MHC CLASS-I GENE(S) IN THE D L REGION BUT NOT THE TNF-ALPHA GENE DETERMINES DEVELOPMENT OF TOXOPLASMIC ENCEPHALITIS IN MICE/

Previous studies revealed that mice with the b or k allele at the H-2D region are susceptible to toxoplasmic encephalitis (TE); those with t he d allele are resistant. To determine whether the b or d allele is d ominant, F-1 hybrids between susceptible C57BL/6 (H-2(b)) and resistan t BALB/c (H-2(d)) mice were infected with T. gondii. TE was not observ ed in the F-1 hybrids, indicating that the d allele is dominant for pr otection against development of TE. Mice with a mutation in the D/L re gion were used to determine whether the D gene or the L gene of MHC cl ass I Ags of the H-2D region is most critical for resistance against d evelopment of TE. B10.D2-H-2(dm1) (dm1) mice that have the mutant D/L hybrid gene formed by fusion of the 5' part of the D-d gene and the 3' part of the L(d) gene developed TE in contrast to their background B1 0.D2 mice. BALB/c-H-2(dm2) (dm2) mice, which have a complete deletion of the L(d) gene, had significantly more T. gondii cysts in their brai ns than did dm1 mice and developed large areas of necrosis in their br ains that were not observed in dm1 mice. These results indicate that a gene(s) in the D/L region determines whether TE will occur and that t he L(d) gene plays a critical role in the resistance against developme nt of TE. Polymorphisms in the TNF-alpha gene (located in the H-2D reg ion) have been reported to correlate with resistance against the devel opment of TE. When development of TE was studied in BALB/c and dm2 mic e that have the same TNF-alpha gene, only dm2 mice developed TE. This indicates that the TNF-alpha gene is not a determining factor for the development of TE. Transcripts for TNF-alpha were detected in brains o f infected dm2 mice but not in BALB/c mice. Injection of neutralizing Abs against TNF-alpha resulted in worsening of the TE in infected dm2 mice but did not induce TE in infected BALB/c mice. Thus, TNF-alpha ap pears to be produced in the brain after TE has developed and is respon sible for preventing the progression of TE.