Cure of progressive murine leishmaniasis: interleukin 4 dominance is abolished by transient CD4(+) T cell depletion and T helper cell type 1-selective cytokine therapy.
Cure of progressive murine leishmaniasis: interleukin 4 dominance is abolished by transient CD4(+) T cell depletion and T helper cell type 1-selective cytokine therapy.
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DOI：
10.1084/jem.189.12.1895
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发表时间：
1999-06-21
期刊：
影响因子：
--
通讯作者：
Rerko RM
中科院分区：
文献类型：
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作者：
Heinzel FP;Rerko RM
在易感BALB/c小鼠中，由产生白细胞介素（IL）-4的2型辅助性T细胞（Th 2）CD 4 + T细胞介导的利什曼原虫进行性感染，一旦建立，就会对重组（r）IL-12和/或中和抗IL-4抗体的Th 1偏离疗法产生抗性。我们试图恢复保护性免疫力在晚期利什曼病的耗竭Th 2偏向的CD 4+细胞群，并在淋巴细胞恢复过程中，由苦参碱直接重建Th 1细胞反应。在3周感染的BALB/c小鼠中，单独使用溶细胞GK 1.5抗CD 4 mAb治疗不能逆转疾病，但GK 1.5与抗IL-4抗体和病灶内注射rIL-12联合治疗80%的小鼠皮肤病变，并建立了对L.抗再感染的主要抗原。GK1.5的疗效未被细胞毒性抗CD 8单克隆抗体2.43或非消耗性抗CD 4 mAb YTS 177所取代，证实了CD 4+细胞的消耗是特异性的，并且对于治疗效果是必不可少的。最后，结合CD 4+耗竭和IL-4中和是治愈性的，表明既不增加寄生虫负担，也不改变辅助细胞功能独立偏向于Th 2重建在晚期利什曼病。晚期利什曼病可以通过T细胞耗竭和马槟榔碱指导的Th 1细胞应答的恢复来治愈，这表明了对其他免疫介导的疾病的新干预措施，并确定了CD 4 + T细胞和非T细胞在维持Th 2和Th 1表型中的不同作用。
Progressive infection with Leishmania major in susceptible BALB/c mice is mediated by interleukin (IL)-4–producing T helper cell type 2 (Th2) CD4+ T cells that, once established, become resistant to Th1-deviating therapies with recombinant (r)IL-12 and/or neutralizing anti–IL-4 antibodies. We sought to restore protective immunity in advanced leishmaniasis by depletion of Th2-biased CD4+ populations and by cytokine-directed reconstitution of Th1 cellular responses during lymphocyte recovery. Treatment with cytolytic GK1.5 anti-CD4 mAb alone did not reverse disease in 3 wk–infected BALB/c mice, but GK1.5 combined with anti–IL-4 antibody and intralesional rIL-12 cured cutaneous lesions in 80% of mice and established a Th1-polarized cytokine response to L. major antigen protective against reinfection. The curative effects of GK1.5 were not replaced by cytotoxic anti-CD8 monoclonal antibody 2.43 or nondepleting anti-CD4 mAb YTS177, confirming that depletion of CD4+ cells was specific and essential for therapeutic effect. Finally, combined CD4+ depletion and IL-4 neutralization were curative, indicating that neither increased parasite burden nor altered accessory cell function independently biased towards Th2 reconstitution in advanced leishmaniasis. Advanced leishmaniasis can be cured by T cell depletion and cytokine-directed recovery of Th1 cellular responses, suggesting novel interventions for other immune-mediated diseases and identifying distinct roles for CD4+ T cell and non-T cell in the maintenance of Th2 and Th1 phenotypes.