Galili Uri
Department of Medicine, Rush University Medical College, Chicago, IL, United States.
Front Mol Biosci. 2023 Jun 28;10:1209974. doi: 10.3389/fmolb.2023.1209974. eCollection 2023.
This review describes the significance of the α-gal epitope (Galα-3Galβ1-4GlcNAc-R) as the core of human blood-group A and B antigens (A and B antigens), determines in mouse models the principles underlying the immune response to these antigens, and suggests future strategies for the induction of immune tolerance to incompatible A and B antigens in human allografts. Carbohydrate antigens, such as ABO antigens and the α-gal epitope, differ from protein antigens in that they do not interact with T cells, but B cells interacting with them require T-cell help for their activation. The α-gal epitope is the core of both A and B antigens and is the ligand of the natural anti-Gal antibody, which is abundant in all humans. In A and O individuals, anti-Gal clones (called anti-Gal/B) comprise >85% of the so-called anti-B activity and bind to the B antigen in facets that do not include fucose-linked α1-2 to the core α-gal. As many as 1% of B cells are anti-Gal B cells. Activation of quiescent anti-Gal B cells upon exposure to α-gal epitopes on xenografts and some protozoa can increase the titer of anti-Gal by 100-fold. α1,3-Galactosyltransferase knockout (GT-KO) mice lack α-gal epitopes and can produce anti-Gal. These mice simulate human recipients of ABO-incompatible human allografts. Exposure for 2-4 weeks of naïve and memory mouse anti-Gal B cells to α-gal epitopes in the heterotopically grafted wild-type (WT) mouse heart results in the elimination of these cells and immune tolerance to this epitope. Shorter exposures of 7 days of anti-Gal B cells to α-gal epitopes in the WT heart result in the production of accommodating anti-Gal antibodies that bind to α-gal epitopes but do not lyse cells or reject the graft. Tolerance to α-gal epitopes due to the elimination of naïve and memory anti-Gal B cells can be further induced by 2 weeks exposure to WT lymphocytes or autologous lymphocytes engineered to present α-gal epitopes by transduction of the α1,3-galactosyltransferase gene. These mouse studies suggest that autologous human lymphocytes similarly engineered to present the A or B antigen may induce corresponding tolerance in recipients of ABO-incompatible allografts. The review further summarizes experimental works demonstrating the efficacy of α-gal therapies in amplifying anti-viral and anti-tumor immune-protection and regeneration of injured tissues.
本综述描述了α-半乳糖表位（Galα-3Galβ1-4GlcNAc-R）作为人类血型A和B抗原（A和B抗原）核心的重要性，在小鼠模型中确定了对这些抗原免疫反应的潜在机制，并提出了在人类同种异体移植中诱导对不相容A和B抗原免疫耐受的未来策略。碳水化合物抗原，如ABO抗原和α-半乳糖表位，与蛋白质抗原不同，它们不与T细胞相互作用，但与它们相互作用的B细胞需要T细胞的帮助才能被激活。α-半乳糖表位是A和B抗原的核心，是天然抗Gal抗体的配体，在所有人类中都很丰富。在A和O个体中，抗Gal克隆（称为抗Gal/B）占所谓抗B活性的85%以上，并在不包括与核心α-半乳糖连接的岩藻糖基化α1-2的方面与B抗原结合。多达1%的B细胞是抗Gal B细胞。静止的抗Gal B细胞在接触异种移植物和一些原生动物上的α-半乳糖表位后被激活，可使抗Gal的滴度增加100倍。α1,3-半乳糖基转移酶基因敲除（GT-KO）小鼠缺乏α-半乳糖表位，可产生抗Gal。这些小鼠模拟了ABO血型不相容的人类同种异体移植的受者。将未成熟和记忆性小鼠抗Gal B细胞在异位移植的野生型（WT）小鼠心脏中暴露于α-半乳糖表位2-4周，会导致这些细胞的消除以及对该表位的免疫耐受。抗Gal B细胞在WT心脏中较短时间（7天）暴露于α-半乳糖表位会产生适应性抗Gal抗体，这些抗体与α-半乳糖表位结合，但不会裂解细胞或排斥移植物。通过将未成熟和记忆性抗Gal B细胞消除而产生的对α-半乳糖表位的耐受性，可以通过暴露于WT淋巴细胞或通过转导α1,3-半乳糖基转移酶基因工程化以呈现α-半乳糖表位的自体淋巴细胞2周来进一步诱导。这些小鼠研究表明，经过类似工程化以呈现A或B抗原的自体人类淋巴细胞可能会在ABO血型不相容的同种异体移植受者中诱导相应的耐受性。该综述进一步总结了实验工作，证明了α-半乳糖疗法在增强抗病毒和抗肿瘤免疫保护以及受损组织再生方面的功效。
