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

摘要 由于单一疗法在T1D临床试验中的失败，人们普遍认为联合疗法 能够控制自身免疫反应并促进？细胞健康和复制对于T1D来说是必要的 干预。作为一个概念，这项提案将测试免疫调节剂抗CD3与GABA， 后者既有免疫调节作用，又是？细胞有丝分裂原/存活因子。既往临床 抗CD3的研究未能维持新糖尿病患者的正常血糖，这可能已经 这是由于1)剩余的？细胞慢性耗尽，2)缺乏足够的？细胞再生和 (3)自身免疫抑制不足。通过将抗CD3抗体与GABA结合起来，这些缺陷中的每一个都可以 也就是说，GABA促进小鼠和人的？细胞存活、？细胞复制和质量，并抑制 炎症免疫细胞，同时增强Treg反应。这与之前测试过的任何组合都不同 使用抗CD3(或其他免疫调节剂)，因为在这些研究中使用的第二种治疗剂 缺乏抑制自身免疫/促进Tregs的能力，或不是？细胞有丝分裂原/生存因子。我们 假设抗CD3+GABA的组合将充分控制自身免疫反应，从而 GABA的促有丝分裂和抗凋亡作用将能够更好地保存甚至扩增？细胞 质量，在新糖尿病NOD小鼠中。因为目前还没有单一疗法或联合疗法能够增强？细胞 在糖尿病NOD小鼠中复制和聚集，成功的结果将是新的，并具有很高的治疗潜力 临床翻译。此外，由于抗CD3和GABA的作用有望协同，我们将 测试每种治疗的低剂量是否有效，这可能在临床上有用，以减少 潜在的副作用。最后，除了监测这种联合治疗对免疫的影响 响应和？细胞复制、质量和功能，我们将确定血浆中GABA的水平 与抑制自身反应和促进细胞复制有关，这将对 临床试验中的GABA剂量。这些结果有很高的临床潜力，可以更好地保存，甚至可能增加 ？？T1D发病后的细胞团。即使是一小部分保留或增加的？细胞团也将在 那些新诊断为T1D的人，由于降低了胰岛素需求，改善了血糖控制， 从而降低并发症的长期风险。我们的方法并不局限于将GABA与反 CD3--未来，GABA可以与其他安全的免疫调节药物联合使用，这样就可以证明- 这一概念可能会为T1D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.