Functional Anti-TIGIT Antibodies Regulate Development of Autoimmunity and Antitumor Immunity.
Functional Anti-TIGIT Antibodies Regulate Development of Autoimmunity and Antitumor Immunity.
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DOI：
10.4049/jimmunol.1700407
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发表时间：
2018-04-15
期刊：
影响因子：
--
通讯作者：
Joller N
中科院分区：
文献类型：
--
作者：
Dixon KO;Schorer M;Nevin J;Etminan Y;Amoozgar Z;Kondo T;Kurtulus S;Kassam N;Sobel RA;Fukumura D;Jain RK;Anderson AC;Kuchroo VK;Joller N
共抑制受体，如CTLA-4和PD-1，通过抑制T细胞应答在维持免疫稳态中起关键作用。最近，它们作为慢性疾病环境中的治疗靶点获得了关注，其中它们的失调表达有助于抑制免疫应答。新的共抑制受体TIGIT（T细胞免疫球蛋白和ITIM结构域）已显示在自身免疫和癌症的背景下在调节免疫应答中起重要作用。然而，TIGIT调节免疫应答的分子机制仍不充分了解。我们已经产生了一组单克隆抗小鼠TIGIT抗体，其在小鼠体内显示出功能特性，并且可以用作研究TIGIT功能的潜在机制的重要工具。我们已经鉴定了能够在体内调节T细胞应答的激动性以及阻断性抗TIGIT抗体克隆。激动剂或阻断性抗TIGIT抗体的施用调节自身免疫疾病的严重程度，而阻断性抗TIGIT抗体的施用与抗PD-1抗体协同作用以影响部分或甚至完全肿瘤消退。因此，本研究中提出的抗体可以作为在不同疾病环境中详细分析TIGIT功能的重要工具，并且所获得的知识将为靶向TIGIT的新型治疗方法的开发提供有价值的见解。
Co-inhibitory receptors, such as CTLA-4 and PD-1, play a critical role in maintaining immune homeostasis by dampening T cell responses. Recently, they have gained attention as therapeutic targets in chronic disease settings where their dysregulated expression contributes to suppressed immune responses. The novel co-inhibitory receptor TIGIT (T cell immunoglobulin and ITIM domain) has been shown to play an important role in modulating immune responses in the context of autoimmunity and cancer. However, the molecular mechanisms by which TIGIT modulates immune responses are still insufficiently understood. We have generated a panel of monoclonal anti-mouse TIGIT antibodies that show functional properties in mice in vivo and can serve as important tools to study the underlying mechanisms of TIGIT function. We have identified agonistic as well as blocking anti-TIGIT antibody clones that are capable of modulating T cell responses in vivo. Administration of either agonist or blocking anti-TIGIT antibodies modulated autoimmune disease severity while administration of blocking anti-TIGIT antibody synergized with anti-PD-1 antibody to affect partial or even complete tumor regression. The antibodies presented in this study can thus serve as important tools for detailed analysis of TIGIT function in different disease settings and the knowledge gained will provide valuable insight for the development of novel therapeutic approaches targeting TIGIT.
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影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
64.8
作者：
McKinney EF;Lee JC;Jayne DR;Lyons PA;Smith KG
通讯作者：
Smith KG
影响因子：
82.9
作者：
Korn, Thomas;Reddy, Jayagopala;Kuchroo, Vijay K.
通讯作者：
Kuchroo, Vijay K.
DOI：
10.1073/pnas.1525360113
发表时间：
2016-04-19
影响因子：
11.1
作者：
Kloepper, Jonas;Riedemann, Lars;Jain, Rakesh K.
通讯作者：
Jain, Rakesh K.
影响因子：
50.3
作者：
Johnston, Robert J.;Comps-Agrar, Laetitia;Grogan, Jane L.
通讯作者：
Grogan, Jane L.