Functional Homology for Antibody-Dependent Phagocytosis Across Humans and Rhesus Macaques.
Functional Homology for Antibody-Dependent Phagocytosis Across Humans and Rhesus Macaques.
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DOI：
10.3389/fimmu.2021.678511
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发表时间：
2021
影响因子：
7.3
通讯作者：
Tomaras GD
中科院分区：
文献类型：
--
作者：
Pollara J;Tay MZ;Edwards RW;Goodman D;Crowley AR;Edwards RJ;Easterhoff D;Conley HE;Hoxie T;Gurley T;Jones C;Machiele E;Tuyishime M;Donahue E;Jha S;Spreng RL;Hope TJ;Wiehe K;He MM;Moody MA;Saunders KO;Ackerman ME;Ferrari G;Tomaras GD
对人类临床 HIV-1 疫苗试验和在恒河猴 (RM) 模型中进行的临床前疫苗研究的分析已经确定了非中和性 Fc 受体 (FcR) 依赖性抗体效应器功能与感染风险降低之间的关联。具体而言，在多项 RM 研究和人类 HVTN505 试验中，抗体依赖性吞噬作用 (ADP) 已成为感染风险降低的常见相关因素。这一反复出现的发现表明，具有介导 ADP 能力的抗体反应很可能是旨在防止 HIV-1 感染的疫苗反应的理想组成部分。由于 RM 模型的使用对于开发下一代候选 HIV-1 疫苗至关重要，因此需要确定在 RM 中观察到的 ADP 活性如何有效地转化为人类的活性。在这项研究中，我们比较了人类和 RM 单核细胞以及多形核白细胞 (PMN) 的 ADP 活性，以弥补这一知识差距。我们观察到，人类个体和 RM 中单核细胞和 PMN ADP 活性的大小存在相当大的差异，这些差异不依赖于 FcR 等位基因，并且仅受细胞表面 FcR 水平的适度影响。重要的是，我们发现对于人和 RM 吞噬细胞，当由人 IgG3 介导时，靶向 CD4 结合位点的抗体的 ADP 活性最大，其次是 RM 和人 IgG1。这些结果表明，这两个物种的 ADP 抗体和 FcR 之间存在功能同源性。我们还使用了带有延长铰链区的新型 RM IgG1 单克隆抗体，以证明铰链延长可增强 RM ADP 活性。具有工程铰链区的 RM IgG 可以实现与人 IgG3 观察到的 ADP 活性相当的活性。这些新型修饰抗体将在被动免疫研究中发挥作用，旨在确定 IgG3 和 ADP 在 RM 模型中免受病毒攻击或控制疾病的作用。我们的结果有助于更好地转化人类和猕猴抗体和 FcR 生物学，并可能有助于提高测试准确性以及对未来主动和被动预防策略的评估。
Analyses of human clinical HIV-1 vaccine trials and preclinical vaccine studies performed in rhesus macaque (RM) models have identified associations between non-neutralizing Fc Receptor (FcR)-dependent antibody effector functions and reduced risk of infection. Specifically, antibody-dependent phagocytosis (ADP) has emerged as a common correlate of reduced infection risk in multiple RM studies and the human HVTN505 trial. This recurrent finding suggests that antibody responses with the capability to mediate ADP are most likely a desirable component of vaccine responses aimed at protecting against HIV-1 acquisition. As use of RM models is essential for development of the next generation of candidate HIV-1 vaccines, there is a need to determine how effectively ADP activity observed in RMs translates to activity in humans. In this study we compared ADP activity of human and RM monocytes and polymorphonuclear leukocytes (PMN) to bridge this gap in knowledge. We observed considerable variability in the magnitude of monocyte and PMN ADP activity across individual humans and RM that was not dependent on FcR alleles, and only modestly impacted by cell-surface levels of FcRs. Importantly, we found that for both human and RM phagocytes, ADP activity of antibodies targeting the CD4 binding site was greatest when mediated by human IgG3, followed by RM and human IgG1. These results demonstrate that there is functional homology between antibody and FcRs from these two species for ADP. We also used novel RM IgG1 monoclonal antibodies engineered with elongated hinge regions to show that hinge elongation augments RM ADP activity. The RM IgGs with engineered hinge regions can achieve ADP activity comparable to that observed with human IgG3. These novel modified antibodies will have utility in passive immunization studies aimed at defining the role of IgG3 and ADP in protection from virus challenge or control of disease in RM models. Our results contribute to a better translation of human and macaque antibody and FcR biology, and may help to improve testing accuracy and evaluations of future active and passive prevention strategies.
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影响因子：
3.7
作者：
Edmonds TG;Ding H;Yuan X;Wei Q;Smith KS;Conway JA;Wieczorek L;Brown B;Polonis V;West JT;Montefiori DC;Kappes JC;Ochsenbauer C
通讯作者：
Ochsenbauer C
影响因子：
3.8
作者：
Boesch AW;Kappel JH;Mahan AE;Chu TH;Crowley AR;Osei-Owusu NY;Alter G;Ackerman ME
通讯作者：
Ackerman ME
免疫途径定义了疫苗介导的对SIV的保护的多种机制。
影响因子：
82.9
作者：
Ackerman ME;Das J;Pittala S;Broge T;Linde C;Suscovich TJ;Brown EP;Bradley T;Natarajan H;Lin S;Sassic JK;O'Keefe S;Mehta N;Goodman D;Sips M;Weiner JA;Tomaras GD;Haynes BF;Lauffenburger DA;Bailey-Kellogg C;Roederer M;Alter G
通讯作者：
Alter G
影响因子：
5.4
作者：
Ackerman, Margaret E.;Dugast, Anne-Sophie;Alter, Galit
通讯作者：
Alter, Galit
影响因子：
2.6
作者：
Diamantopoulos, Panagiotis T.;Kalotychou, Vassiliki;Viniou, Nora-Athina
通讯作者：
Viniou, Nora-Athina