Primary Sjogren's syndrome (SS) is a chronic autoimmune disease characterized by 1) serum autoantibodies, 2) increased numbers of CD5+ B cells, 3) lymphocytic infiltration of salivary, lacrimal and other exocrine glands with a tendency to generalized lymphoproliferation that can terminate as a malignant lymphoma. The long-term objective of this application is to acquire knowledge leading to 1) a better understanding of the mechanisms responsible for the immune dysregulation in SS, and 2) possible development of new therapeutic modalities (such as polyamine inhibitors) for this disease. Peripheral blood mononuclear cells (PBMNC) from SS patients produce decreased amounts of interleukin-2 (IL-2) following stimulation with PHA or anti-CD3. There is also a transmembrane signalling defect in SS T cells revealed by exposure to PMA and ionomycin. Since oxidation products of polyamines diminish IL-2 production by normal and rheumatoid arthritis (RA) T cells, a similar mechanism may be operating and primary SS.
The specific aims and methodologies are the following: 1. Measure polyamine levels (by HPLC), IL2 production (by bioassay) and the effect of polyamine inhibitors (like DEMO) on IL2 production in SS PBMNC. 2. Measure IL2 mRNA levels in SS PBMNC (by slot and Northern blots) and identify possible pre- or post-transcriptional defects (hydrolysis of phosphoinositides by ion exchange chromatography, rise in intracellular calcium by Indo-1 and FACS analysis, diacylglycerol-dependent activation, IL2 protein biosynthesis and secretion by ELISA). 3. Attempt to correct a possible defect in SS by polyamine inhibitors, or create a defect in normal PBMNC using polyamines plus polyamine oxidase.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE009311-01
Application #
3223101
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Project Start
1990-07-01
Project End
1993-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Kong, L; Ogawa, N; McGuff, H S et al. (1998) Bcl-2 family expression in salivary glands from patients with primary Sjogren's syndrome: involvement of Bax in salivary gland destruction. Clin Immunol Immunopathol 88:133-41
Kong, L; Robinson, C P; Peck, A B et al. (1998) Inappropriate apoptosis of salivary and lacrimal gland epithelium of immunodeficient NOD-scid mice. Clin Exp Rheumatol 16:675-81
Kong, L; Ogawa, N; Nakabayashi, T et al. (1997) Fas and Fas ligand expression in the salivary glands of patients with primary Sjogren's syndrome. Arthritis Rheum 40:87-97
Nakabayashi, T; Letterio, J J; Geiser, A G et al. (1997) Up-regulation of cytokine mRNA, adhesion molecule proteins, and MHC class II proteins in salivary glands of TGF-beta1 knockout mice: MHC class II is a factor in the pathogenesis of TGF-beta1 knockout mice. J Immunol 158:5527-35
Ogawa, N; Dang, H; Kong, L et al. (1996) Lymphocyte apoptosis and apoptosis-associated gene expression in Sjogren's syndrome. Arthritis Rheum 39:1875-85
Flescher, E; Vela-Roch, N; Ogawa, N et al. (1996) Abnormality of Oct-1 DNA binding in T cells from Sjogren's syndrome patients. Eur J Immunol 26:2006-11
DeKeyser, F; DeKeyser, H; Kazatchkine, M D et al. (1996) Pooled human immunoglobulins contain anti-idiotypes with reactivity against the SLE-associated 4B4 cross-reactive idiotype. Clin Exp Rheumatol 14:587-91
Anaya, J M; Ogawa, N; Talal, N (1995) Sjogren's syndrome in childhood. J Rheumatol 22:1152-8
Anaya, J M; Liu, G T; D'Souza, E et al. (1995) Primary Sjogren's syndrome in men. Ann Rheum Dis 54:748-51
Ogawa, N; Dang, H; Talal, N (1995) Apoptosis and autoimmunity. J Autoimmun 8:1-19

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