经疟原虫孢子和氯喹免疫的人源化 DRAGA 小鼠可诱导出保护性的红细胞前期免疫。

Humanized DRAGA mice immunized with Plasmodium falciparum sporozoites and chloroquine elicit protective pre-erythrocytic immunity.

机构信息

US Military Malaria Vaccine Program, Naval Medical Research Center/Walter Reed Army Institute of Research, Silver Spring, MD, USA.

Department of Medicine, Uniformed Services University of Health Sciences, Bethesda, MD, USA.

出版信息

Malar J. 2018 Mar 14;17(1):114. doi: 10.1186/s12936-018-2264-y.

BACKGROUND

Human-immune-system humanized mouse models can bridge the gap between humans and conventional mice for testing human vaccines. The HLA-expressing humanized DRAGA (HLA-A2.HLA-DR4.Rag1KO.IL2RγcKO.NOD) mice reconstitute a functional human-immune-system and sustain the complete life cycle of Plasmodium falciparum. Herein, the DRAGA mice were investigated for immune responses following immunization with live P. falciparum sporozoites under chloroquine chemoprophylaxis (CPS-CQ), an immunization approach that showed in human trials to confer pre-erythrocytic immunity.

RESULTS

The CPS-CQ immunized DRAGA mice (i) elicited human CD4 and CD8 T cell responses to antigens expressed by P. falciparum sporozoites (Pfspz) and by the infected-red blood cells (iRBC). The Pfspz-specific human T cell responses were found to be systemic (spleen and liver), whereas the iRBCs-specific human T cell responses were more localized to the liver, (ii) elicited stronger antibody responses to the Pfspz than to the iRBCs, and (iii) they were protected against challenge with infectious Pfspz but not against challenge with iRBCs.

CONCLUSIONS

The DRAGA mice represent a new pre-clinical model to investigate the immunogenicity and protective efficacy of P. falciparum malaria vaccine candidates.

背景

人免疫系统人源化小鼠模型可以在人类和常规小鼠之间架起桥梁，用于测试人类疫苗。表达 HLA 的人源化 DRAGA（HLA-A2.HLA-DR4.Rag1KO.IL2RγcKO.NOD）小鼠重建了功能性的人免疫系统，并维持恶性疟原虫的完整生命周期。在此，研究了在氯喹化学预防（CPS-CQ）下用活恶性疟原虫孢子虫免疫后 DRAGA 小鼠的免疫反应，这是一种在人体试验中显示可赋予红细胞前期免疫的免疫接种方法。

结果

CPS-CQ 免疫的 DRAGA 小鼠（i）对恶性疟原虫孢子虫（Pfspz）和感染的红细胞（iRBC）表达的抗原产生了人类 CD4 和 CD8 T 细胞反应。发现 Pfspz 特异性人类 T 细胞反应是全身性的（脾脏和肝脏），而 iRBCs 特异性人类 T 细胞反应更局限于肝脏，（ii）对 Pfspz 的抗体反应强于对 iRBCs 的抗体反应，和（iii）它们对感染性 Pfspz 具有保护作用，但对 iRBCs 的感染没有保护作用。