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

摘要 由于 T1D 临床试验中单一疗法的失败，人们普遍认为联合治疗 可以控制自身免疫反应并促进 ß 细胞健康和复制对于 T1D 是必要的 干预。作为一个概念验证，该提案将测试带有 GABA 的免疫调节剂抗 CD3， 后者具有免疫调节作用，并且是 β 细胞有丝分裂原/生存因子。既往临床 抗 CD3 的研究未能使新糖尿病患者维持正常血糖，这可能与 是由于 1) 剩余 ß 细胞的慢性耗竭，2) 缺乏足够的 ß 细胞再生和 3）自身免疫抑制不足。通过将抗 CD3 与 GABA 结合，这些缺陷中的每一个都可以 得到改善，即 GABA 促进小鼠和人类 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。这不同于之前测试过的任何组合 与抗 CD3（或其他免疫调节剂）一起使用，因为这些研究中使用了第二种治疗剂 缺乏抑制自身免疫/促进 Tregs 的能力，或者不是 β 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展 ß 细胞 新患糖尿病的 NOD 小鼠中的质量。由于尚无单一或联合疗法能够增强 ß-细胞 糖尿病 NOD 小鼠中的复制和质量，成功的结果将是新颖的，并且具有很高的潜力 临床翻译。此外，由于抗 CD3 和 GABA 的作用预计会协同作用，我们将 测试每种治疗的较低剂量是否有效，这可能有助于临床减少 潜在的副作用。最后，除了监测这种联合治疗对免疫的影响外， 反应和 β 细胞复制、质量和功能，我们将确定血浆中 GABA 的水平 与抑制自身反应性和促进 ß-cell 细胞复制有关，这将为以下方面提供信息： 临床试验中的 GABA 剂量。结果具有很高的临床潜力，可以更好地保存甚至增加 T1D 发病后的 ß-细胞量。即使是少量保留或增加 β 细胞量也会在以下方面产生临床益处： 那些通过降低胰岛素需求、改善血糖控制和治疗而新诊断出患有 T1D 的人 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- CD3——未来，GABA可以与其他安全的免疫调节药物联合使用，从而证明—— 这一概念很可能为 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.