Combination immunotherapy to preserve beta-cell function in the context of autoimmunity

摘要 由于T1 D临床试验中单药治疗的失败，人们普遍认为联合治疗 能够控制自身免疫反应并促进T细胞健康和复制的药物将是T1 D所必需的 干预作为一个概念，这项建议将测试免疫调节剂抗CD 3与GABA， 后者具有免疫调节作用并且是一种β-细胞有丝分裂原/存活因子。既往临床 抗CD 3的研究未能在新发糖尿病患者中维持正常血糖，这可能 这是由于1）剩余的胰岛细胞的慢性衰竭，2）缺乏足够的胰岛细胞再生， 3)自身免疫抑制不足。通过将抗CD 3与GABA结合，这些缺陷中的每一种都可以 改善，即，GABA促进小鼠和人的β细胞存活、β细胞复制和质量，并抑制 炎症免疫细胞，同时增强Treg反应。这与以前测试的任何组合都不同 与抗CD 3（或其他免疫调节剂），因为这些研究中使用的第二种治疗剂 缺乏抑制自身免疫/促进T细胞增殖的能力或不是T细胞有丝分裂原/存活因子。我们 假设抗CD 3 +GABA的组合将充分控制自身免疫应答， GABA的促有丝分裂和抗凋亡作用将能够更好地保存，甚至可能扩大细胞增殖。 在新糖尿病NOD小鼠中。由于没有单一或联合疗法能够提高胰岛细胞增殖， 复制和质量，成功的结果将是新颖的，并具有很高的潜力， 临床翻译此外，由于抗CD 3和GABA的作用预期会协同作用，我们将 测试每种治疗的较低剂量是否有效，这在临床上可能有助于减少 潜在的副作用最后，除了监测这种联合治疗对免疫功能的影响外， 反应和γ-细胞复制，质量和功能，我们将确定血浆中的GABA水平， 与自身反应性的抑制和β细胞复制的促进有关，这将为 临床试验中的GABA剂量。这些结果具有很高的临床潜力，可以更好地保存， T1 D发作后的β-细胞团块。即使是少量的保留或增加的胰岛细胞群也会有临床益处， 那些新诊断为T1 D的患者，由于降低胰岛素需求，改善血糖控制， 从而降低并发症的长期风险。我们的方法不仅限于将GABA与抗- CD 3--将来，GABA可以与其他安全的免疫调节药物联合使用， 这一概念很可能为T1 D干预带来许多新的可能性。

Abstract Due to the failure of monotherapies in T1D clinical trials it is widely thought that combination treatments that can control autoimmune responses and promote ß-cell health and replication will be necessary for T1D intervention. As a poof-of-concept, this proposal will test the immunoregulatory agent anti-CD3 with GABA, the latter of which has both immunoregulatory actions and is a ß-cell mitogen/survival factor. Previous clinical studies with anti-CD3 have failed to maintain normoglycemia in newly diabetic individuals, which may have been due to 1) the chronic exhaustion of the remaining ß-cells, 2) the lack of sufficient ß-cell regeneration and 3) insufficient suppression of autoimmunity. By combining anti-CD3 with GABA, each of these deficiencies can be improved, i.e., GABA promotes mouse and human ß-cell survival, ß-cell replication and mass, and inhibits inflammatory immune cells while enhancing Treg responses. This is unlike any previously tested combination with anti-CD3 (or other immunoregulatory agent) because the second therapeutic agent used in those studies lacked the ability to inhibit autoimmunity/promote Tregs or was not a ß-cell mitogen/survival factor. We hypothesize that the combination of anti-CD3+GABA will sufficiently control autoimmune responses such that GABA's mitogenic and anti-apoptotic actions will be able to better preserve, and perhaps even expand ß-cell mass, in newly diabetic NOD mice. Since no mono- or combined therapy has yet been able to enhance ß-cell replication and mass in diabetic NOD mice, a successful outcome would be novel and have high potential for clinical translation. Additionally, because the actions of anti-CD3 and GABA are expected to synergize, we will test whether lower dosages of each treatment can be effective, which could be useful in the clinic to reduce potential side-effects. Finally, in addition to monitoring the effect of this combination treatment on immune responses and ß-cell replication, mass and function, we will determine the levels of GABA in plasma that are associated with inhibition of autoreactivity and promotion of ß-cell cell replication, which will be informative for GABA dosing in clinical trials. The results have high clinical potential to better preserve and perhaps increase ß-cell mass after T1D onset. Even a small preservation or increase of ß-cell mass will have clinical benefits in those newly diagnosed with T1D by virtue of lowering insulin requirements, improving glucose control and thereby reducing the long-term risk for complications. Our approach is not limited to combining GABA with anti- CD3--in the future, GABA could be combined with other safe immunoregulatory drugs, so that a proof-of- concept is likely to lead to many new possibilities for T1D intervention.