Anti-polysaccharide (PS) antibodies (Ab) are critical to host defense against encapsulated bacteria. The function of anti-PS Ab includes complement fixation and opsonization of bacteria for killing by phagocytes, and modulation of cytokine producing cells via binding to Fcgamma receptors (FcgammaR). IgG anti-PS Ab response has delayed ontogeny and isotype restriction (IgG3 in mice IgG2 in man), and conjugation of PS to proteins induces class switching to IgG1. Determining the effect of isotype restriction and IgG subclass on function of anti-PS Ab is crucial to better understand immunity to PS-encapsulated bacteria, the pathogenesis of human IgG subclass deficiency and for improved serological correlates of immunity with PS and PS conjugate vaccines. In this proposal, we will continue our studies of the role of IgG subclass in anti-PS Ab effector function, determine the role of constant region genes and the dominant IgG subclass in immunity to encapsulated bacteria and in class switching that occurs when PS are conjugated to proteins, and investigate the effect of lgG subclass on FcyR mediated regulation of cytokine production. We will utilize V region-identical human monoclonal Abs of all four IgG subclasses against P. aeruginosa LPS O-side chain and S. pneumoniae (Pn) capsular PS made in a new transgenic mouse reconstituted with human Ig genes, to determine the mechanism of functional differences in Ab protective efficacy. Next, to determine the in vivo relevance of the dominant IgG subclass made to PS, we will use the new BALB/c IgG3 knockout mouse to determine the importance of anti-PS Ab subclass in the host response to PS, PS-protein conjugates and to infection with encapsulated bacteria. We have found that the absence of IgG3 renders these animals more susceptible to fatal infection with Pn but that induction of anti-PS IgG1 can correct this defect. Finally, we will investigate the FcR mediated regulatory role of IgG subclass in cytokine production by macrophages, and we hypothesize that there are differences in the ability of IgG subclass to modulate cytokine production based on differential binding to FcgammaR. These studies will allow more rational strategies of active and passive immunization against bacteria, improved understanding of IgG subclass deficiency, and new information about which IgG subclass has the best FcgammaR-mediated anti-inflammatory properties.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI032596-10
Application #
6640275
Study Section
Special Emphasis Panel (ZRG1-EVR (01))
Program Officer
Taylor, Christopher E,
Project Start
1993-01-01
Project End
2004-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
10
Fiscal Year
2003
Total Cost
$339,750
Indirect Cost
Name
Case Western Reserve University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Lai, Zengzu; Schreiber, John R (2011) Outer membrane protein complex of Meningococcus enhances the antipolysaccharide antibody response to pneumococcal polysaccharide-CRM??? conjugate vaccine. Clin Vaccine Immunol 18:724-9
Kaur, Kulwant; Chowdhury, Shimul; Greenspan, Neil S et al. (2007) Decreased expression of tumor necrosis factor family receptors involved in humoral immune responses in preterm neonates. Blood 110:2948-54
Lai, Zengzu; Kimmel, Rhonda; Petersen, Sheryl et al. (2005) Multi-valent human monoclonal antibody preparation against Pseudomonas aeruginosa derived from transgenic mice containing human immunoglobulin loci is protective against fatal pseudomonas sepsis caused by multiple serotypes. Vaccine 23:3264-71
Latz, Eicke; Franko, Jennifer; Golenbock, Douglas T et al. (2004) Haemophilus influenzae type b-outer membrane protein complex glycoconjugate vaccine induces cytokine production by engaging human toll-like receptor 2 (TLR2) and requires the presence of TLR2 for optimal immunogenicity. J Immunol 172:2431-8
Maaser, Christian; Housley, Michael P; Iimura, Mitsutoshi et al. (2004) Clearance of Citrobacter rodentium requires B cells but not secretory immunoglobulin A (IgA) or IgM antibodies. Infect Immun 72:3315-24
Leonard, Ethan G; Canaday, David H; Harding, Clifford V et al. (2003) Antigen processing of the heptavalent pneumococcal conjugate vaccine carrier protein CRM(197) differs depending on the serotype of the attached polysaccharide. Infect Immun 71:4186-9
McCool, T L; Schreiber, J R; Greenspan, N S (2003) Genetic variation influences the B-cell response to immunization with a pneumococcal polysaccharide conjugate vaccine. Infect Immun 71:5402-6
Kamboj, Kulwant K; Kirchner, H Lester; Kimmel, Rhonda et al. (2003) Significant variation in serotype-specific immunogenicity of the seven-valent Streptococcus pneumoniae capsular polysaccharide-CRM197 conjugate vaccine occurs despite vigorous T cell help induced by the carrier protein. J Infect Dis 187:1629-38
Gor, Dennis O; Ding, Xuedong; Li, Qing et al. (2002) Enhanced immunogenicity of pneumococcal surface adhesin A by genetic fusion to cytokines and evaluation of protective immunity in mice. Infect Immun 70:5589-95
McLay, John; Leonard, Ethan; Petersen, Sheryl et al. (2002) Gamma 3 gene-disrupted mice selectively deficient in the dominant IgG subclass made to bacterial polysaccharides. II. Increased susceptibility to fatal pneumococcal sepsis due to absence of anti-polysaccharide IgG3 is corrected by induction of anti-polysa J Immunol 168:3437-43

Showing the most recent 10 out of 15 publications