Interleukin-12 amplifies the M-Leprae hsp65-cytotoxic response in the presence of tumour necrosis factor-alpha and interferon-gamma generating CD56(+) effector cells: Interleukin-4 downregulates this effect

Interleukin-12 (IL-12) is a major immunomodulatory cytokine that represents a functional bridge between the early resistance and the subsequent antige n specific adaptive immunity. TNF-alpha and IFN-gamma have an important rol e in the generation of hsp65 specific cytotoxic T lymphocytes (CTL) that ly se hsp65-pulsed autologous macrophages (hsp65 CTL). Since a positive feedba ck mechanism between TNF-alpha, IFN-gamma and IL-12 has been described, we undertook to evaluate the role of IL-12 on the hsp65 CTL generation in lepr osy patients. Our results show that the presence of IL-12 during the first 24 h of the in vitro antigen stimulation amplifies the hsp65 cytotoxic resp onse whenever both IFN-gamma and TNF-alpha are present. The addition of the se three cytokines (CKs) was able to abrogate the inhibitory effect of IL-1 0 on hsp65 CTL in cells from paucibacillary patients (PB) but not that of I L-4 in PB and normal controls (N). Both IL-12 or anti IL-4 enhanced the cyt otoxic activity in cells from multibacillary patients (MB). Anti IL-4 upreg ulated the binding of IFN-gamma and did not modify that of TNF-alpha so the low CTL activity could be as a result of IL-4 by a decrease of the IFN-gam ma binding on MB cells. Cells from those MB patients taking thalidomide (MB -T) did neither bind IFN-gamma nor TNF-alpha even when antigen or anti-IL-4 were added, demonstrating that thalidomide inhibits either the in vitro bi nding or receptor expression of both TNF-alpha and IFN-gamma. Development o f CD56 effector cells during the hsp65 stimulation was observed in PB and N by the addition of IL-12 plus TNF-alpha and IFN-gamma, while in MB and MB- T anti IL-4 was also required. So, the inhibitory effect of IL-4 on either production of IFN-gamma, TNF-alpha and/or IL-12 or their receptors could be the mechanism underlying the lack of the hsp65 CTL generation in cells fro m MB.