Cryptococcal meningitis remains a cause of morbidity and mortality in HIV-infected (HIV+) individuals and new modalities are needed for therapy. Profound CD4+ T cell deficiency is found in HIV+ individuals with cryptococcosis, though only a subset of patients develop infection. Therefore, additional immunologic defects probably predispose some patients to cryptococcal infection. In the previous grant period, this group demonstrated differences in the specificity and titer of antibodies to GXM in HIV- and HIV+ individuals. These groups are relatively resistant and susceptible to infection, respectively. The authors showed that human antibodies to GXM are derived from VH3 genes. Together with others' reports of decreased VH3 positive B cells in HIV+ individuals, their findings support the idea that combined with underlying cell-mediated immunity, qualitative and quantitative differences in antibodies to GXM may play a role in the protection of HIV-, and susceptibility of HIV+ individuals to cryptococcosis. This hypothesis will be investigated in this proposal with 3 interrelated aims. First, the authors will use purified antibody subsets from HIV- and HIV+ individuals to determine if idiotype and isotype-specific subsets of antibodies to GXM alter the course of experimental cryptococcosis in normal and immunodeficient mouse strains. In this aim they will also construct and compare VH3 gene libraries from B cells of HIV- and HIV+ individuals with and without cryptococcosis to determine if the frequency of specific VH3 gene segment expression of somatic mutation is correlated with resistance or susceptibility to C. neoformans. Second, they will generate human mAbs to GXM in human immunoglobulin transgenic mice by splenic fusion and determine their VH3 usage, specificity, and functional efficacy in vitro and in experimental cryptococcosis. Third, they will isolate peptide epitopes of the mAbs from phage libraries and use them to compare the specificity of antibodies to GXM from HIV- and HIV+ individuals with and without cryptococcosis. The authors believe that these studies will reveal if antibody repertoire differences contribute to cryptococcal pathogenesis and provide novel human mAbs and peptide mimotopes for passive and active vaccination approaches for therapy of human cryptococcosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI035370-06
Application #
2718238
Study Section
AIDS and Related Research Study Section 5 (ARRE)
Program Officer
Laughon, Barbara E
Project Start
1993-12-01
Project End
2003-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
6
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
Szymczak, Wendy A; Sellers, Rani S; Pirofski, Liise-anne (2012) IL-23 dampens the allergic response to Cryptococcus neoformans through IL-17-independent and -dependent mechanisms. Am J Pathol 180:1547-59
Casadevall, Arturo; Pirofski, Liise-Anne (2011) A new synthesis for antibody-mediated immunity. Nat Immunol 13:21-8
Pirofski, Liise-Anne (2010) Why antibodies disobey the Hippocratic Oath and end up doing harm: a new clue. J Clin Invest 120:3099-102
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Subramaniam, Krishanthi S; Datta, Kausik; Quintero, Eric et al. (2010) The absence of serum IgM enhances the susceptibility of mice to pulmonary challenge with Cryptococcus neoformans. J Immunol 184:5755-67
Subramaniam, Krishanthi; Metzger, Brian; Hanau, Lawrence H et al. (2009) IgM(+) memory B cell expression predicts HIV-associated cryptococcosis status. J Infect Dis 200:244-51
Pirofski, Liise-anne; Casadevall, Arturo (2009) Rethinking T cell immunity in oropharyngeal candidiasis. J Exp Med 206:269-73
Ritter, M L; Pirofski, L (2009) Mycophenolate mofetil: effects on cellular immune subsets, infectious complications, and antimicrobial activity. Transpl Infect Dis 11:290-7
Datta, Kausik; Lees, Andrew; Pirofski, Liise-anne (2008) Therapeutic efficacy of a conjugate vaccine containing a peptide mimotope of cryptococcal capsular polysaccharide glucuronoxylomannan. Clin Vaccine Immunol 15:1176-87
Datta, Kausik; Pirofski, Liise-anne (2006) Towards a vaccine for Cryptococcus neoformans: principles and caveats. FEMS Yeast Res 6:525-36

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