Cytokine and Costimulatory Factor-Encoding Plasmids as Adjuvants for DNA Vaccination

互联网2014-02-13

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The induction of a potent and long-lasting immunity is one of the most important elements to consider in developing an effective vaccine. DNA vaccines induce markedly stronger CD8⁺ cytotoxic T lymphocyte (CTL) activity than do traditional peptide vaccines through their particular mechanism of antigen presentation mediated by MHC class I molecules. Induction of CTL specific to pathogenic viruses is thought to provide a reliable means of protecting a host from infection and halting disease progression, as these cells can directly recognize and lyse infected cells. However, in most of the early studies showing induction of pathogen-specific CTL, antigen-encoding immunogenic DNA alone was used and DNA vectors encoding immunomodulating molecules were not considered. It now appears that various types of immunomodulatory molecules such as cytokines (IL-1 [1 ], IL-2 [2 ], IL-12 [3 ], IFN-γ [4 ], IL-7 [5 –7 ], and GM-CSF [8 ,9 ]), chemokines (TCA-3 [10 ], RANTES [11 ], MIP-1 [11 ]), and costimulatory molecules (CD40L [12 ], B7-1 [13 ] and B7-2 [14 ]) could enhance or modify the specific immune responses elicited by DNA immunization (see Table 1 ).

Table 1 Summary of Effects of Cytokines after Conventional Vaccination and of Expression Plasmids following DNA Immunization

Immunomodulatory Molecules	Effect		Ref.
A. Cytokine proteins
IL-1	Antibody (Ab)	↑	(23 ,24 )
IL-2	Ab	↑	(2 ,25 ,26 )
IL-12	TH1(DTH)	↑	(3 )
IFN-γ	Ab, DTH	↑	(4 ,25 ,27 )
GM-CSF	Ab	↑	(28 ,29 )
B. Expression plasmids
IL-12	CTL	↑(i.m. and i.n.)	(15 ,21 ,22 ,30 )
	DTH	↑(i.m. and i.n.)	(5 ,21 )
	Ab	→(i.m. and i.n.)	(15 ,22 )
GM-CSF	Ab	↑(i.m.)	(9 ,18 ,22
	CTL	↑(i.m.)	(18 )
	³ H-TdR uptake	↑(i.m.)	(9 )
TCA3	CTL	↑(i.m.)	(31 )
	DTH	↑(i.m.)	(31 )
	Ab	→(i.m.)	(31 )
B7-1	CTL	→(i.m.)	(19 )
	DTH	→(i.m.)	(19 )
	Ab	→(i.m.)	(19 )
B7-2	CTL	↑(i.m.)	(19 )
	DTH	↑(i.m.)	(19 )
	Ab	→(i.m.)	(19 )
CD40(L)
	Ab	→(i.m.)	(A. Ihata et al., Unpublished data)
	CTL	↑(i.m.)	(A. Ihata et al., Unpublished data)

i.m., intramuscular administration; i.n., intranasal administration; Ab, antibody production; DTH, delayed type hypersensitivity; ³ H-TdR, incorporation of ³ H-Thymidine; ↑, activated immune response.