Role of T regulatory suppression in autoimmunity and cancer

T 调节抑制在自身免疫和癌症中的作用

• 批准号: 8157403
• 负责人: JOOST J OPPENHEIM
• 金额: $ 46.76万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8157403
• 关键词: Autoimmunity; Malignant Neoplasms; Role

Our studies of Tregs have revealed that TNF by acting on the TNFR2 receptor, which is highly expressed by Tregs, unexpectedly results in their proliferative expansion and functional activation both in mice and in man. In view of the well known proinflammatory effects of TNF, our data showing that TNF in a more delayed manner can also down-regulate immune responses is rather surprising. One clarification of these contradictory effects of TNF is based on our data showing that TNF by activating Teffector cells also induces them to express TNFR2 and to become more resistant to the suppressive effects of Tregs. Thus, activated T cells at inflammatory sites or in autoimmune status can prevail over the suppressive effects of Tregs. However, as inflammation subsides in healing wounds or in noninflamed tumors Tregs prevail. Most tumor infiltrating T cells (TIL's) actually express TNFR2 and are activated by tumor-derived TNF to be even more immunosuppressive than Tregs in peripheral lymphoid tissues. Suppression of Tregs should enable more effect host anti-tumor responses to become evident. Consequently, our preliminary results show that anti-TNF reduced the growth of mouse Lewis lung and breast (4T1) tumors. Thus, by identifying better means of countering Tregs, we may be able to enhance antitumor responses to tumor vaccines.

我们的研究表明，TNF通过作用于TNFR2受体，这是高度表达的TGF1 α，出乎意料地导致他们的增殖扩张和功能激活在小鼠和人。鉴于众所周知的促炎作用的TNF，我们的数据显示，TNF在一个更延迟的方式也可以下调免疫反应是相当令人惊讶的。TNF的这些矛盾作用的一个澄清是基于我们的数据，该数据显示TNF通过激活T效应细胞也诱导它们表达TNFR 2并变得对TGF1 α的抑制作用更具抗性。因此，在炎症部位或自身免疫状态下的活化T细胞可以胜过Tcl3的抑制作用。然而，随着炎症在愈合的伤口或非炎症性肿瘤中消退，炎症占上风。大多数肿瘤浸润性T细胞（TIL）实际上表达TNFR2，并被肿瘤来源的TNF激活，从而在外周淋巴组织中比T细胞更具有免疫抑制性。抑制TGFAP应该能够使更有效的宿主抗肿瘤应答变得明显。因此，我们的初步结果表明，抗TNF减少小鼠刘易斯肺和乳腺（4T1）肿瘤的生长。因此，通过确定更好的方法来对抗TcB，我们可能能够增强对肿瘤疫苗的抗肿瘤反应。