Abstract

The somatic cell genetics of the instability of immunoglobulin genes in cultured hybridoma and myeloma cells will be studied. Earlier studies had shown that mutants with changes in the variable and constant regions of immunoglobulins arise frequently and spontaneously in cultured cells. The molecular and genetic mechanisms of these events will be examined by determining the relative rates of V and C region mutations and the base changes that occur in these mutants. Similar mutants will be sought in vivo. Mutants with both increases and decreases in antigen binding and changes in effector functions will be identified. The structural basis of these changes will be determined and the information gained will be used to construct antibodies that could be more effective reagents in protection against infection, neutralization of toxins, and targeting to tumors. (HI)

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA039838-04
Application #
3479183
Study Section
(SRC)
Project Start
1985-07-01
Project End
1992-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
4
Fiscal Year
1988
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

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