Abstract

We will investigate the molecular mechanisms responsible for the tissue specific and developmentally regulated hypermutation of immunoglobulin variable region genes. This will be done by introducing manipulated transfected genes into: 1) B cell lines whose endogenous immunoglobulin genes are constitutively unstable or whose instability is triggered by T cells and 2) transgenic mice. We will also study the role and impact of V region mutations and isotype switching on the immune response to viruses and fungi in normal mice and on the production of autoantibodies in lupus prone autoimmune mice. We will study the role of affinity and avidity in targeting to a model tumor system. We will use the insight gained from these studies to generate antibodies that can be passively administered to protect against HIV and cryptococcus infections and to target to drug resistant tumors.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
2R35CA039838-08
Application #
3479180
Study Section
Special Emphasis Panel (SRC (88))
Project Start
1985-07-01
Project End
1999-06-30
Budget Start
1992-09-01
Budget End
1993-06-30
Support Year
8
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
Albert Einstein College of Medicine
Department
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461

  Publications

Wiesendanger, M; Kneitz, B; Edelmann, W et al. (2000) Somatic hypermutation in MutS homologue (MSH)3-, MSH6-, and MSH3/MSH6-deficient mice reveals a role for the MSH2-MSH6 heterodimer in modulating the base substitution pattern. J Exp Med 191:579-84
Zuckier, L S; Berkowitz, E Z; Sattenberg, R J et al. (2000) Influence of affinity and antigen density on antibody localization in a modifiable tumor targeting model. Cancer Res 60:7008-13
Yuan, R; Clynes, R; Oh, J et al. (1998) Antibody-mediated modulation of Cryptococcus neoformans infection is dependent on distinct Fc receptor functions and IgG subclasses. J Exp Med 187:641-8
Casadevall, A; Cleare, W; Feldmesser, M et al. (1998) Characterization of a murine monoclonal antibody to Cryptococcus neoformans polysaccharide that is a candidate for human therapeutic studies. Antimicrob Agents Chemother 42:1437-46
Yuan, R R; Spira, G; Oh, J et al. (1998) Isotype switching increases efficacy of antibody protection against Cryptococcus neoformans infection in mice. Infect Immun 66:1057-62
Green, N S; Lin, M M; Scharff, M D (1998) Immunoglobulin hypermutation in cultured cells. Immunol Rev 162:77-87
Valadon, P; Nussbaum, G; Oh, J et al. (1998) Aspects of antigen mimicry revealed by immunization with a peptide mimetic of Cryptococcus neoformans polysaccharide. J Immunol 161:1829-36
Nussbaum, G; Cleare, W; Casadevall, A et al. (1997) Epitope location in the Cryptococcus neoformans capsule is a determinant of antibody efficacy. J Exp Med 185:685-94
Yuan, R R; Casadevall, A; Oh, J et al. (1997) T cells cooperate with passive antibody to modify Cryptococcus neoformans infection in mice. Proc Natl Acad Sci U S A 94:2483-8
Lin, M M; Zhu, M; Scharff, M D (1997) Sequence dependent hypermutation of the immunoglobulin heavy chain in cultured B cells. Proc Natl Acad Sci U S A 94:5284-9

Showing the most recent 10 out of 46 publications