Increased T cell proliferative responses to islet antigens identify clinical responders to anti-CD20 monoclonal antibody (rituximab) therapy in type 1 diabetes.
Increased T cell proliferative responses to islet antigens identify clinical responders to anti-CD20 monoclonal antibody (rituximab) therapy in type 1 diabetes.
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DOI：
10.4049/jimmunol.1100539
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发表时间：
2011-08-15
期刊：
影响因子：
--
通讯作者：
Type 1 Diabetes TrialNet Anti-CD20 Study Group
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文献类型：
--
作者：
Herold KC;Pescovitz MD;McGee P;Krause-Steinrauf H;Spain LM;Bourcier K;Asare A;Liu Z;Lachin JM;Dosch HM;Type 1 Diabetes TrialNet Anti-CD20 Study Group
1型糖尿病（T1DM）被认为是由于T淋巴细胞对β细胞的自身免疫性破坏，但单疗程利妥昔单抗（一种单克隆抗CD20 B淋巴细胞抗体）可在疾病的第一年内减轻C肽丢失。尚未研究B细胞耗竭对疾病相关T细胞应答的影响。我们在安慰剂对照的TrialNet试验中比较了利妥昔单抗治疗一年后显示β细胞保存迹象的参与者（应答者）或未显示β细胞保存迹象的参与者（无应答者）的淋巴细胞亚群、T细胞对疾病相关靶抗原的增殖反应和C肽水平的变化。4周一次mAb给药后，利妥昔单抗降低了B淋巴细胞水平。在基线时，75%的抗CD20治疗受试者和82%的安慰剂治疗受试者存在对糖尿病相关抗原的T细胞增殖应答，且随时间推移无差异。然而，在利妥昔单抗治疗的受试者中，在6个月时具有显著的C肽保留（58%），在12个月的观察期内，对糖尿病相关的总抗原（p=0.032）、胰岛特异性抗原（p=0.048）和神经元自身抗原（p=0.005）的增殖反应增加。在安慰剂治疗患者中未观察到这种关系。我们的结论是，在T1DM患者中，抗B细胞mAb导致对糖尿病抗原的增殖反应增加，并减少β细胞丢失。这些反应影响疾病进程的方式仍然未知。
Type 1 diabetes mellitus (T1DM) is believed to be due to the autoimmune destruction of β-cells by T lymphocytes, but a single course of rituximab, a monoclonal anti-CD20 B lymphocyte antibody can attenuate C-peptide loss over the first year of disease. The effects of B cell depletion on disease associated T cell responses have not been studied. We compare changes in lymphocyte subsets, T cell proliferative responses to disease- associated target antigens, and C-peptide levels of participants that did (responders) or did not (non-responders) show signs of β-cell preservation one year after rituximab therapy in a placebo-controlled TrialNet trial. Rituximab decreased B lymphocyte levels after 4 weekly doses of mAb. T cell proliferative responses to diabetes –associated antigens were present at baseline in 75% of anti-CD20- and 82% of placebo-treated subjects and were not different over time. However, in rituximab-treated subjects with significant C-peptide preservation at 6 months (58%), the proliferative responses to diabetes associated total (p=0.032), islet-specific (p=0.048), and neuronal auto-antigens (p=0.005) increased over the 12 month observation period. This relationship was not seen in placebo treated patients. We conclude that in patients with T1DM, anti-B cell mAb causes increased proliferative responses to diabetes antigens and attenuated β cell loss. The way in which these responses affect the disease course remains unknown.
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