Infections with extracellular, polysaccharide (PS)-encapsulated, bacteria represent a major source of morbidity and mortality in the U.S. Increasing antibiotic resistance to these agents, makes their control by immunotherapeutic means more compelling. Induction of PS- and protein-specific Ig play major roles in immunity to these bacteria. Preliminary results, using a model gram-positive extracellular bacterium, Streptococcus pneumoniae (strain R36A), indicate that both PS- and protein-specific humoral responses to R36A are T cell-dependent and B7 ligand-dependent. Modulating B7 ligand interactions has therapeutic potential for modifying the ongoing immune response and for vaccine development, yet few studies have examined the role of these interactions during the T cell-dependent immune response to bacterial pathogens. This proposal will examine the role of B7 interactions during primary and memory Ig isotype responses to the PS and protein components of R36A. CD28 and CTLA-4 function will be examined using genetically deficient mice and blocking antibodies with the working hypothesis that these molecules differentially regulate the progression of the anti-PS and anti-protein response and that they may be useful targets for modifying this in vivo immune response, both at the initiation stage and subsequent to immunization. The individual roles of B7-1 and B7-2 will also be examined, and the specific APCs that provide B7-1 vs. B7-2-mediated costimulation will be identified using adoptive transfer experiments in genetically deficient mice. These experiments will provide insight into the mechanism of why B7-1 vs. B7-2 blockade differentially influences the R36A response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046551-03
Application #
6511164
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Rothermel, Annette L
Project Start
2000-07-01
Project End
2005-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
3
Fiscal Year
2002
Total Cost
$368,532
Indirect Cost
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
City
Rockville
State
MD
Country
United States
Zip Code
20817
Snapper, Clifford M (2006) Differential regulation of protein- and polysaccharide-specific Ig isotype production in vivo in response to intact Streptococcus pneumoniae. Curr Protein Pept Sci 7:295-305
Colino, Jesus; Snapper, Clifford M (2006) Exosomes from bone marrow dendritic cells pulsed with diphtheria toxoid preferentially induce type 1 antigen-specific IgG responses in naive recipients in the absence of free antigen. J Immunol 177:3757-62
Khan, Abdul Q; Chen, Quanyi; Wu, Zheng-Qi et al. (2005) Both innate immunity and type 1 humoral immunity to Streptococcus pneumoniae are mediated by MyD88 but differ in their relative levels of dependence on toll-like receptor 2. Infect Immun 73:298-307
Lee, Katherine S; Sen, Goutam; Snapper, Clifford M (2005) Endogenous CD4+ CD25+ regulatory T cells play no apparent role in the acute humoral response to intact Streptococcus pneumoniae. Infect Immun 73:4427-31
Khan, Abdul Q; Lees, Andrew; Snapper, Clifford M (2004) Differential regulation of IgG anti-capsular polysaccharide and antiprotein responses to intact Streptococcus pneumoniae in the presence of cognate CD4+ T cell help. J Immunol 172:532-9
Colino, Jesus; Snapper, Clifford M (2003) Opposing signals from pathogen-associated molecular patterns and IL-10 are critical for optimal dendritic cell induction of in vivo humoral immunity to Streptococcus pneumoniae. J Immunol 171:3508-19
Wu, Zheng-Qi; Khan, Abdul Q; Shen, Yi et al. (2003) 4-1BB (CD137) differentially regulates murine in vivo protein- and polysaccharide-specific immunoglobulin isotype responses to Streptococcus pneumoniae. Infect Immun 71:196-204
Colino, Jesus; Snapper, Clifford M (2003) Two distinct mechanisms for induction of dendritic cell apoptosis in response to intact Streptococcus pneumoniae. J Immunol 171:2354-65
Khan, Abdul Q; Shen, Yi; Wu, Zheng-Qi et al. (2002) Endogenous pro- and anti-inflammatory cytokines differentially regulate an in vivo humoral response to Streptococcus pneumoniae. Infect Immun 70:749-61
Wu, Zheng-Qi; Shen, Yi; Khan, Abdul Q et al. (2002) The mechanism underlying T cell help for induction of an antigen-specific in vivo humoral immune response to intact Streptococcus pneumoniae is dependent on the type of antigen. J Immunol 168:5551-7

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