Immunosuppressive Effects of Streptozotocin-Induced Diabetes Result in Absolute Lymphopenia and a Relative Increase of T Regulatory Cells
Immunosuppressive Effects of Streptozotocin-Induced Diabetes Result in Absolute Lymphopenia and a Relative Increase of T Regulatory Cells
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DOI：
10.2337/db11-0159
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发表时间：
2011-09-01
期刊：
影响因子：
7.7
通讯作者：
Seebach, Joerg D.
中科院分区：
文献类型：
--
作者：
Muller, Yannick D.;Golshayan, Dela;Seebach, Joerg D.
目的：链脲佐菌素(STZ)是胰岛移植动物模型中应用最广泛的促糖尿病药物。然而，STZ和随之而来的高血糖对淋巴细胞亚群的免疫调节作用，特别是对T调节细胞(Tregs)的免疫调节作用仍不清楚。研究设计和方法-本研究评估了STZ诱导的糖尿病如何影响获得性免疫，以及其对小鼠胰岛和皮肤移植模型移植排斥反应的影响。体外检测STZ和高血糖对淋巴细胞亚群的毒性。在体内，通过去除移植的同种胰岛，使用胰岛素泵，以及使用大鼠胰岛素启动子白喉毒素受体转基因小鼠，评估高血糖的影响。结果：给予STZ后，血和脾中早期淋巴细胞减少。在体外，STZ对淋巴细胞，特别是对CD8(+)细胞和B细胞有直接毒性作用。体内高血糖也与血液和脾淋巴细胞减少有关，但在体外不具有淋巴毒性。与高血糖无关，STZ在体内导致Tregs的相对增加，而后者在体外保持其抑制能力。Treg的高频率与血液中Treg的增殖有关，但与脾中的Treg无关，以及血液中较高的转化生长因子-β水平。结论--这些数据分别强调了STZ和急性高血糖的直接和间接免疫抑制作用。因此，这些结果对基于耐受性的方案的未来发展以及它们从实验室到临床的转化具有重要的意义。糖尿病60：2331-2340,2011
OBJECTIVE-Streptozotocin (STZ) is the most widely used diabetogenic agent in animal models of islet transplantation. However, the immunomodifying effects of STZ and the ensuing hyperglycemia on lymphocyte subsets, particularly on T regulatory cells (Tregs), remain poorly understood.RESEARCH DESIGN AND METHODS-This study evaluated how STZ-induced diabetes affects adaptive immunity and the consequences thereof on allograft rejection in murine models of islet and skin transplantation. The respective toxicity of STZ and hyperglycemia on lymphocyte subsets was tested in vitro. The effect of hyperglycemia was assessed independently of STZ in vivo by the removal of transplanted syngeneic islets, using an insulin pump, and with rat insulin promoter diphtheria toxin receptor transgenic mice.RESULTS-Early lymphopenia in both blood and spleen was demonstrated after STZ administration. Direct toxicity of STZ on lymphocytes, particularly on CD8(+) cells and B cells, was shown in vitro. Hyperglycemia also correlated with blood and spleen lymphopenia in vivo but was not lymphotoxic in vitro. Independently of hyperglycemia, STZ led to a relative increase of Tregs in vivo, with the latter retaining their suppressive capacity in vitro. The higher frequency of Tregs was associated with Treg proliferation in the blood, but not in the spleen, and higher blood levels of transforming growth factor-beta. Finally, STZ administration delayed islet and skin allograft rejection compared with naive mice.CONCLUSIONS-These data highlight the direct and indirect immunosuppressive effects of STZ and acute hyperglycemia, respectively. Thus, these results have important implications for the future development of tolerance-based protocols and their translation from the laboratory to the clinic. Diabetes 60:2331-2340, 2011