Our objectives are to define the functions and regulation of intestinal lymphoid organs. These goals are relevant to oral immunization, intestinal infection, M cell uptake of antigens and particles, including HTLV III, and to pathogenesis of immunologic diseases. The first specific aim is to define uptake and transport of particulate microbial antigens, tracer particles, and liposomes in animal models. We propose to study the entry route(s) of chlamydia organisms through small intestinal and rectal lymphoid follicle epithelia and the mechanism of transport of these organisms into lymphoid tissues. The consequences of chlamydia-induced hyperplasia of lymphoid follicles on M cell proliferation and uptake of luminal particles will be evaluated. Modulation of antigen uptake from the intestinal lumen by secretory IgA will be assessed using cholera vibrios and also microspheres with and without IgA antibody. Liposomes containing 3H labeled proteins or colloidal gold particles will be used to evaluate peroral delivery of antigens and drugs through M cells. Migration pathways of mononuclear leukocytes will be traced to determine whether cells can carry antigen from the intestinal lumen into Peyer's patches. The second specific aim is to investigate modulation of Peyer's patch cytoarchitecture and function by antigenic stimulation and by depletion of regulatory lymphocyte subsets in normal mice and in a mouse model of systemic lupus erythematosus (SLE). The mechanisms by which intestinal antigen stimulation regulates surface Ig isotype switching in Peyer's patches will be evaluated by immunolabeling and fluorescence activated cell sorting (FACS). Monoclonal antibodies will be used to deplete lymphocyte subsets; the effects of subsequent changes in immunoregulatory cells on the cytoarchitecture of mucosal lymphoid organs will be assessed by immunolabeling in normal mice and in autoimmune mice in which helper T cell depletion treats SLE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK038550-04
Application #
3237952
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1987-05-01
Project End
1992-04-30
Budget Start
1990-09-01
Budget End
1991-04-30
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Kabok, Z; Ermak, T H; Pappo, J (1995) Microdissected domes from gut-associated lymphoid tissues: a model of M cell transepithelial transport in vitro. Adv Exp Med Biol 371A:235-8
Ermak, T H; Bhagat, H R; Pappo, J (1994) Lymphocyte compartments in antigen-sampling regions of rabbit mucosal lymphoid organs. Am J Trop Med Hyg 50:14-28
Sakaguchi, S; Ermak, T H; Toda, M et al. (1994) Induction of autoimmune disease in mice by germline alteration of the T cell receptor gene expression. J Immunol 152:1471-84
Ohtsuka, A; Piazza, A J; Ermak, T H et al. (1992) Correlation of extracellular matrix components with the cytoarchitecture of mouse Peyer's patches. Cell Tissue Res 269:403-10
Owen, R L; Piazza, A J; Ermak, T H (1991) Ultrastructural and cytoarchitectural features of lymphoreticular organs in the colon and rectum of adult BALB/c mice. Am J Anat 190:10-8
Carteron, N L; Wofsy, D; Schimenti, C et al. (1990) F(ab')2 anti-CD4 and intact anti-CD4 monoclonal antibodies inhibit the accumulation of CD4+ T cells, CD8+ T cells, and B cells in the kidneys of lupus-prone NZB/NZW mice. Clin Immunol Immunopathol 56:373-83
Ermak, T H; Steger, H J; Pappo, J (1990) Phenotypically distinct subpopulations of T cells in domes and M-cell pockets of rabbit gut-associated lymphoid tissues. Immunology 71:530-7
Owen, R L; Ermak, T H (1990) Structural specializations for antigen uptake and processing in the digestive tract. Springer Semin Immunopathol 12:139-52
Ermak, T H; Steger, H J; Pappo, J (1990) Intrathymic changes in murine CD3, CD5 and CD8 expression after in vivo administration of anti-CD4. Immunobiology 180:351-61
Walker, R I; Owen, R L (1990) Intestinal barriers to bacteria and their toxins. Annu Rev Med 41:393-400

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