A new approach to reverse onset of autoimmune diabetes

描述（由申请人提供）：非肥胖糖尿病（NOD）小鼠自发发展为自身免疫性糖尿病。该疾病的特征是T细胞精心策划的胰岛进行性浸润（胰岛素炎），淋巴细胞和巨噬细胞导致显性糖尿病。许多研究人员已经确定了预防NOD小鼠糖尿病发展的治疗方法。然而，恢复正常的胰岛细胞形态和解决富含T细胞的浸润性自身免疫性胰岛素炎要困难得多，只有很少的治疗方法才能实现。更具有挑战性的是，如何让患有糖尿病的老鼠恢复到正常的血糖状态。只有一种令人满意的治疗方法，抗CD3单抗，已经被开发出来，虽然暂时停止了从新发到永久性糖尿病的进展。因此，确定能够逆转小鼠已建立的自身免疫的治疗方法，作为确定临床试验新策略的手段，可能是有用的。为此，我们现在建议研究一种方案，旨在选择性地破坏糖尿病源性自身免疫T细胞，同时使调节性T （Treg）免于类似的损失，从而打破自身免疫到免疫保护的平衡。

DESCRIPTION (provided by applicant): Nonobese diabetic (NOD) mice spontaneously develop autoimmune diabetes. The disease is characterized by T cell orchestrated progressive infiltration of the islets (insulitis) by lymphocytes and macrophages leading to overt diabetes. Numerous investigators have identified treatments that prevent the development of diabetes in NOD mice. However, restoration of normal islet cell morphology and resolution of the T cell rich, infiltrative autoimmune insulitis is far more difficult and has been achieved with only very few therapies. Even more challenging is the restoration of a euglycemic state in mice that have developed frank diabetes. Only one satisfactory treatment, anti- CD3 mAb, has been developed that halts albeit temporarily, the progression from new onset to permanent diabetes in man. Therefore, it may prove useful to identify therapies able to reverse established autoimmunity in mice as means to identify new strategies for clinical testing. To this end we are now proposing study of a regimen that is aimed at selective destruction of diabetogenic, autoimmune T cells while sparing regulatory T (Treg) from comparable loss, thereby tipping the balance from autoimmunity to immune protection. We have developed a novel strategy that includes agonist (wild type) IL-2/Fc fusion protein as a component to enhance AICD; a high affinity IL-15Ralpha antagonist mutant IL-15/Fc fusion protein (mIL-15/Fc) to block proliferative and anti-apoptotic IL-15 signals as a component to harness PCD; and rapamycin (RPM) to antagonize the proliferative response of activated T cells to T cell growth factors (TCGF) without inhibiting the AICD signal imparted by EL-2. Moreover, the agonist IL-2 and antagonist IL-15 related proteins were designed as IgG 2a derived Fc fusion proteins to ensure a prolonged circulating half-life and also provide a potential means to kill activated IL-2R+ and IL-15R+ target cells via complement dependent (CDC) and antibody dependent (ADCC) cell cytotoxicity activating. This strategy has proven useful in extremely stringent transplant models, including a model in which allogeneic T cells are transplanted into diabetic NOD mice. The objective of this project is to further explore the utility of this treatment method to restore euglycemia in new onset, spontaneously diabetic autoimmune NOD mice. We hope that our approach will lead to a better understanding of the mechanisms that generate and maintain tolerance to islet beta cells and to establish models that will examine the interaction of the immune system and beta-cell turnover within islets during the invasive stages of the autoimmune process. The ultimate goal is to develop a safe and effective strategy for the treatment and potential cure of early onset of T1DM in human.