Makhlouf Leila, Grey Shane T, Dong Victor, Csizmadia Eva, Arvelo Maria B, Auchincloss Hugh, Ferran Christiane, Sayegh Mohamed H
Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
Transplantation. 2004 Apr 15;77(7):990-7. doi: 10.1097/01.tp.0000118410.61419.59.
The prevention of recurrent autoimmunity is a prerequisite for successful islet transplantation in patients with type I diabetes. Therapies effective in preserving pancreatic beta-cell mass in patients with newly diagnosed diabetes are good candidates for achieving this goal. Anti-CD3 monoclonal antibody (mAb) and antilymphocyte antisera are the only therapies to date that have cured early diabetic disease in the nonobese diabetic (NOD) mouse. We investigated whether other immunosuppressive therapies, including short-term depleting anti-CD4 mAb or costimulation blockade, would affect the disease progression in recently diabetic NOD mice. We also evaluated the effect of the anti-CD4 mAb on syngeneic and allogeneic graft survival in diabetic NOD recipients.
We demonstrate that a short course of anti-CD4 mAb early after hyperglycemia onset cured diabetes. Normal islets and islets with CD4+ and CD8+ T-cell peri-insulitic infiltrate were found in the pancreata of cured NOD mice. A similar regimen prevented the recurrence of autoimmune diabetes in NOD/severe combined immunodeficient disease (SCID) islet isografts and delayed the rejection of allogeneic C57BL/6 islet allografts in diabetic female NOD mice. The co-transfer of diabetogenic splenocytes with splenocytes from anti-CD4 mAb-treated and cured NOD mice into 7-week-old, irradiated, NOD male mice was not able to protect from diabetes occurrence. This indicates that an anti-CD4-mediated cure of diabetes is independent of the induction of immunoregulatory T cells. Anti-CD154 mAb and cytotoxic T-lymphocyte antigen 4 immunoglobulin were ineffective in early-onset diabetes.
Our results provide the first evidence that newly established autoimmune islet destruction in NOD mice responds to a short course of anti-CD4 mAb. In contrast, costimulation blockade is ineffective in this clinically relevant model.
预防自身免疫复发是I型糖尿病患者胰岛移植成功的前提条件。对新诊断糖尿病患者有效的保留胰腺β细胞量的疗法是实现这一目标的理想选择。抗CD3单克隆抗体（mAb）和抗淋巴细胞抗血清是迄今为止仅有的能治愈非肥胖糖尿病（NOD）小鼠早期糖尿病疾病的疗法。我们研究了其他免疫抑制疗法，包括短期耗竭性抗CD4 mAb或共刺激阻断，是否会影响近期患糖尿病的NOD小鼠的疾病进展。我们还评估了抗CD4 mAb对糖尿病NOD受体中同基因和异基因移植物存活的影响。
我们证明，在高血糖发作后早期给予短疗程抗CD4 mAb可治愈糖尿病。在治愈的NOD小鼠胰腺中发现了正常胰岛以及有CD4 +和CD8 + T细胞胰岛周围浸润的胰岛。类似的方案可预防NOD/重症联合免疫缺陷病（SCID）胰岛同基因移植物中自身免疫性糖尿病的复发，并延迟糖尿病雌性NOD小鼠中异基因C57BL/6胰岛移植物的排斥反应。将致糖尿病脾细胞与来自抗CD4 mAb治疗并治愈的NOD小鼠的脾细胞共同移植到7周龄、经辐照的NOD雄性小鼠中，无法预防糖尿病的发生。这表明抗CD4介导的糖尿病治愈与免疫调节性T细胞的诱导无关。抗CD154 mAb和细胞毒性T淋巴细胞抗原4免疫球蛋白对早期发作的糖尿病无效。
我们的结果首次证明，NOD小鼠新建立的自身免疫性胰岛破坏对短疗程抗CD4 mAb有反应。相比之下，在这个临床相关模型中，共刺激阻断无效。
