The immunotherapeutic role of regulatory T cells in Leishmania (Viannia) panamensis infection.
The immunotherapeutic role of regulatory T cells in Leishmania (Viannia) panamensis infection.
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DOI：
10.4049/jimmunol.1400728
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发表时间：
2014-09-15
期刊：
影响因子：
--
通讯作者：
McMahon-Pratt D
中科院分区：
文献类型：
--
作者：
Ehrlich A;Castilho TM;Goldsmith-Pestana K;Chae WJ;Bothwell AL;Sparwasser T;McMahon-Pratt D
利什曼原虫(Viannia)是新大陆皮肤利什曼病的病原体。感染的特征是混合的Th1/Th2炎症反应，这有助于疾病病理。然而，T调节细胞(Treg)在利什曼病(Viannia)发病机制中的作用尚不清楚。采用慢性L.(V.)在Panamens感染中，我们检验了Treg功能有助于控制发病的假设。T调节细胞(CD4+Foxp3+)在感染后表现为异常的表型，产生干扰素-γ，表达Tbet，体外抑制T细胞增殖的能力降低。靶向消融Treg可导致病变扩大，寄生虫载量增加，IL-17和干扰素-γ的产生增加，而IL-10和IL-13水平无变化。因此，这表明炎症反应的增加与疾病的恶化是相称的，剩余的受损的Treg细胞在疾病病理的调节中是重要的。相反，过继转移幼稚小鼠的Treg阻止了疾病的进展，降低了寄生虫负担，并减少了细胞因子(IL-10、IL-13、IL-17、干扰素-γ)的产生。由于Tregs似乎对控制感染很重要，我们假设Tregs的扩增可以作为一种免疫治疗方法。作为原理的证明，慢性感染的小鼠被rIL-2-抗IL-2抗体复合体治疗以扩大Tregs。治疗一过性增加了Treg(引流淋巴结、脾)的数量和百分比，导致细胞因子反应降低，皮损改善，寄生虫载量减少(105倍)。因此，以Tregs为靶点的免疫治疗可以为由文氏菌寄生虫引起的利什曼病提供另一种治疗策略。
Leishmania (Viannia) parasites are etiological agents of cutaneous leishmaniasis in the New World. Infection is characterized by a mixed Th1/Th2 inflammatory response, which contributes to disease pathology. However, the role of T regulatory cells (Treg) in Leishmania (Viannia) disease pathogenesis is unclear. Using the mouse model of chronic L. (V.) panamensis infection, we have examined the hypothesis that Treg functionality contributes to control of pathogenesis. Upon infection, T regulatory cells (CD4+Foxp3+) presented with a dysregulated phenotype, in that they produced IFN-γ, expressed Tbet and had a reduced ability to suppress T cell proliferation in vitro. Targeted ablation of Tregs resulted in enlarged lesions, increased parasite load and enhanced production of IL-17 and IFN-γ with no change in IL-10 and IL-13 levels. Thus, indicating that an increased inflammatory response was commensurate with disease exacerbation and that the remaining impaired Treg cells were important in regulation of disease pathology. Conversely, adoptive transfer of Tregs from naïve mice halted disease progression, lowered parasite burden and reduced cytokine production (IL-10, IL-13, IL-17, IFN-γ). As Tregs appeared important for controlling infection, we hypothesized the expansion of Tregs could be used as an immunotherapeutic treatment approach. As a proof of principle, chronically infected mice were treated with rIL-2-anti-IL-2 antibody complex to expand Tregs. Treatment transitorily increased numbers and percentage of Treg (draining lymph node, spleen), that resulted in reduced cytokine responses, ameliorated lesions and reduced parasite load (105-fold). Thus, immunotherapy targeting Tregs could provide an alternate treatment strategy for leishmaniasis caused by L. (Viannia) parasites.
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影响因子：
5.4
作者：
Castilho, Tiago M.;Goldsmith-Pestana, Karen;Lozano, Caterin;Valderrama, Liliana;Saravia, Nancy G.;McMahon-Pratt, Diane
通讯作者：
McMahon-Pratt, Diane
影响因子：
3.8
作者：
Diaz-Gonzalez R;Kuhlmann FM;Galan-Rodriguez C;Madeira da Silva L;Saldivia M;Karver CE;Rodriguez A;Beverley SM;Navarro M;Pollastri MP
通讯作者：
Pollastri MP
影响因子：
4.4
作者：
Esposito, Marianna;Ruffini, Francesca;Furlan, Roberto
通讯作者：
Furlan, Roberto
影响因子：
4.4
作者：
Aseffa, A;Gumy, A;Tacchini-Cottier, F
通讯作者：
Tacchini-Cottier, F
影响因子：
20.3
作者：
Duhen, Thomas;Duhen, Rebekka;Campbell, Daniel J.
通讯作者：
Campbell, Daniel J.