DEVELOPMENTAL &IMMUNOREGULATORY EFFECTS OF TNFA LTA LTB

Stanford University, Stanford CA

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Abstract

DESCRIPTION: Tumor necrosis factor (TNF), lymphotoxin-alpha (LTA), and lymphotoxin-beta (LTb) have major effects on the development and function of lymph nodes, spleen, thymus and particularly on T-cell function in several autoimmune diseases. In this research application, transgenic mice expressing high levels of soluble TNFRp60 and LTbetaR will be used as single and double transgenic lines to probe the function of TNFalpha and LTbeta on the embryologic development of lymph nodes, spleen and thymus. In several autoimmune strains of mice [(NZB x NZW)F1 and NOD], TNF administration in adult life suppresses autoimmunity. Paradoxically, TNF administration to neonatal NOD mice increases the incidence and hastens the onset of diabetes, while anti-TNF in neonatal life completely prevents all manifestations of autoimmunity. Experiments in this research application will test whether neonatal TNF administration in NOD mice and in T-cell receptor transgenic mice induces a shift towards a Th1 cell response while anti-TNF induces a shift towards a Th2 T-cell response. TNFRp60 and TNFRp80 targeted recombination chromosomes will be bred onto the NOD background to determine whether the effect of TNF on autoimmunity in the NOD mouse is mediated via the p60 or the p80 receptor. Finally, expression of TNF under the control of the rat insulin promoter, beginning either in fetal life or at 8-10 weeks of age, will test whether the effects of TNF on autoimmunity in the NOD mouse are due to the local effects of TNF in the islets of Langerhans, or due to a systemic effect on T cell development and function.