Meraldi Valentin, Romero Jackeline F, Kensil Charlotte, Corradin Giampietro
Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
Vaccine. 2005 Apr 15;23(21):2801-12. doi: 10.1016/j.vaccine.2004.10.044.
Stable protective immunity can be achieved against malaria by the injection of radiation-attenuated sporozoites (gamma-spz) and is mediated by IFN-gamma producing CD8+ T cells targeting the pre-erythrocytic stages. An efficient malaria vaccine should mimic this immunity. We compared the immune response specific for the circumsporozoite protein (CSP) of Plasmodium berghei (P. berghei), an important target of this protective response, elicited in mice immunized with the long synthetic polypeptide (LSP) PbCS 242-310, representing the C-terminus of the CSP of P. berghei, with the adjuvant QS-21 or injected with gamma-spz. The ex vivo evaluation of the CD8+ T cell response by IFN-gamma ELISPOT assay revealed that the injection of LSP with QS-21 induced, compared to gamma-spz, a similar frequency of peptide-specific lymphocytes in the spleen but a eight-fold increase in the draining lymph-nodes. A very high frequency of CD8+ T cells, specific for the sequence PbCS 245-253, a H-2Kd-restricted CTL epitope, was obtained in the liver and spleen of mice immunized with the two regimens. Even though the frequency of H-2Kd PbCS 245-253 multimer+, CD8+ T cells was higher in gamma-spz immunized mice, the frequency of IFN-gamma producing CD8+ T cells was comparable. The phenotype of the CD8+ T cell responses was characterized with the help H-2Kd PbCS 245-253 multimer and most of the CSP-specific CD8+ T cells represented an intermediate subset between effector and central memory with CD44(high), CD45RB(high), CD62L(low) and CD122(high). The number of memory CD8+ T cells decreased after the last LSP immunization but could be boosted to higher level with live spz. The unique combination of LSP PbCS 242-310 and the adjuvant QS-21 induced an immune response that was comparable in terms of quality to the one generated with gamma-spz. This confirmed the potential of LSP as malaria vaccine candidates as well as for the study of the repertoire of targets of protective immunity in the gamma-spz vaccine model.
通过注射辐射减毒子孢子（γ-子孢子）可实现针对疟疾的稳定保护性免疫，且这种免疫由靶向红细胞前期阶段的产生干扰素-γ的CD8⁺ T细胞介导。一种有效的疟疾疫苗应模拟这种免疫。我们比较了在分别用长合成多肽（LSP）PbCS 242 - 310（代表伯氏疟原虫环子孢子蛋白（CSP）的C端）与佐剂QS - 21免疫的小鼠以及注射γ-子孢子的小鼠中，针对伯氏疟原虫CSP（这种保护性反应的一个重要靶点）引发的免疫反应。通过干扰素-γ ELISPOT试验对CD8⁺ T细胞反应进行的体外评估显示，与γ-子孢子相比，用QS - 21注射LSP在脾脏中诱导出相似频率的肽特异性淋巴细胞，但在引流淋巴结中增加了八倍。在用这两种方案免疫的小鼠的肝脏和脾脏中，获得了针对序列PbCS 245 - 253（一种H - 2Kd限制性CTL表位）的非常高频率的CD8⁺ T细胞。尽管在γ-子孢子免疫的小鼠中H - 2Kd PbCS 245 - 253多聚体⁺、CD8⁺ T细胞的频率更高，但产生干扰素-γ的CD8⁺ T细胞的频率相当。借助H - 2Kd PbCS 245 - 253多聚体对CD8⁺ T细胞反应的表型进行了表征，大多数CSP特异性CD8⁺ T细胞代表效应细胞和中央记忆细胞之间的一个中间亚群，其特征为CD44（高）、CD45RB（高）、CD62L（低）和CD122（高）。在最后一次LSP免疫后，记忆性CD8⁺ T细胞的数量减少，但可用活子孢子将其提升至更高水平。LSP PbCS 242 - 310与佐剂QS - 21的独特组合诱导出的免疫反应在质量上与γ-子孢子产生的免疫反应相当。这证实了LSP作为疟疾疫苗候选物的潜力，以及在γ-子孢子疫苗模型中用于研究保护性免疫靶点库的潜力。
