Protection from autoimmune diabetes and T-cell lymphoproliferation induced by FasL mutation are differentially regulated and can be uncoupled pharmacologically
Protection from autoimmune diabetes and T-cell lymphoproliferation induced by FasL mutation are differentially regulated and can be uncoupled pharmacologically
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DOI：
10.2353/ajpath.2007.070148
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发表时间：
2007-07-01
影响因子：
6
通讯作者：
Hamad, Abdel Rahim A.
中科院分区：
文献类型：
--
作者：
Mohamood, Abdiaziz S.;Guler, Mehmet L.;Hamad, Abdel Rahim A.
Fas（lpr）或FasL（gld）的自发突变完全保护非肥胖糖尿病小鼠免于自身免疫性糖尿病，但也引起大量双阴性T细胞淋巴细胞增殖。在这项研究中，我们使用骨髓嵌合体和过继转移分析来进一步研究FasL在自身免疫性糖尿病发病机制中的作用，并确定gld诱导的耐受和双阴性T细胞淋巴增殖是否可以彼此解偶联。我们发现，FasL表达的造血和非造血车厢发挥非多余的作用，在自身免疫性糖尿病的发病机制。FasL在任一区室中的突变干扰自身免疫过程并防止糖尿病的发作，但在造血区室中表达的FasL是T细胞稳态的主要调节剂。此外，糖尿病的发病机制依赖于两个隔室中的正常FasL表达，而仅需要最小的FasL功能来维持T细胞稳态。因此，FasL的部分破坏保护免受自身免疫性糖尿病，而不引起T细胞淋巴增殖。通过使用FasL中和抗体在非肥胖糖尿病-gld/+小鼠和Wistar大鼠中证实了这一点。这些结果对于理解Fas通路在自身免疫性疾病发病机制中的作用和设计新的FasL调节疗法具有重要意义。
Spontaneous mutation of Fas (lpr) or FasL (gld) completely protects nonobese diabetic mice from autoimmune diabetes but also causes massive double-negative T-cell lymphoproliferation. in this study, we used bone marrow chimeras and adoptive transfer analysis to investigate further the role of FasL in the pathogenesis of autoimmune diabetes and to determine whether gld-induced tolerance and double-negative T-cell lymphoproliferation can be uncoupled from each other. We show that FasL expressed on hematopoietic and nonhematopoietic compartments plays nonredundant roles in the pathogenesis of autoimmune diabetes. Mutation of FasL in either compartment interferes with the autoimmune process and prevents onset of diabetes, but FasL expressed in the hematopoietic compartment is the dominant regulator of T-cell homeostasis. Furthermore, pathogenesis of diabetes is dependent on normal FasL expression in both compartments, whereas only minimal FasL function is required to maintain T-cell homeostasis. Consequently, partial disruption of FasL protects from autoimmune diabetes without causing T-cell lymphoproliferation. This is demonstrated genetically in nonobese diabetic-gld/+ mice and pharmacologically by using FasL-neutralizing antibody. These results have important implications for understanding the role of the Fas pathway in pathogenesis of autoimmune diseases and for designing novel FasL-modulating therapies.