Skeiky Y A, Kennedy M, Kaufman D, Borges M M, Guderian J A, Scholler J K, Ovendale P J, Picha K S, Morrissey P J, Grabstein K H, Campos-Neto A, Reed S G
Corixa Corporation, Seattle, WA 98104, USA.
J Immunol. 1998 Dec 1;161(11):6171-9.
We have evaluated the ability of the Leishmania protein LeIF to influence the Th1/Th2 cytokine responses and the generation of LeIF-specific T cell clones in the absence of adjuvant. We characterized LeIF-specific T cell responses in Leishmania major-infected and uninfected BALB/c mice. These mice develop a strong Th2 response during infection with L. major. When lymph node cells from infected BALB/c mice were stimulated in vitro with LeIF, only IFN-gamma (and no detectable IL-4) was found in the culture supernatant. In addition, LeIF down-regulated Leishmania Ag-specific IL-4 production by lymph node cells from infected BALB/c mice. Subsequently, Th responses were evaluated in naive BALB/c mice following immunization with LeIF. T cell clones derived from mice immunized with LeIF preferentially secreted IFN-gamma. Finally, to understand the basis for the preferential Th1 cytokine bias observed with LeIF, the ability of LeIF to influence the early cytokine profile was evaluated in splenocytes of SCID mice. We found that LeIF stimulated fresh spleen cells from naive SCID mice to secrete IFN-gamma by IL-12/IL-18-dependent mechanisms. The N-terminal half of the molecule (amino acid residues 1-226) maintained the ability to stimulate IFN-gamma from splenocytes of SCID mice. Finally, we also demonstrated that LeIF was able to provide partial protection of BALB/c mice against L. major. Thus, our results suggest the potential of LeIF as a Th1-type adjuvant and as a therapeutic and prophylactic vaccine Ag for leishmaniasis when used with other leishmanial Ags.
我们评估了利什曼原虫蛋白LeIF在无佐剂情况下影响Th1/Th2细胞因子反应以及产生LeIF特异性T细胞克隆的能力。我们对感染和未感染硕大利什曼原虫的BALB/c小鼠中LeIF特异性T细胞反应进行了表征。这些小鼠在感染硕大利什曼原虫期间会产生强烈的Th2反应。当用LeIF体外刺激感染的BALB/c小鼠的淋巴结细胞时，在培养上清液中仅发现干扰素-γ（未检测到白细胞介素-4）。此外，LeIF下调了感染的BALB/c小鼠淋巴结细胞中利什曼原虫抗原特异性白细胞介素-4的产生。随后，在用LeIF免疫后的幼稚BALB/c小鼠中评估了Th反应。源自用LeIF免疫的小鼠的T细胞克隆优先分泌干扰素-γ。最后，为了解观察到的LeIF优先偏向Th1细胞因子的基础，在SCID小鼠的脾细胞中评估了LeIF影响早期细胞因子谱的能力。我们发现LeIF通过依赖白细胞介素-12/白细胞介素-18的机制刺激幼稚SCID小鼠的新鲜脾细胞分泌干扰素-γ。该分子的N端一半（氨基酸残基1-226）保持了刺激SCID小鼠脾细胞产生干扰素-γ的能力。最后，我们还证明LeIF能够为BALB/c小鼠提供针对硕大利什曼原虫的部分保护。因此，我们的结果表明LeIF作为Th1型佐剂以及与其他利什曼原虫抗原一起使用时作为利什曼病的治疗性和预防性疫苗抗原的潜力。
