Synergistic reversal of type 1 diabetes in NOD mice with anti-CD3 and interleukin-1 blockade: evidence of improved immune regulation.
Synergistic reversal of type 1 diabetes in NOD mice with anti-CD3 and interleukin-1 blockade: evidence of improved immune regulation.
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作者：
Ablamunits V;Henegariu O;Hansen JB;Opare-Addo L;Preston-Hurlburt P;Santamaria P;Mandrup-Poulsen T;Herold KC
炎性细胞因子参与自身免疫性糖尿病：其中最突出的是白细胞介素（IL）-1β。我们推测，阻断IL-1β可调节抗CD 3单克隆抗体（mAb）治疗NOD小鼠糖尿病的效果。为了验证这一点，我们用抗CD 3 mAb的F（ab′）2片段与或不与IL-1受体拮抗剂（IL-1 RA）或抗IL-1β mAb治疗高血糖NOD小鼠。我们研究了糖尿病的逆转和治疗对免疫系统的影响。接受抗CD 3 mAb和IL-1 RA联合治疗的小鼠比单独接受抗CD 3 mAb或IL-1 RA治疗的小鼠显示出更快的糖尿病缓解率。联合治疗的小鼠循环中的IL-5、IL-4和干扰素（IFN）-γ水平增加。在胰腺淋巴结中存在减少的致病性NOD相关V7肽-V7 + T细胞。他们的脾细胞分泌更多的IL-10，在巨噬细胞和树突状细胞中增加了α-淀粉酶的表达，并延迟了糖尿病的过继转移。1个月后，尽管脾细胞细胞因子分泌正常，但IgG 1同种型抗体浓度增加，胰腺内IFN-γ、IL-6和IL-17表达减少。这些研究表明，抗CD 3 mAb与IL-1 RA的组合通过多种机制的组合在逆转糖尿病方面具有协同作用。该组合引起胰岛炎症的持续缓解。
Inflammatory cytokines are involved in autoimmune diabetes: among the most prominent is interleukin (IL)-1β. We postulated that blockade of IL-1β would modulate the effects of anti-CD3 monoclonal antibody (mAb) in treating diabetes in NOD mice. To test this, we treated hyperglycemic NOD mice with F(ab′)2 fragments of anti-CD3 mAb with or without IL-1 receptor antagonist (IL-1RA), or anti–IL-1β mAb. We studied the reversal of diabetes and effects of treatment on the immune system. Mice that received a combination of anti-CD3 mAb with IL-1RA showed a more rapid rate of remission of diabetes than mice treated with anti-CD3 mAb or IL-1RA alone. Combination-treated mice had increased IL-5, IL-4, and interferon (IFN)-γ levels in circulation. There were reduced pathogenic NOD-relevant V7 peptide-V7+ T cells in the pancreatic lymph nodes. Their splenocytes secreted more IL-10, had increased arginase expression in macrophages and dendritic cells, and had delayed adoptive transfer of diabetes. After 1 month, there were increased concentrations of IgG1 isotype antibodies and reduced intrapancreatic expression of IFN-γ, IL-6, and IL-17 despite normal splenocyte cytokine secretion. These studies indicate that the combination of anti-CD3 mAb with IL-1RA is synergistic in reversal of diabetes through a combination of mechanisms. The combination causes persistent remission from islet inflammation.
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影响因子：
7.7
作者：
Eizirik, DL;Darville, MI
通讯作者：
Darville, MI
DOI：
10.1073/pnas.0902745106
发表时间：
2009-04-28
影响因子：
11.1
作者：
Ben-Sasson, Shlomo Z.;Hu-Li, Jane;Paul, William E.
通讯作者：
Paul, William E.
影响因子：
15.9
作者：
Hu, Chang-Yun;Rodriguez-Pinto, Daniel;Wen, Li
通讯作者：
Wen, Li
影响因子：
7.7
作者：
Bertin-Maghit S;Pang D;O'Sullivan B;Best S;Duggan E;Paul S;Thomas H;Kay TW;Harrison LC;Steptoe R;Thomas R
通讯作者：
Thomas R
影响因子：
7.7
作者：
Herold KC;Gitelman SE;Masharani U;Hagopian W;Bisikirska B;Donaldson D;Rother K;Diamond B;Harlan DM;Bluestone JA
通讯作者：
Bluestone JA