IMMUNOTHERAPY TRIAL FOR NEW ONSET TYPE 1 DIABETES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 人类1型糖尿病是一种慢性、缓慢进展的自身免疫性疾病，目前正在探索免疫抑制疗法。Stiller和他的同事[1]首次表明，环孢素在新发患者确诊后1年内维持C-肽，但肾毒性限制了它的使用。我们选择霉酚酸酯(MMF)和抗IL2受体抗体Daclizumab对新发的1型糖尿病进行干预是基于它们对移植和自身免疫的有效性。我们预测，MMF单独或与抗IL2R抗体联合使用，将导致自身反应性淋巴细胞的激活诱导细胞死亡。如果假设是正确的，该假说预测MMF将阻止1型糖尿病患者胰岛细胞的破坏。抗IL2R抗体在阻止排斥反应方面特别有效--可能是通过饥饿激活的IL-2 T细胞。由于1型糖尿病受试者活化的T细胞数量增加，我们假设抗IL2受体抗体将针对这些潜在的自身反应细胞，而保留静止的NA和记忆性T细胞。我们预测在这项研究的四年过程中，在免疫系统副作用最小的情况下，有意义地保留胰岛功能。我们从以前的工作中得到支持，定义了在没有免疫抑制的情况下β细胞损失率。我们的方法是基于这样的观点，即免疫抑制干预必须在两年内将胰岛细胞的损失减少到控制的50%才有潜在的用处。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Type 1 diabetes in humans is a chronic, slowly progressive autoimmune disease for which immunosuppressive treatments are being explored. Stiller and colleagues [1] first showed that Cyclosporine maintained C-peptide at 1 year from diagnosis in new onset patients but nephrotoxicity limited its use. Our choice of Mycophenolate mofetil (MMF) and Daclizumab, anti-IL2 Receptor antibody, for interventions in new onset type 1 diabetes is based on their effectiveness for transplants and autoimmunity. We predict that MMF, alone or in combination with anti-IL2R antibody, will cause activation-induced cell death of self-reactive lymphocytes. If correct, the hypothesis predicts that MMF will halt islet cell destruction in type 1 diabetes. The anti-IL2R antibody is particularly effective in arresting rejection episodes - presumably through starving activated T cells of IL2. Since type 1 diabetic subjects have an increased number of activated T cells, we hypothesize that the anti-IL2 Receptor antibody will target these potentially autoreactive cells while sparing the resting na¿ve and memory T cells. We predict meaningful preservation of islet function with minimal immune system side effects over the 4-year course of this study. We have powered our study from previous work defining the rate of beta cell loss in the absence of immunosuppression. Our approach is predicated on the view that an immunosuppressive intervention has to reduce the loss of islet cells to < 50% of control over 2 years to have potential usefulness.