I propose to test the idea that normal immunoglobulin production is controlled by specific cellular interactions. Consistent with this hypothesis is the evidence recently obtained that genetically unexpected (latent) variable region allotypes and allotypic internal images can be routinely induced by immunizing rabbits or mice with anti-allotype antibody. In the studies described here, I intend to define the mechanism(s) for induction of unexpected allotypes and to determine the molecular basis for latent allotypes and allotypic internal images. I will assess the ability of anti-immunoglobulin antibodies to cause shifts in allotype-specific and isotype-specific regulatory influences that operate during chronic allotype suppression, normal immunoglobulin production, and antigen-induced antibody responses. The major experimental systems and methods to be employed are in vivo immunizations, in vitro culturing of cells from allotype-defined and MHC-matched rabbits, and monoclonal antibodies that display rabbit allotypic images. The information obtained should help clarify our understanding of immune system homeostasis and be of relevance for the biological modification of human immunodeficiency states such as AIDS and the immunotherapy of cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI018880-05
Application #
3128279
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1983-04-01
Project End
1989-11-30
Budget Start
1987-12-01
Budget End
1988-11-30
Support Year
5
Fiscal Year
1988
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Fitts, M G; Metzger, D W (1990) Identification of rabbit genomic Ig-VH pseudogenes that could serve as donor sequences for latent allotype expression. J Immunol 145:2713-7
Metzger, D W; Naeve, C W; Van Cleave, V H (1989) Epitope mimicry by anti-idiotype sequences in reverse orientation. Adv Exp Med Biol 251:187-90
Van Cleave, V H; Naeve, C W; Metzger, D W (1988) Do antibodies recognize amino acid side chains of protein antigens independently of the carbon backbone? J Exp Med 167:1841-8
Metzger, D W; Walker, W S (1988) In vivo activation of quiescent B cells by anti-immunoglobulin. II. Production of lysozyme-specific monoclonal antibodies of desired isotype. J Immunol Methods 107:47-52
Metzger, D W; Fried, V A; Van Cleave, V H (1987) In vivo activation of quiescent B cells by anti-immunoglobulin. I. Induction of latent VH allotype production in adult rabbits by treatment with heterologous antibodies or antibody fragments. J Immunol 138:2982-7
Van Cleave, V H; Murti, K G; Metzger, D W (1986) Mouse monoclonal antibodies induced by anti-allotype antibody display internal images of the rabbit VHa1 allotype: direct visualization by immunoelectron microscopy. Eur J Immunol 16:701-7
Van Cleave, V H; Metzger, D W (1986) Heating of immunoglobulins for immunoblot analysis destroys variable region antigenicity. J Immunol Methods 93:237-40
Metzger, D W (1985) The nature of antiidiotype molecules induced by antiallotype. Presence of both latent allotype and allotypic internal images. J Exp Med 162:35-44