The autoimmune prone NZBxNZW F1 (B/W) mouse is a useful model of systemic lupus erythematosus (SLE). Moderate calorie restriction (CR) delays the onset of disease and doubles the life span of these animals. Both CR and diets enriched in fish oil ((w-3) fatty acids decrease inflammatory cytokines, maintain (CD4+ CD44Low) T cell subsets and prevent the rise of memory (CD4+/CD44High) T cells with age. The involvement of Th-1 and Th-2 T cells subsets in the pathogenesis of murine (and probably human) lupus raises the question of whether CR and w-3 supplementation produce their effects by modulating anti- inflammatory cytokines. We propose that CR delays differentiation of CD44High T cells into Th-0, and/or Th-1 and Th-2 subsets by maintaining higher levels of adrenocorticosteroid (CORT) levels and apoptosis. In addition w-3 lipids and CR may also influence co-stimulatory molecules by increasing expression of antioxidant enzymes and reducing chronic oxidative stress. We propose that supplementation with w-3 fatty acids combined with CR maintains a youthful immune system by decreasing formation of free radicals and inflammatory cytokines and decreasing B cells autoantibody production. We hypothesize that CR delays formation of Th-1/Th-2 subsets by co-stimulatory interaction including lowering CD40 ligand expression and by normalizing apoptosis in both lymphoid cells and target tissues. Studies in specific aim 1 will determine if corn oil vs. fish oil lipids with and without CR affect the differentiation pathways and functional activity of Th-1 and Th-2 cells by modulating the interaction between CD28/CTLA-4 and B7-1/B7-2 co- stimulatory molecules in CD4+ T cells and B cells. Experiments in specific aim 2 will determine if prolongation of life span by w-3 fatty acids and/or CR is accompanied by increased anti-CD3 or dexamethasone induced apoptosis in thymic and splenic cells. Studies in specific aim 3 will determine whether prolongation of lifespan by w-3 fatty acids and/or CR is accompanied by decreased autoantibody production in B/W mice. In summary, our studies will examine whether w-3 fatty acids combined with moderate CR can further ameliorate autoimmune disease in B/W mice. These studies are especially important in view of the significant rise in the consumption of vegetable oils in recent years which may promote obesity and autoimmune disorders in the USA. In contrast, the anti-inflammatory w-3 fatty acids are consumed in negligible amounts. It is possible that moderate dietary changes will delay the onset of autoimmune diseases as well as significantly decrease the required doses of cytotoxic and immunosuppressive drugs normally used to treat SLE and other autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG014541-05
Application #
6509822
Study Section
Special Emphasis Panel (ZRG2-GMA-2 (01))
Program Officer
Fuldner, Rebecca A
Project Start
1998-04-15
Project End
2004-03-31
Budget Start
2002-04-01
Budget End
2004-03-31
Support Year
5
Fiscal Year
2002
Total Cost
$258,594
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Kim, You Jung; Kim, Hyon Jeen; No, Jae Kyung et al. (2006) Anti-inflammatory action of dietary fish oil and calorie restriction. Life Sci 78:2523-32
Bhattacharya, Arunabh; Rahman, Mizanur; Banu, Jameela et al. (2005) Inhibition of osteoporosis in autoimmune disease prone MRL/Mpj-Fas(lpr) mice by N-3 fatty acids. J Am Coll Nutr 24:200-9
Sun, Dongxu; Krishnan, Aparna; Su, Jianrong et al. (2004) Regulation of immune function by calorie restriction and cyclophosphamide treatment in lupus-prone NZB/NZW F1 mice. Cell Immunol 228:54-65
Fernandes, Gabriel; Lawrence, Richard; Sun, Dongxu (2003) Protective role of n-3 lipids and soy protein in osteoporosis. Prostaglandins Leukot Essent Fatty Acids 68:361-72
Muthukumar, Alagarraju; Zaman, Khaliquz; Lawrence, Richard et al. (2003) Food restriction and fish oil suppress atherogenic risk factors in lupus-prone (NZB x NZW) F1 mice. J Clin Immunol 23:23-33
Sun, Dongxu; Fernandes, Gabriel (2003) Lovastatin inhibits bone marrow-derived dendritic cell maturation and upregulates proinflammatory cytokine production. Cell Immunol 223:52-62
Sun, Dongxu; Krishnan, Aparna; Zaman, Khaliquz et al. (2003) Dietary n-3 fatty acids decrease osteoclastogenesis and loss of bone mass in ovariectomized mice. J Bone Miner Res 18:1206-16
Bhattacharya, Arunabh; Lawrence, Richard A; Krishnan, Aparna et al. (2003) Effect of dietary n-3 and n-6 oils with and without food restriction on activity of antioxidant enzymes and lipid peroxidation in livers of cyclophosphamide treated autoimmune-prone NZB/W female mice. J Am Coll Nutr 22:388-99
Avula, C P Reddy; Fernandes, Gabriel (2002) Inhibition of H2O2-induced apoptosis of lymphocytes by calorie restriction during aging. Microsc Res Tech 59:282-92
Reddy Avula, C P; Lawrence, Richard A; Zaman, Khaliquz et al. (2002) Inhibition of intracellular peroxides and apoptosis of lymphocytes in lupus-prone B/W mice by dietary n-6 and n-3 lipids with calorie restriction. J Clin Immunol 22:206-19

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