Role of T regulatory suppression in autoimmunity and can

最近发现，T细胞的一个亚群，例如T调节(Treg)细胞，对免疫反应具有反馈抑制作用。据报道，这些Treg细胞可以抑制自身免疫反应，因此，不幸的是，也有报道说，它们还可以保护肿瘤免受免疫排斥。在本财年，我们发现用于治疗自身免疫性疾病的免疫抑制剂地塞米松(DEX)和淋巴增殖性细胞因子白细胞介素2(IL-2)分别上调了小鼠Treg细胞的数量和功能。此外，当它们一起使用时，它们在促进免疫抑制Treg细胞活性方面有更大的效果。当在抗原(MOG)诱导实验性自身免疫性脑脊髓炎(EAE)之前联合应用IL-2和DEX时，可降低易感小鼠EAE的发生率和严重程度。因此，上调Tregs可以抵消自身免疫反应的诱导。百日咳毒素(PTX)作为佐剂与适当的自身抗原一起加入完全弗氏佐剂(CFA)中，以诱导易感小鼠品系的EAE。PTX的这种辅助作用被归因于诱导血脑屏障通透性增加。然而，我们观察到，在EAE发育过程中，小鼠的功能Treg细胞数量减少。对给予小鼠的不同药物的独立评估表明，PTX本身而不是CFA或抗原导致了抑制性Treg细胞的减少。显然，PTX在体内具有抑制Treg细胞、干扰GiPCR信号转导等多种生物学效应。在另一项单独的研究中，我们观察到PTX也激活了体外树突状细胞的成熟，这需要TLR4的表达和信号转导。因此，PTX的佐剂作用除了抑制Treg细胞外，还包括激活免疫增强的TLR4反应。在这些观察的基础上，将研究PTX诱导肿瘤免疫的作用。我们计划进一步寻找影响Treg细胞功能的药物，因为它们可以用来调节自身免疫和肿瘤细胞的生长。

It has recently become clear that a subset of T cells e.g. T regulatory (Treg) cells have feedback suppressive effects on immune responses. These Treg cells have been reported to suppress autoimmune responses and consequently, unfortunately, also reported to protect tumors from immune rejection. During this fiscal year, we showed that the immunosuppressive agent dexamethasone (DEX), which is used to treat autoimmune disease, and the lymphoproliferative cytokine Interleukin-2, each upregulated the number and function of Treg cells in mice. Furthermore, when administered together they had even greater effects in promoting immunosuppressive Treg cell activities. When administered together prior to an antigen (MOG) that induces experimental autoimmune encephalomyelitis (EAE), IL-2 plus DEX reduced the incidence and severity of EAE in susceptible mice. Thus, upregulation of Tregs can counteract induction of autoimmune reactions.Pertussis toxin (PTX) is coadministered as an adjuvant along with an appropriate autoantigen in Complete Freunds adjuvant (CFA) in order to induce EAE in susceptible mouse strains. This co-adjuvant effect of PTX has been ascribed to induction of increased permeability of the blood brain barrier. However, we observed that mice in the course of developing EAE experienced a decrease in the number of functional Treg cells. Independent evaluation of the different agents given to mice revealed that the PTX by itself rather than the CFA or antigen was responsible for the decrease in suppressive Treg cells. Obviously PTX has multiple biological effects of suppressing Treg cells in vivo and interfering with GiPCR signal transduction. In a separate study we observed that PTX also activated dendritic cell maturation in vitro and this required TLR4 expression and signal transduction. Thus, the adjuvant effects of PTX in addition to inhibiting Treg cells also involve activation of immunoenhancing TLR4 responses. Based on these observations the effects of PTX on inducing tumor immunity will be investigated. We plan to further pursue the identification of agents that influence Treg cell functions, since they can be used to modulate autoimmunity and tumor cell growth.