ABSTRACT
Antigen-specific cytotoxic T lymphocytes (CTL) are essential for the immunotherapy against cancer or infection diseases although, conventionally, immunization with antigens in soluble form cannot induce CTL. In the present study, we have demonstrated for the first time that ovalbumin (OVA)-specific CTL can be induced without any adjuvants by immunization with soluble OVA with negative charges through scavenger-mediated delivery of antigens to antigen presenting cells (APC). Succinylated, maleylated and aconitylated derivatives were synthesized to allow the introduction of negative charges. All these derivatives can induce OVA-specific CTL and, especially, the CTL activity of mice immunized with maleylated derivatives was comparable with that with OVA emulsified with CFA, known to be the strongest adjuvant. Efficient antigen-specific T cell proliferation and IFN-gamma production were also observed for the OVA derivatives. The OVA derivatives also showed significant protective effects on the growth of OVA-expressing E.G7 tumor cells. In conclusion, the present study demonstrates that the introduction of negative charges to soluble antigens will be a useful strategy for the development of vaccines.
Subject(s)
Antigens/administration & dosage , Antigens/immunology , Ovalbumin/administration & dosage , Ovalbumin/immunology , Receptors, Scavenger/metabolism , T-Lymphocytes, Cytotoxic/immunology , Animals , Antigen-Presenting Cells , Antigens/chemistry , Cell Line, Tumor , Female , Immunization/methods , Lymphocyte Activation , Lymphoma, T-Cell/prevention & control , Male , Mice , Mice, Inbred C57BL , Ovalbumin/chemistry , SolubilityABSTRACT
Antigen presentation on major histocompatibility complex (MHC) class I and subsequent priming of antigen-specific cytotoxic T lymphocytes (CTLs) are essential steps for vaccination but exogenous soluble proteins are conventionally taken up by endosomes and presented on MHC class II rather than class I. In this study, we demonstrated, for the first time, that ovalbumin (OVA) chemically cationized with hexamethylenediamine (HMD) can induce OVA-specific CTLs without any adjuvants. Cationization of OVA greatly enhances cellular uptake by antigen-presenting cells (APCs) through adsorptive endocytosis. Two kinds of Cat-OVAs with different cationic charges were evaluated to elicit a CTL response through enhanced uptake by APCs and concomitant participation in the class I pathway. Cat(20)-OVA, a cationized OVA derivative with more cationic charges, showed pronounced induction of the OVA-specific CTL response after subcutaneous immunization. The CTL response was comparable with that induced by OVA with CFA. In contrast to the CFA formulation that actually produced local tissue damage in this study, local damage at the injection sites was not observed with Cat-OVAs. Cat(20)-OVA also showed a significant protective effect on the growth of OVA-expressing E.G7 tumor cells. In conclusion, cationization of soluble antigen is a useful and safe vaccination strategy.
