MODULATION OF ADJUVANT ARTHRITIS IN LEWIS RATS BY RECOMBINANT VACCINIA VIRUS EXPRESSING THE HUMAN 60-KILODALTON HEAT-SHOCK PROTEIN

The immune response to the mycobacterial 65-kDa heat shock protein (hs p65) is considered an important event in the induction of adjuvant art hritis (AA) in rats; this induction probably occurs through a molecula r mimicry mechanism involving cross-reactivity against the rat homolog hsp60. To analyze the role of mammalian molecule hsp60 in arthritis, we generated a recombinant vaccinia virus (hsp60-VV) carrying the huma n hsp60 gene inserted into the thymidine kinase locus under the contro l of the 7.5k vaccinia virus promoter. Human hsp60 is almost identical to its rat homolog (97.4% linear amino acid homology) and shares abou t 50% of amino acid positions with Mycobacterium tuberculosis hsp65. T he latter supposedly carries a critical epitope for AA induction that is not present in human hsp60. Infections with hsp60-VV of monkey cell cultures led to the expression of the human hsp60 molecule, as eviden ced by immunoblotting analysis with specific monoclonal antibodies. Al so, Lewis rats infected with hsp60-VV produced specific antibodies, de monstrating the in vivo expression of human hsp60 in the infected anim als. Therefore, we used hsp60-VV to analyze whether the delivery of hs p60 could affect the induction of AA in Lewis rats. hsp60-VV clearly r educed and retarded arthritic symptoms when administered to rats at da y 7 after AA induction. In contrast, inoculation of rats with a contro l recombinant vaccinia virus did not affect the course of the disease. The improvement in AA with hsp60-VV administration was associated wit h a specific immune response, as determined by the presence of antibod ies to hsp60 in the sera and the proliferation induced by hsp60 of T c ells from popliteal lymph nodes. These results support a critical role for immunity to heat shock proteins in AA. Since the protective const ruct is virtually identical to rat homolog hsp60, we conclude that imm unity directed to conserved areas of this family of proteins is direct ly involved in the pathogenesis of AA.