Interleukin-4-independent acceleration of cutaneous leishmaniasis in susceptible BALB/c mice following treatment with anti-CTLA4 antibody.
Interleukin-4-independent acceleration of cutaneous leishmaniasis in susceptible BALB/c mice following treatment with anti-CTLA4 antibody.
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使用抗 CTLA4 抗体治疗后，易感 BALB/c 小鼠皮肤利什曼病的加速不依赖于白细胞介素 4。
DOI：
10.1128/iai.67.12.6454-6460.1999
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发表时间：
1999
影响因子：
3.1
通讯作者：
MaierJr,RA
中科院分区：
文献类型：
--
作者：
Heinzel,FP;MaierJr,RA
BALB/c小鼠容易感染主要利什曼原虫，这是因为分泌Th2细胞因子的CD4+T细胞优先发展。尽管在感染早期，CD86功能的阻断会扰乱Th2细胞的发育和敏感性，但CD28缺陷的BALB/c小鼠仍然容易患利什曼病。因此，我们研究了替代的CD86配体CTLA4是否有助于易感性的表达。经抗CTLA4单抗感染2周的BALB/c小鼠较假手术组进展更迅速，而正常耐药的C57BL/6小鼠未受影响。在感染的前2周，经抗CTLA4处理的BALB/c小鼠引流淋巴结细胞产生的IL-4和IL-13是对照组的6倍，而干扰素-γ的合成却相反地减少。用中和抗IL-4抗体或IL-4基因缺陷的BALB/c小鼠进行抗CTLA4治疗也可导致利什曼病的显著恶化。IL-4KO小鼠的病情加重与体内IL-13升高、干扰素(干扰素-γ)和诱导型一氧化氮合酶(INOSmRNA)表达降低有关。这些数据表明，抗CTLA4抗体在感染L。少校。疾病恶化的机制部分不依赖于IL-4，提示IL-13的增加和/或干扰素-γ的产生减少可能扰乱了基于一氧化氮的杀微生物剂反应。我们的结论是，CTLA4显著调节小鼠利什曼病Th2的发展，抗CTLA4治疗的Th2极化效应导致IL-4非依赖的疾病恶化。
BALB/c mice are susceptible to progressive infection withLeishmania majordue to the preferential development of CD4+T cells that secrete Th2 cytokines. Although Th2 cell development and susceptibility are disrupted by blockade of CD86 function early in infection, CD28-deficient BALB/c mice remain susceptible to leishmaniasis. We therefore examined whether the alternative CD86 ligand, CTLA4, contributes to the expression of susceptibility. BALB/c mice treated for 2 weeks of infection with anti-CTLA4 monoclonal antibody developed more rapidly progressive disease than sham-treated mice, whereas normally resistant C57BL/6 mice were unaffected. The draining lymph node cells of anti-CTLA4-treated BALB/c mice produced up to sixfold more interleukin-4 (IL-4) and IL-13 than control mice in the first 2 weeks of infection, but IFN-γ synthesis was reciprocally decreased. Anti-CTLA4 treatment of BALB/c mice pretreated with neutralizing anti-IL-4 antibody or genetically deficient in IL-4 also caused significant worsening of leishmaniasis. Exacerbation in IL-4 KO mice was associated with increased IL-13 and decreased gamma interferon (IFN-γ) and inducible nitric oxide synthase (iNOS) mRNA expression in vivo. These data indicate that anti-CTLA4 antibody induced earlier and more-polarized Th2 responses in susceptible BALB/c mice infected withL. major. The mechanism of disease worsening was partially IL-4 independent, indicating that increased IL-13 and/or decreased IFN-γ production may have disrupted nitric oxide-based microbicidal responses. We conclude that CTLA4 significantly modulates Th2 development in murine leishmaniasis and that the Th2-polarizing effects of anti-CTLA4 treatment result in IL-4-independent exacerbation of disease.