Our previous studies showed that arthritic Lewis (LEW) rats produced the highest levels of tumour necrosis factor (TNF)alpha in the recovery phase of adjuvant arthritis (AA), suggesting a correlation between high TNFalpha levels and reduced severity of arthritis. To further explore this correlation, we compared the TNFalpha secretion profile of the AA-resistant Wistar Kyoto (WKY) rats with that of LEW rats, determined the effect of exogenous TNFalpha on the course of AA in LEW rats, and examined various mechanisms involved in TNFalpha-induced disease modulation.
A cohort each of LEW and WKY rats was immunised subcutaneously with heat-killed Mycobacterium tuberculosis H37Ra (Mtb). At different time points thereafter, subgroups of rats were killed and their draining lymph node cells were tested for cytokine production. Another group of LEW rats was injected with TNFalpha intraperitoneally daily for a total of 10 injections, 3 before and 6 after Mtb challenge, and then observed for signs of AA. In parallel, TNFalpha-treated rats were examined for changes in other cytokines, in CD4+CD25+ T cell frequency, and in indoleamine 2,3-dioxygenase (IDO) mRNA expression levels.
LEW rats displayed a TNFalpha secretion profile that was opposite to that of the WKY rats. Furthermore, TNFalpha treatment significantly down modulated the severity of AA in LEW rats, and decreased the interferon (IFN)-gamma secretion in response to the pathogenic determinant of the disease-related antigen. No significant alterations were observed in other parameters tested.
The role of endogenous TNFalpha in the induction and propagation of arthritis is well established. However, exogenous TNFalpha can down modulate the course of AA, displaying an immunoregulatory functional attribute of this cytokine.