Farhadi Shaheen A, Hudalla Gregory A
J Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA.
J Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA
Exp Biol Med (Maywood). 2016 May;241(10):1074-83. doi: 10.1177/1535370216650055.
Galectins, a 15-member family of soluble carbohydrate-binding proteins, are receiving increasing interest as therapeutic targets for immunotherapy and immunomodulation due to their role as extracellular signals that regulate innate and adaptive immune cell phenotype and function. However, different galectins can have redundant, synergistic, or antagonistic signaling activity in normal immunological responses, such as resolution of inflammation and induction of antigen-specific tolerance. In addition, certain galectins can be hijacked to promote progression of immunopathologies, such as tumor immune privilege, metastasis, and viral infection, while others can inhibit these processes. Thus, eliciting a desired immunological outcome will likely necessitate therapeutics that can precisely enhance or inhibit particular galectin-glycan interactions. Multivalency is an important determinant of the affinity and specificity of natural galectin-glycan interactions, and is emerging as a key design element for therapeutics that can effectively manipulate galectin bioactivity. This minireview surveys current molecular and biomaterial engineering approaches to create therapeutics that can stabilize galectin multivalency or recapitulate natural glycan multivalency (i.e. "the glycocluster effect"). In particular, we highlight examples of using natural and engineered multivalent galectins for immunosuppression and immune tolerance, with a particular emphasis on treating autoimmune diseases or avoiding transplant rejection. In addition, we present examples of multivalent inhibitors of galectin-glycan interactions to maintain or restore T-cell function, with a particular emphasis on promoting antitumor immunity. Finally, we discuss emerging opportunities to further engineer galectin-glycan interactions for immunotherapy and immunomodulation.
半乳糖凝集素是一个由15种可溶性碳水化合物结合蛋白组成的家族，由于它们作为细胞外信号调节先天性和适应性免疫细胞表型及功能，作为免疫治疗和免疫调节的治疗靶点正受到越来越多的关注。然而，在正常免疫反应中，如炎症消退和抗原特异性耐受的诱导，不同的半乳糖凝集素可能具有冗余、协同或拮抗的信号活性。此外，某些半乳糖凝集素可能被利用来促进免疫病理的进展，如肿瘤免疫逃逸、转移和病毒感染，而其他半乳糖凝集素则可以抑制这些过程。因此，要获得理想的免疫结果可能需要能够精确增强或抑制特定半乳糖凝集素-聚糖相互作用的治疗方法。多价性是天然半乳糖凝集素-聚糖相互作用亲和力和特异性的重要决定因素，并且正成为能够有效操纵半乳糖凝集素生物活性的治疗方法的关键设计要素。本综述调查了当前用于创建能够稳定半乳糖凝集素多价性或重现天然聚糖多价性（即“糖簇效应”）的治疗方法的分子和生物材料工程方法。特别是，我们重点介绍了使用天然和工程化多价半乳糖凝集素进行免疫抑制和免疫耐受的例子，尤其强调治疗自身免疫性疾病或避免移植排斥。此外，我们展示了半乳糖凝集素-聚糖相互作用的多价抑制剂以维持或恢复T细胞功能的例子，尤其强调促进抗肿瘤免疫。最后，我们讨论了进一步设计半乳糖凝集素-聚糖相互作用用于免疫治疗和免疫调节的新机会。
