GOLD AND D-PENICILLAMINE INDUCE VASCULITIS AND UP-REGULATE MESSENGER-RNA FOR IL-4 IN THE BROWN-NORWAY RAT - SUPPORT FOR A ROLE FOR TH2 CELL-ACTIVITY

D-penicillamine (DP) and gold salts which are used as immune-modulatin g agents in the treatment of rheumatoid arthritis are known to be capa ble of causing autoimmune manifestations. Most autoimmune diseases in man are dominated by Th1-type responses, and one might presume that ef fective immunotherapy counteracts Th1 activity, perhaps by causing a s hift to a Th2 response. The mechanism of action of gold and DP is not clear, but some clues may be obtained from their effects in animal mod els. DP, gold salts and mercuric chloride (HgCl2) are known to induce Th2-dominated autoimmune syndromes in genetically susceptible rodent s trains, and we have demonstrated recently that HgCl2 upregulates messe nger RNA (mRNA) for IL-4 in the Brown Norway (BN) rat. In the BN rat H gCl2 treatment is also associated with the development of vasculitis, and anti-myeloperoxidase (MPO) antibodies are found in the serum. The present study examined and confirmed the hypothesis that, since gold a nd DP induce an autoimmune syndrome similar to HgCl2 in the BN rat, th ey may also induce vasculitis and an up-regulation in mRNA for IL-4. T issue injury was assessed macroscopically and histologically on day 5 and day 15 after the start of injections with gold, DP or HgCl2, serum titres of IgE and presence of anti-MPO antibodies were determined usi ng ELISA, and a semi-quantitative assay using reverse transcription-po lymerase chain reaction was used to assay the level of mRNA for IL-4 i n spleen and caecum. The relative degree of tissue injury reflected th e potency of induction of IgE by the three agents (HgCl2 being most po tent and DP least potent). The lesions were identical histologically, supporting the premise that the vasculitis is a manifestation of the a utoimmune syndrome rather than non-specific HgCl2 toxicity. Both gold and DP induced less up-regulation of mRNA for IL-4 than HgCl2. HgCl2 ( but not gold or DP) induced anti-MPO antibodies. It would be interesti ng to examine patients treated with gold and DP to see if there is evi dence of a Th2-type response in those developing autoimmune complicati ons, and whether or not the bias to a Th2 environment contributes to e fficacy of treatment of the underlying disease.