阿卡西考普特（一种双重 CD28 和诱导性 T 细胞共刺激抑制剂）全身给药可改善实验性自身免疫性葡萄膜炎。
Systemic Administration of Acazicolcept, a Dual CD28 and Inducible T cell Costimulator Inhibitor, Ameliorates Experimental Autoimmune Uveitis.
机构信息
Department of Ophthalmology, University of Washington, Seattle, WA, USA.
Roger and Angie Karalis Johnson Retina Center, University of Washington School of Medicine, Seattle, WA, USA.
出版信息
Transl Vis Sci Technol. 2023 Mar 1;12(3):27. doi: 10.1167/tvst.12.3.27.
PURPOSE
Combined inhibition of CD28 and inducible T cell costimulator (ICOS) pathways with acazicolcept (ALPN-101) represents a potential new treatment for uveitis. Here, we evaluate preclinical efficacy using experimental autoimmune uveitis (EAU) in Lewis rats.
METHODS
Efficacy was tested in 57 Lewis rats treated with either systemic (subcutaneous) or local (intravitreal) administration of acazicolcept and compared to treatment with a matched Fc-only control or corticosteroid. Impact of treatment on uveitis was assessed using clinical scoring, optical coherence tomography (OCT), and histology. Ocular effector T cell populations were determined using flow cytometry, and multiplex ELISA used to measure aqueous cytokine concentrations.
RESULTS
When compared to Fc control treatment, systemic acazicolcept led to statistically significant decreases in clinical score (P < 0.01), histologic score (P < 0.05), and number of ocular CD45+ cells (P < 0.01). Number of ocular CD4+ and CD8+ T cells expressing IL-17A+ and IFNγ+ were also decreased with statistical significance (P < 0.01). Similar results were achieved with corticosteroids. Intravitreal acazicolcept decreased inflammation scores when compared to untreated fellow eyes and to Fc control treated eyes, although not statistically significant. Systemic toxicity, measured by weight loss, occurred in the corticosteroid-treated, but not in the acazicolcept-treated animals.
CONCLUSIONS
Systemic treatment with acazicolcept statistically significantly suppressed EAU. Acazicolcept was well-tolerated without the weight loss associated with corticosteroids. Acazicolcept may be an effective alternative to corticosteroids for use in treating autoimmune uveitis. Additional studies are needed to clarify the optimal dose and route for use in humans.
TRANSLATIONAL RELEVANCE
We show that T cell costimulatory blockade could be an effective mechanism for treating uveitis.
目的
通过联合抑制 CD28 和诱导性 T 细胞共刺激分子（ICOS）通路，使用 acazicolcept（ALPN-101）为葡萄膜炎提供一种新的潜在治疗方法。在这里，我们使用 Lewis 大鼠的实验性自身免疫性葡萄膜炎（EAU）来评估临床前疗效。
方法
对 57 只接受 acazicolcept 全身（皮下）或局部（玻璃体内）给药治疗的 Lewis 大鼠进行疗效测试，并与匹配的 Fc 对照或皮质类固醇治疗进行比较。通过临床评分、光学相干断层扫描（OCT）和组织学评估治疗对葡萄膜炎的影响。使用流式细胞术确定眼效应 T 细胞群体，并使用多重 ELISA 测量眼房水中细胞因子浓度。
结果
与 Fc 对照治疗相比，全身 acazicolcept 治疗可使临床评分（P < 0.01）、组织学评分（P < 0.05）和眼 CD45+细胞数量（P < 0.01）均显著降低。眼 CD4+和 CD8+T 细胞中表达 IL-17A+和 IFNγ+的细胞数量也显著减少（P < 0.01）。皮质类固醇也取得了类似的结果。与未治疗的对侧眼和 Fc 对照治疗的眼相比，玻璃体内 acazicolcept 降低了炎症评分，但差异无统计学意义。体重减轻是皮质类固醇治疗的毒性指标，但在 acazicolcept 治疗的动物中没有发生。
结论
全身给予 acazicolcept 可显著抑制 EAU。Acazicolcept 耐受性良好，无皮质类固醇相关的体重减轻。Acazicolcept 可能是治疗自身免疫性葡萄膜炎的皮质类固醇的有效替代药物。需要进一步研究以阐明其在人类中的最佳剂量和途径。
翻译
田纳西大学健康科学中心
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