Short-Term Administrations of a Combination of Anti-LFA-1 and Anti-CD154 Monoclonal Antibodies Induce Tolerance to Neonatal Porcine Islet Xenografts in Mice
Short-Term Administrations of a Combination of Anti-LFA-1 and Anti-CD154 Monoclonal Antibodies Induce Tolerance to Neonatal Porcine Islet Xenografts in Mice
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DOI：
10.2337/db09-0413
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发表时间：
2010-04-01
期刊：
影响因子：
7.7
通讯作者：
Rayat, Gina R.
中科院分区：
文献类型：
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作者：
Arefanian, Hossein;Tredget, Eric B.;Rayat, Gina R.
目的 - 本研究的目的是确定是否可以通过短期施用抗 LFA-1 和抗 CD154 单克隆抗体 (mAb) 来实现对新生猪胰岛 (NPI) 异种移植物的耐受。 研究设计和方法 - 糖尿病 B6 小鼠接受 NPI 移植并短期注射抗 LFA-1 和抗 CD154 联合抗体 单克隆抗体。具有长期胰岛移植功能的小鼠接受消耗型抗 CD25 mAb 治疗或使用第二方 NPI 进行重新移植。研究结束时，对具有长期胰岛功能的小鼠移植物进行了检查。对他们的脾细胞进行了表征并用于体外增殖和过继转移研究。 结果 - 所有 mAb 治疗的 NPI 受体在移植后均维持正常血糖超过 100 个粘土。 50 只小鼠中只有 5 只在移植后 300 天之前排斥移植物。在耐受小鼠的 NPI 异种移植物中检测到完整的胰岛、foxp3(+) 免疫细胞以及白细胞介素 (IL)-10 和转化生长因子 (TGF)-β 调节细胞因子转录物。这些小鼠中较高比例的 CD4(+) T 细胞群表达调节标记，表明对 NPI 异种移植物的耐受可能是由 T 调节细胞介导的。当用消耗性抗 CD25 mAb 治疗的耐受小鼠患上糖尿病时，这一点得到了证实。来自耐受小鼠的淋巴细胞抑制了用猪细胞免疫的 B6 小鼠的淋巴细胞增殖，并且在过继转移时表现出有限的增殖。所有移植有第二方 NPI 异种移植物的受保护 B6 小鼠，即使在切除第一个 NPI 移植肾后，仍能维持长期无血糖。 结论 - 这些结果表明，通过瞬时施用抗 LFA-1 和抗 CD154 mAb 联合疗法可以实现对 NPI 异种移植物的耐受。糖尿病 59:958-966, 2010
OBJECTIVE-The objective of this study was to determine whether tolerance to neonatal porcine islet (NPI) xenografts could be achieved by short-term administrations of anti-LFA-1 and anti-CD154 monoclonal antibodies (mAbs).RESEARCH DESIGN AND METHODS-Diabetic B6 mice received NPI transplants and short-term injections of combined anti-LFA-1 and anti-CD154 mAbs. Mice with long-term islet graft function were treated with depleting anti-CD25 mAb or retransplanted with a second-party NPI. At the end of the study, grafts from mice with long-term islet function were examined. Their spleen cells were characterized and used for in vitro proliferation and adoptive transfer studies.RESULTS-All mAb-treated NPI recipients maintained normoglycemia for >100 clays post-transplantation. Only 5 of 50 mice rejected their grafts before 300 days post-transplantation. Intact islets, foxp3(+) immune cells, as well as interleukin (IL)-10 and transforming growth factor (TGF)-beta regulatory cytokine transcripts were detected in the NPI xenografts from tolerant mice. A higher percentage of CD4(+) T-cell population from these mice expressed regulatory markers, suggesting that tolerance to NPI xenografts may be mediated by T regulatory cells. This was confirmed when tolerant mice treated with depleting anti-CD25 mAb became diabetic. Lymphocytes from tolerant mice inhibited the proliferation of lymphocytes from B6 mice immunized with porcine cells and they displayed limited proliferation when adoptively transferred. All protected B6 mice transplanted with a second-party NPI xenograft maintained long-term nonaloglycemia even after removal of the first NPI graft-bearing kidney.CONCLUSIONS-These results demonstrate that tolerance to NPI xenografts can be achieved by transient administrations of combined anti-LFA-1 and anti-CD154 mAb therapy. Diabetes 59:958-966, 2010