SUPPRESSION AND REVERSAL OF GLD DISEASE BY PARABIOSIS WITH NORMAL MICE

The disruption of the Fas receptor or Fas ligand by the lpr or gld mut ations, respectively, results in severe autoimmune and lymphoprolifera tive disease due to the failure of Fas-mediated deletion of self-react ive lymphocytes, Recently, we have shown in mixed chimeras that gld-in duced autoimmunity could be corrected by normal bone marrow, in partic ular by normal T cells, In contrast, lpr-mediated autoimmunity could n ot be influenced by normal bone marrow-derived cells. In the present r eport, we have studied the role of normal lymphocytes in suppressing o r reversing gld-induced autoimmunity by parabiosis with normal mice. O ur results show a suppression of lymphadenopathy, fewer CD4(-)CD8(-) T cells, and lower levels of autoantibody production in gld mice parabi osed with normal mice at 4-6 weeks of age. The gld mice parabiosed wit h normal mice at 4 months of age also exhibited a substantial reductio n of both total and CD4(-)CD8(-) T cells in the periphery 2 months aft er surgery. However, they showed little reduction of autoantibodies co mpared to gld mice parabiosed with gld mice. In contrast, older lpr mi ce did not exhibit any reduction in lymphadenopathy or autoantibody pr oduction after parabiosis with normal mice. The prevention or reversal of lymphadenopathy in parabiosed gld mice suggests that ongoing Fas-m ediated deletion in the periphery may play an important role in mainta ining self-tolerance. The relative irreversibility of autoantibody syn thesis in older parabiosed gld mice suggests that autoantibody-produci ng B cells or their committed precursors are long lived and do not exp ress functional Fas receptor. (C) 1996 Academic Press Inc.