Interplay of cytokines and adjuvants in the regulation of mucosal and systemic HIV-specific CTL.
We examined the interplay between cytokines and adjuvants to optimize the induction of CTL by a mucosal HIV peptide vaccine. We show synergy between IL-12 and GM-CSF when administered together with the HIV peptide PCLUS3-18IIIB and cholera toxin (CT) in the induction of CTL activity and protection against mucosal viral transmission. Further, we examine the efficacy of mutant Escherichia coli labile toxin, LT(R192G), as a less toxic adjuvant than CT. LT(R192G) was as effective as or more effective than CT at inducing a mucosal CTL response. Moreover, LT(R192G) was as effective without IL-12 as CT was when combined with IL-12, and the response elicited by LT(R192G) with the vaccine was not further enhanced by the addition of IL-12. GM-CSF synergized with LT(R192G) without exogenous IL-12. Therefore, LT(R192G) may induce a more favorable cytokine response by not inhibiting IL-12 production. In particular, less IL-4 is made after LT(R192G) than CT immunization, and the response is less susceptible to anti-IL-12 inhibition. Thus, the choice of mucosal adjuvant affects the cytokine environment, and the mucosal response and protection can be enhanced by manipulating the cytokine environment with synergistic cytokine combinations incorporated in the vaccine.
Belyakov
I M
IM
Molecular Immunogenetics and Vaccine Research Section, Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Ahlers
J D
JD
Clements
J D
JD
Strober
W
W
Berzofsky
J A
JA
D016475:3T3 Cells; D016915:AIDS Vaccines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000276:immunology; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000502:physiology*; D000285:Administration, Rectal; D000595:Amino Acid Sequence; D000818:Animals; D016207:Cytokines / Q000008:administration & dosage / Q000502:physiology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004357:Drug Synergism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage; D015497:HIV-1 / Q000276:immunology*; D007113:Immunity, Innate; D018664:Interleukin-12 / Q000008:administration & dosage; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010581:Peyer's Patches / Q000166:cytology / Q000276:immunology / Q000821:virology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000821:virology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology
D016915:AIDS Vaccines; D000276:Adjuvants, Immunologic; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D014614:Vaccines, Synthetic; D018664:Interleukin-12; D016178:Granulocyte-Macrophage Colony-Stimulating Factor