Sjogren's syndrome (SS) is a chronic progressive autoimmune disorder that causes inflammation of the salivary and lacrimal glands affecting over 2 million Americans. This inflammation devastates the oral health of the victim and can result in infection, ulceration and tooth loss. Recently, a well defined transgenic mouse model carrying the human T lymphotropic virus type 1 (HTLV-1) trans-activator (tax) gene salivary and lacrimal glands resembling SS. The tax gene also activates the nuclear factor- kappaBeta (NF-kappaB). However, this process is suppressed in the presence of antioxidants. In the past, we observed the inhibition of autoimmune disease in mice by calorie restriction or w-3 lipid therapy that enhances the immunological and antioxidant defense systems. Our pilot studies strongly indicate a similar protective action of food restriction in tax+ mice. These mice fed ad libitum diets revealed the early appearance of neurofibromatosis and increased tax mRNA expression, whereas in food restricted mice, a delay in the growth of neurofibromatosis and increased tax mRNA expression, whereas in food restricted mice, delay in the growth of neurofibromas and an absence of tax mRNA was observed. We therefore anticipate that a similar mechanism may prevent or delay salivary gland dysfunction in food restricted tax+mice. Thus, the primary objective of this proposal is to establish whether HTLV-1 tax-induced salivary gland hyperplasia and inflammation can be prevented or delayed by diet therapies, such as calorie restriction, diet enrichment with w-3 fatty acids (FA) and/or antioxidant supplementation, with thiols or vitamin E. Our working hypothesis is that both antioxidants and/or anti-inflammatory lipids, or calorie restriction may facilitate greater interaction within the immune system and exocrine glands by altering their membrane FA and antioxidant defense system, thereby preventing free radical-induced oxidative stress. This in turn may reduce pro-inflammatory cytokines (such as interleukin- (IL)1, IL-2, IL-6, etc) and transforming growth factor Beta1 (TGFBeta1), which are elevated in salivary glands and linked to the onset and progression of SS in tax+mice. We will carry out detailed survival studies with extensive histopathological examination of the salivary and lacrimal glands. Immunological and molecular studies will focus on the effects of tax expression on NF-kB, cytokines and growth factors by diet therapy. Specific use of Northern analysis, reverse transcriptase-polymerase chain reaction and immunohistochemistry will aid in observing the changes in salivary glands of tax+ and tax-mice. These studies will enable us to understand the fundamental mechanisms involved in the damage of salivary glands, and develop effective dietary therapies with anti-inflammatory lipids and/or antioxidants to reduce immunosuppressive drug toxicity and maintain optimal oral health in patients with SS.
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