Differential Impact of Chronic Hyperglycemia on Humoral Versus Cellular Primary Alloimmunity
Differential Impact of Chronic Hyperglycemia on Humoral Versus Cellular Primary Alloimmunity
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DOI：
10.2337/db16-0218
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发表时间：
2017-04-01
期刊：
影响因子：
7.7
通讯作者：
Gill, Ronald G.
中科院分区：
文献类型：
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作者：
Bishop, Nicholas H.;Nelsen, Michelle K.;Gill, Ronald G.
糖尿病在实体器官移植受者中普遍存在，并且在胰岛移植受者中普遍存在。尽管糖尿病通常被认为导致免疫受损状态，但慢性高血糖对宿主同种免疫的影响尚不清楚。肥胖、自身免疫或致糖尿病药物（如链脲佐菌素）的潜在免疫调节作用可能会混淆对糖尿病实验模型中同种免疫的理解。因此，我们试图使用非自身免疫性、自发性糖尿病H-2（B）表达的C57 BL/6 Ins 2（秋田）小鼠（秋田）来确定由于胰岛素减少引起的慢性高血糖对同种免疫的作用。秋田小鼠携带突变的Ins 2等位基因，该等位基因主要抑制胰岛素分泌，导致终身糖尿病。我们使用BALB/c供体（H-2（d））来评估秋田受体的同种免疫和胰岛移植结果。令人惊讶的是，慢性高血糖对同种异体免疫后的原发性T细胞反应性几乎没有影响。此外，秋田小鼠很容易排斥胰岛同种异体移植物，慢性高血糖对移植物内T细胞反应的大小或质量没有影响。相反，同种异体免疫后，秋田小鼠的同种异体特异性IgM和IgG显著降低。因此，尽管糖尿病影响宿主的免疫防御，但高血糖症本身并不引起全身性同种免疫损伤。我们的数据表明，糖尿病患者由于高血糖引起的免疫功能损害可能不适用于移植的细胞排斥反应。
Diabetes is prevalent among solid organ transplant recipients and is universal among islet transplant recipients. Whereas diabetes is often considered to result in an immune-compromised state, the impact of chronic hyperglycemia on host alloimmunity is not clear. Potential immune-modifying effects of obesity, autoimmunity, or diabetogenic agents like streptozotocin may confound understanding alloimmunity in experimental models of diabetes. Therefore, we sought to determine the role of chronic hyperglycemia due to insulinopenia on alloimmunity using the nonautoimmune, spontaneously diabetic H-2(b)-expressing C57BL/6 Ins2(Akita) mice (Akita). Akita mice harbor a mutated Ins2 allele that dominantly suppresses insulin secretion, resulting in lifelong diabetes. We used BALB/c donors (H-2(d)) to assess alloimmunization and islet transplantation outcomes in Akita recipients. Surprisingly, chronic hyperglycemia had little effect on primary T-cell reactivity after alloimmunization. Moreover, Akita mice readily rejected islet allografts, and chronic hyperglycemia had no impact on the magnitude or quality of intragraft T-cell responses. In contrast, allospecific IgM and IgG were significantly decreased in Akita mice after alloimmunization. Thus, whereas diabetes influences host immune defense, hyperglycemia itself does not cause generalized alloimmune impairment. Our data suggest that immune compromise in diabetes due to hyperglycemia may not apply to cellular rejection of transplants.