TG) mice were restored to normal levels with expression in all the tissues notably in the kidney and spleen. Histopathology showed reduced inflammation in all target tissues, especially in the heart. Interestingly unlike TGF-? (-/-) mice, the TGF-?1(-/-/TG) mice have glomerulonephritis in their kidneys similar to the TG mice. Thus, the phenotype of TGF-?1 (-/-/TG) animal model indicates the potential role of circulating active-TGF-_1 in reducing inflammation, but its failure to rescue lethality in TGF-_1 null mice indicates a critical role of autocrine TGF-?1.