LPR and GLD mutations ameliorate experimental allergic encephalomyelitis

The autosomal recessive mutations of CD95 and CD95L, Ipr and gld , respectively, produce lymphadenopathy and are associated with spontaneous autoimmune disease, especially a renal disease with similarities to the human disease systemic lupus erythematosus. CD95 and CD95L appear to regulate autoreactive T cell expansion by causing T cell death when previously activated T cells are stimulated through their T cell receptor. CD95L expression on testes and corneal epithelia has been implicated as the molecular basis of immune privilege, serving to lyse invading CU95+ T cell effectors. In animals with the Ipr and gld mutations, either of these processes would exacerbate experimental allergic encephalomyelitîs (EAE), an animal model of the autoimmne demyelinating disease multiple sclerosis. However, initial experiments examining the effect of these mutations on EAE in C57BL/6 mice (H - 2^b) indicate that they ameliorate, rather than exacerbate, the duration and severity of clinical signs of EAE. To better examine the magnitude of this effect, we introduced the mutations onto the more susceptible B10.PL (H-T) background, and have generated mice that are homozygous for H - 2", but +/+, +/-, or -/- with respect to the Ipr or gld mutation. Our results in these mice to date support the interpretation that the Ipr and gld mutations dramatically ameliorate induced EAE. We are currently delineating the mechanism by which these mutations exert their effect. Preliminary studies suggest that Ipr and gld mice are capable of producing a normal delayed type hypersensitivity (DTH) response to the purified protein derivative (PPD) of Bacillus calumttti guerin (BCG) in vivo and that MBP-specific T cell lines generated from these mice exhibit a Thl cytokine profile. The levels of TNFo and lymphotoxin, cytokines associated with the pathogenesis of EAE, in wildtype and mutant mice are also being determined, as is the expression of TGF-/3, a cytokine associated with the resolution of EAE.