Abstract
Invocation of cellular immunity by epitopic peptides remains largely dependent on empirically developed protocols, such as interfusion of aluminum salts or emulsification using terpenoids and surfactants. To explore novel vaccine formulation, epitopic peptide motifs were co-programmed with structural motifs to produce artificial antigens using our “motif-programming” approach. As a proof of concept, we used an ovalbumin (OVA) system and prepared an artificial protein library by combinatorially polymerizing MHC class I and II sequences from OVA along with a sequence that tends to form secondary structures. The purified endotoxin-free proteins were then examined for their ability to activate OVA-specific T-cell hybridoma cells after being processed within dendritic cells. One clone, F37A (containing three MHC I and two MHC II OVA epitopes), possessed a greater ability to evoke cellular immunity than the native OVA or the other artificial antigens. The sensitivity profiles of drugs that interfered with the F37A uptake differed from those of the other artificial proteins and OVA, suggesting that alteration of the cross-presentation pathway is responsible for the enhanced immunogenicity. Moreover, F37A, but not an epitopic peptide, invoked cellular immunity when injected together with monophosphoryl lipid A (MPL), and retarded tumor growth in mice. Thus, an artificially synthesized protein antigen induced cellular immunity in vivo in the absence of incomplete Freund's adjuvant or aluminum salts. The method described here could be potentially used for developing vaccines for such intractable ailments as AIDS, malaria and cancer, ailments in which cellular immunity likely play a crucial role in prevention and treatment.
Highlights
Adjuvants are agents that enhance immune responses when coadministered with antigens
The most effective adjuvant is complete Freund’s adjuvant (CFA) [2], which is composed of inactivated Mycobacteria in an oil emulsion often termed ‘‘incomplete Freund’s adjuvant’’ (IFA)
Combinatorial synthesis of artificial proteins As an immunotherapeutic treatment for cancer, vaccination using a synthetic peptide whose sequence corresponds to an epitope of a tumor antigen has been extensively explored
Summary
Adjuvants are agents that enhance immune responses when coadministered with antigens. The most effective adjuvant is complete Freund’s adjuvant (CFA) [2], which is composed of inactivated Mycobacteria in an oil emulsion often termed ‘‘incomplete Freund’s adjuvant’’ (IFA). Aluminum salt has been approved for use in various vaccines, but it is a poor inducer of Th1 cellular responses [3]. MF59 and AS03 are the other approved physical adjuvants They are composed of an oil emulsion and have been used in some vaccines [4]. Monophosphoryl lipid A (MPL), a derivative of lipopolysaccharide (LPS), is approved for use in vaccines in combination with aluminum salt [7]. Physical adjuvants are indispensable for efficient immune induction, less understanding of their mechanism of action and quality control difficulties have hindered their development
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