Cytokines And Growth Factors In Autoimmune Diseases

细胞因子和生长因子在免疫功能的正常稳态中起关键作用。TGF-？1是炎症反应的主要调节因子。我们之前已经产生了TGF-？1-/-小鼠表现出与白细胞与内皮细胞粘附增加、MHC I类和II类抗原异常表达以及类似于舍格伦综合征的自身免疫表现相关的多灶性炎症。此外，耗尽的CD 8细胞改善健康状况的TGF-？1只无效小鼠。探讨TGF-？1异常MHC表达，TGF-？在MHC-I和MHC-II缺陷背景中产生1个无效小鼠。TGF-？IX MHC-I缺失小鼠表现出与炎症减少、自身免疫表现减少和骨髓生成显著升高相关的寿命增加。虽然TGF-？1X MHC-II小鼠表现出缺乏炎症和自身免疫应答，它们表现出与增加的骨髓生成和化生相关的新生儿死亡率。这些结果表明，TGF-？1在白细胞成熟和功能中的作用。 为了评估治疗潜力的循环水平的活性TGF-？1，我们产生的小鼠内分泌表达活性TGF-？1个TGF-？1个空白背景（TGF-？1（-/-/TG））杂交。1（+/-）小鼠与转基因小鼠（TG）表达重组TGF-？1特别是在肝脏和分泌它在血液中。TGF-1（-/-/TG）小鼠表现出与TGF-？1（-/-）小鼠，表明未能挽救致死表型。血清TGF-？1水平的TGF-？1（-/-/TG）小鼠恢复到正常水平，在所有组织中表达，特别是在肾和脾中。组织学显示所有靶组织的炎症减少，特别是心脏。有趣的是，与TGF-？（-/-）小鼠，TGF-？1（-/-/TG）小鼠在其肾脏中具有与TG小鼠相似的肾小球肾炎。因此，表型的TGF-？1（-/-/TG）动物模型表明循环活性TGF-1在减轻炎症中的潜在作用，但其未能挽救TGF-1敲除小鼠的致死性，表明自分泌TGF-？1.

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.