The overall objective of this application is to determine by which types of mechanisms antibody (Ab) protects against or reduces influenza-associated morbidity, how specificity, heavy chain isotype and avidity affect its protective activity and how activities provided by memory T cell responses enhance it. The studies are conducted in the mouse influenza model system. The basic experimental approach is to measure the effects of passive Abs on the course of the infection in various knockout mouse strains. The application has four major aims. The first is to determine how important the concomitant action of neutralization of progeny-virus (VN activity) and inhibition of release of progeny virus from infected cells (cell targeting, CT activity) is for effective Ab-mediated clearance of an established infection. This will be investigated by topical treatment of infected SCID mice with combinations of F(ab) and intact Ab reagents, which mediate solely VN or CT activity, respectively. Second, the effect of heavy chain isotype on Ab-mediated VN and CT activity in vivo will be determined by means of switch variants. In addition, Fc-dependent mechanisms involved in Ab mediated VN and CT activity will be identified by measuring the protective activity of passive Abs in mouse strains with deleted complement factor C3 and various Fcgamma receptors. Further, the reason for the previously reported low therapeutic efficacy of polymeric IgM and IgA will be determined. Third, the effect of Ab avidity on its protective activity in vivo will be investigated. Fourth, synergistic activities between Ab and CD4+ memory T cell responses will be explored by measuring the effect of passive Ab on the course of the infection in immune CD8+ cells depleted (B cell-deficient) uMT mice. Synergistic interactions between Ab and CD4+ T cell-mediated activities will be further investigated by adoptive transfer of CD4+ virus-specific T cell clones/populations and Ab into infected SCID mice. These studies will greatly improve our understanding of the mechanisms involved in Ab-mediated protection against influenza and may lead to new methods for decreasing the still very high influenza-associated severe morbidity and mortality in humans with underlying risk factors like age (>65y), diabetes and chronic lung, cardiovascular and renal diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI013989-26
Application #
6631635
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Lambert, Linda C
Project Start
1977-04-01
Project End
2005-02-28
Budget Start
2003-03-01
Budget End
2004-02-29
Support Year
26
Fiscal Year
2003
Total Cost
$368,747
Indirect Cost
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Mozdzanowska, Krystyna; Feng, Jingqi; Eid, Mark et al. (2006) Enhancement of neutralizing activity of influenza virus-specific antibodies by serum components. Virology 352:418-26
Zharikova, Darya; Mozdzanowska, Krystyna; Feng, Jingqi et al. (2005) Influenza type A virus escape mutants emerge in vivo in the presence of antibodies to the ectodomain of matrix protein 2. J Virol 79:6644-54
Mozdzanowska, Krystyna; Furchner, Michelle; Zharikova, Darya et al. (2005) Roles of CD4+ T-cell-independent and -dependent antibody responses in the control of influenza virus infection: evidence for noncognate CD4+ T-cell activities that enhance the therapeutic activity of antiviral antibodies. J Virol 79:5943-51
Mozdzanowska, Krystyna; Feng, JinQi; Eid, Mark et al. (2003) Induction of influenza type A virus-specific resistance by immunization of mice with a synthetic multiple antigenic peptide vaccine that contains ectodomains of matrix protein 2. Vaccine 21:2616-26
Feng, Jing Qi; Mozdzanowska, Krystyna; Gerhard, Walter (2002) Complement component C1q enhances the biological activity of influenza virus hemagglutinin-specific antibodies depending on their fine antigen specificity and heavy-chain isotype. J Virol 76:1369-78
Mozdzanowska, K; Maiese, K; Gerhard, W (2000) Th cell-deficient mice control influenza virus infection more effectively than Th- and B cell-deficient mice: evidence for a Th-independent contribution by B cells to virus clearance. J Immunol 164:2635-43
Mozdzanowska, K; Maiese, K; Furchner, M et al. (1999) Treatment of influenza virus-infected SCID mice with nonneutralizing antibodies specific for the transmembrane proteins matrix 2 and neuraminidase reduces the pulmonary virus titer but fails to clear the infection. Virology 254:138-46
Mozdzanowska, K; Furchner, M; Washko, G et al. (1997) A pulmonary influenza virus infection in SCID mice can be cured by treatment with hemagglutinin-specific antibodies that display very low virus-neutralizing activity in vitro. J Virol 71:4347-55
Mozdzanowska, K; Furchner, M; Maiese, K et al. (1997) CD4+ T cells are ineffective in clearing a pulmonary infection with influenza type A virus in the absence of B cells. Virology 239:217-25
Gerhard, W; Mozdzanowska, K; Furchner, M et al. (1997) Role of the B-cell response in recovery of mice from primary influenza virus infection. Immunol Rev 159:95-103

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