Hydroxamate-based therapy to target T cell homing in IDDM

描述（由申请人提供）：我们的目标是通过使用小分子异羟肟酸抑制剂（MMPI）阻断胰岛素依赖型糖尿病（I型糖尿病; IDDM）的进展。海曲康聚糖结合CD 44是一种粘附和信号传导受体。细胞表面相关的CD 44和膜1型基质金属蛋白酶（MT 1-MMP）之间的相互关系是必要的有效的粘附和跨内皮迁移的T杀伤细胞进入胰岛。细胞毒性T细胞进入胰岛后，会破坏产生胰岛素的β细胞。我们已经证明，MT 1-MMP蛋白水解是T细胞CD 44的动态调节和随后的致糖尿病IS-CD 8 * T杀伤细胞的胰岛特异性归巢的关键因素。抑制剂诱导的MT 1-MMP和CD 44之间相互关系的变化干扰了T杀伤细胞粘附、迁移和归巢到胰腺，并导致NOD小鼠糖尿病发作的显著延迟。这种啮齿动物模型发展出一种与人类胰岛素依赖型糖尿病非常相似的疾病。我们将扩展我们的研究结果，并开发一种具有成本效益和可靠的体内策略，通过使用现有的和可用的无毒异羟肟酸MMPIs来抑制T细胞CD 44的MT 1-MMP蛋白水解。这些MMPI已经在癌症患者中进行了测试，证明是无毒的，并且可以从主要的制药公司获得。我们推测，通过低剂量的MMPIs抑制T细胞CD 44的MT 1-MMP蛋白水解是一种新的、非常有前途的方法和改善的IDDM治疗。我们的方法基于我们对MMPs的广泛而深入的了解，特别是我们对MT 1-MMP/CD 44相互作用在癌症和糖尿病中的功能作用的理解。作为“主要证据”，我们将测试可用的异羟肟酸GM 6001和AG 3340。作为对照，我们将使用对MMP-2和MMP-9有效但对MT 1-MMP无效的非异羟肟酸SB 3CT硫醇抑制剂。我们的具体目标是：（1）确定T细胞CD 44的MT 1-MMP蛋白水解对IS-CD 8 * T杀伤细胞粘附和迁移的生理影响。（2）验证MT 1-MMP小分子拮抗剂的药理学价值（异羟肟酸GM 6001和AG 3340，以及硫醇化合物SB 3CT）在糖尿病过继转移的啮齿动物模型中的作用，（3）验证MT 1-MMP小分子拮抗剂（异羟肟酸GM 6001、AG 3340和巯基化合物SB 3CT）在糖尿病前期和新患病NOD小鼠中的药理学价值。我们坚信， 我们的实验计划将导致对IDDM患者的新的和有效的抗糖尿病疗法的发展。

DESCRIPTION (provided by applicant): Our goal is to block the progression of insulin-dependent diabetes mellitus (type I diabetes; IDDM) by using small molecule hydroxamate inhibitors (MMPIs). Hyaluronan-binding CD44 is an adhesion and signaling receptor. The reciprocal relationship between cell surface-associated CD44 and membrane-type 1 matrix metalloproteinase (MT1-MMP) is essential for both efficient adhesion and for transendothelial migration of T killer cells into the islets of Langerhans. After penetration into the islets, cytotoxic T cells cause the destruction of insulin-producing p cells. We have demonstrated that MT1-MMP proteolysis is a key factor in the dynamic regulation of T cell CD44 and the subsequent islet-specific homing of diabetogenic IS-CD8* T killer cells. Inhibitor-induced changes in the reciprocal relationship between MT1-MMP and CD44 interfere with adhesion, transmigration and homing of T killer cells to the pancreas, and cause a significant delay in the onset of diabetes in NOD mice. This rodent model develops a disease closely resembling human IDDM. We will extend our findings and develop a cost-efficient and reliable in vivo strategy to inhibit MT1-MMP proteolysis of T cell CD44 by using existing and available, non-toxic hydroxamate MMPIs. These MMPIs have been tested in cancer patients, proved to be non-toxic and are readily available from major pharmaceutical companies. We hypothesize that the inhibition of MT1-MMP proteolysis of T cell CD44 by low dosages of MMPIs is a novel, highly promising approach and improved therapy of IDDM. Our approach is soundly based on our extensive and in-depth knowledge of MMPs and, especially, on our understanding of the functional role of the MT1-MMP/CD44 interactions in cancer and diabetes. As a "proof-of-principal" we will test the available hydroxamates GM6001 and AG3340. As a control, we will use the non-hydroxamate SB3CT thiol inhibitor that is potent against MMP-2 and MMP-9 but it is not effective against MT1-MMP. Our specific aims are: (1) To determine the physiological impact of the MT1-MMP proteolysis of T cell CD44 on the adhesion and migration of IS-CD8* T killer cells, (2) To validate the pharmacological value of the small molecule antagonists of MT1-MMP (the hydroxamates GM6001 and AG3340, and the thiol compound SB3CT) in a rodent model of adoptive transfer of diabetes, and (3) To validate the pharmacological value of the small molecule antagonists of MT1-MMP (the hydroxamates GM6001 and AG3340, and the thiol compound SB3CT) in pre-diabetic and freshly diseased NOD mice. We strongly believe that the results of our experimental program will lead to the development of new and effective anti-diabetic therapies for IDDM patients.