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.
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