The purpose of this study is to determine whether intranasal administration of interleukin-12 (IL-12) will shift lung cytokine and antibody expression during immune responses and enhance the effectiveness of vaccination against respiratory pathogens. IL-12 may be especially beneficial for increasing the usefulness of viral vaccines since it stimulates production of interferon-gamma and secretion of antibody isotypes that are most efficient in mediating complement fixation and opsonization. For the experiments in this study, BALB/c and C57BL/6 mice will be inoculated intranasally with IL-12 and influenza or HIV-1 subunit proteins, and levels of induced cytokines and antibodies in the lungs and serum will be monitored at various times thereafter. The ability of IL-12 to cause shifts in cytokine RNA expression will be examined by RT-PCR and ribonuclease protection assays. The levels and specificities of induced antibodies will be quantitated using isotype-specific ELISAs. Intermediary cytokines potentially responsible for the observed protective capacity of IL-12 against lethal influenza infection will be identified using mice with targeted disruptions in cytokine genes and the role of endogenous IL-12 in regulating responsiveness will be examined using IL-12 knockout mice. Passive transfer of serum or bronchoalveolar lavage from intranasally immunized mice and immunodeficient mice lacking specific lymphoid cell subsets will be used to determine whether the protective effects of IL-12 are due to induced antibodies or activated cytotoxic T cells. Most parenterally administered vaccines have limited effectiveness at inducing optimal mucosal immunity and there are no suitable mucosal adjuvants available for clinical use at the present time. Thus, the application of IL-12 as a mucosal vaccine adjuvant may provide a novel approach for protection against respiratory diseases and could have immediate impact on human health.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062120-05
Application #
6390235
Study Section
Special Emphasis Panel (ZHL1-CSR-N (S2))
Program Officer
Colombini-Hatch, Sandra
Project Start
1998-09-30
Project End
2003-08-31
Budget Start
2001-09-01
Budget End
2003-08-31
Support Year
5
Fiscal Year
2001
Total Cost
$193,750
Indirect Cost
Name
Albany Medical College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Albany
State
NY
Country
United States
Zip Code
12208
Metzger, Dennis W (2010) Interleukin-12 as an adjuvant for induction of protective antibody responses. Cytokine 52:102-7
Albu, Diana I; Jones-Trower, Agnes; Woron, Amy M et al. (2003) Intranasal vaccination using interleukin-12 and cholera toxin subunit B as adjuvants to enhance mucosal and systemic immunity to human immunodeficiency virus type 1 glycoproteins. J Virol 77:5589-97
Lynch, Joyce M; Briles, David E; Metzger, Dennis W (2003) Increased protection against pneumococcal disease by mucosal administration of conjugate vaccine plus interleukin-12. Infect Immun 71:4780-8
Huber, Victor C; Arulanandam, Bernard P; Arnaboldi, Paul M et al. (2003) Delivery of IL-12 intranasally leads to reduced IL-12-mediated toxicity. Int Immunopharmacol 3:801-9
Potvin, Daniel M; Metzger, Dennis W; Lee, William T et al. (2003) Exogenous interleukin-12 protects against lethal infection with coxsackievirus B4. J Virol 77:8272-9
Arulanandam, B P; Lynch, J M; Briles, D E et al. (2001) Intranasal vaccination with pneumococcal surface protein A and interleukin-12 augments antibody-mediated opsonization and protective immunity against Streptococcus pneumoniae infection. Infect Immun 69:6718-24
Refici, M L; Metzger, D W; Arulanandam, B P et al. (2001) Fcgamma-receptor signaling augments the LPS-stimulated increase in serum tumor necrosis factor-alpha levels. Am J Physiol Regul Integr Comp Physiol 280:R1037-44
Huber, V C; Lynch, J M; Bucher, D J et al. (2001) Fc receptor-mediated phagocytosis makes a significant contribution to clearance of influenza virus infections. J Immunol 166:7381-8
Buchanan, R M; Briles, D E; Arulanandam, B P et al. (2001) IL-12-mediated increases in protection elicited by pneumococcal and meningococcal conjugate vaccines. Vaccine 19:2020-8
Arulanandam, B P; Raeder, R H; Nedrud, J G et al. (2001) IgA immunodeficiency leads to inadequate Th cell priming and increased susceptibility to influenza virus infection. J Immunol 166:226-31

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