Cryptococcus neoformans is a fungus that causes a lethal meningoencephalomyelitis in immunosuppressed individuals. Since anti-fungal agents alone do not clear the infection, mouse monoclonal antibodies (mabs) have been generated to the capsular polysaccharide of the fungus. In the course of studying the protective potential of a large library of these mabs in vivo in both immunocompetent and immunoincompetent mice, we have identified protective, non-protective and enhancing antibodies. We have shown that the ability of the antibodies to modulate the infection depends upon the isotype, epitope specificity and state of the effector cells. In particular, IgG3 mabs do not prolong the life of the animals, and in certain situations can enhance the infection, while IGGI, IgG2b and IgG2a isotype switch variants of these mab can prolong the life of the animal. This suggests that the FcRs on effector cells are also playing a role. In determining the efficacy of these antibodies in vivo. Furthermore, CD4+ and CD8+ T cells and interferon-y play a role in the ability of the passively administered antibodies to modulate infection. Preliminary experiments reveal that the different effects of IgG3 and IGGI can also be observed in vitro with primary macrophages. We propose here to do in vitro and in vivo experiments with genetically defective mice to learn why antibodies of different isotypes modulate the infection of mice with C neoformans in different ways. It is hoped that these studies will provide new insights into the mechanism of action of antibodies in preventing and treating infection with C neoformans, and perhaps other encapsulated organisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043937-04
Application #
6511084
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Duncan, Rory A
Project Start
1999-05-01
Project End
2004-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
4
Fiscal Year
2002
Total Cost
$404,703
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
Laskov, Reuven; Berger, Nir; Scharff, Matthew D et al. (2006) Tumor necrosis factor-alpha and CD40L modulate cell surface morphology and induce aggregation in Ramos Burkitt's lymphoma cells. Leuk Lymphoma 47:507-19
Iglesias-Ussel, Maria D; Fan, Manxia; Li, Ziqiang et al. (2006) Forced expression of AID facilitates the isolation of class switch variants from hybridoma cells. J Immunol Methods 316:59-66
Larijani, Mani; Frieder, Darina; Sonbuchner, Timothy M et al. (2005) Methylation protects cytidines from AID-mediated deamination. Mol Immunol 42:599-604
Li, Ziqiang; Luo, Zhonghui; Scharff, Matthew D (2004) Differential regulation of histone acetylation and generation of mutations in switch regions is associated with Ig class switching. Proc Natl Acad Sci U S A 101:15428-33
Luo, Zhonghui; Ronai, Diana; Scharff, Matthew D (2004) The role of activation-induced cytidine deaminase in antibody diversification, immunodeficiency, and B-cell malignancies. J Allergy Clin Immunol 114:726-35; quiz 736
Li, Ziqiang; Woo, Caroline J; Iglesias-Ussel, Maria D et al. (2004) The generation of antibody diversity through somatic hypermutation and class switch recombination. Genes Dev 18:1-11
Li, Ziqiang; Scherer, Stefan J; Ronai, Diana et al. (2004) Examination of Msh6- and Msh3-deficient mice in class switching reveals overlapping and distinct roles of MutS homologues in antibody diversification. J Exp Med 200:47-59
Bardwell, Philip D; Martin, Alberto; Wong, Edmund et al. (2003) Cutting edge: the G-U mismatch glycosylase methyl-CpG binding domain 4 is dispensable for somatic hypermutation and class switch recombination. J Immunol 170:1620-4
May, Rena J; Beenhouwer, David O; Scharff, Matthew D (2003) Antibodies to keyhole limpet hemocyanin cross-react with an epitope on the polysaccharide capsule of Cryptococcus neoformans and other carbohydrates: implications for vaccine development. J Immunol 171:4905-12
Martin, Alberto; Li, Ziqiang; Lin, Diana P et al. (2003) Msh2 ATPase activity is essential for somatic hypermutation at a-T basepairs and for efficient class switch recombination. J Exp Med 198:1171-8

Showing the most recent 10 out of 16 publications