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

• Published in: Scandinavian journal of immunology 2000-03, Vol.51 (3), p.262
• Main Authors: Aleman, M, De La Barrera, S, Fink, S, Finiasz, M, Farina, M H, Pizzariello, G, Sasiain, M D
• Format: Article
• Language: English
• Subjects: Adult; Aged; Bacterial Proteins; CD56 Antigen - biosynthesis; Cells, Cultured; Chaperonin 60; Chaperonins - immunology; Cytotoxicity, Immunologic - immunology; Down-Regulation - immunology; Drug Synergism; Female; Humans; Immune Sera - pharmacology; Interferon-gamma - antagonists & inhibitors; Interferon-gamma - biosynthesis; Interferon-gamma - metabolism; Interferon-gamma - physiology; Interleukin-10 - physiology; Interleukin-12 - immunology; Interleukin-12 - metabolism; Interleukin-12 - physiology; Interleukin-4 - physiology; Interphase - immunology; Leprosy - immunology; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Lymphocyte Activation - immunology; Major Histocompatibility Complex - immunology; Male; Middle Aged; Mycobacterium leprae - immunology; Protein Binding - immunology; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - physiology
• ISSN: 0300-9475; 1365-3083
• DOI: 10.1046/j.1365-3083.2000.00675.x

Interleukin-12 (IL-12) is a major immunomodulatory cytokine that represents a functional bridge between the early resistance and the subsequent antigen specific adaptive immunity. TNF-alpha and IFN-gamma have an important role in the generation of hsp65 specific cytotoxic T lymphocytes (CTL) that lyse hsp65-pulsed autologous macrophages (hsp65 CTL). Since a positive feedback 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 leprosy 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 response whenever both IFN-gamma and TNF-alpha are present. The addition of these three cytokines (CKs) was able to abrogate the inhibitory effect of IL-10 on hsp65 CTL in cells from paucibacillary patients (PB) but not that of IL-4 in PB and normal controls (N). Both IL-12 or anti IL-4 enhanced the cytotoxic activity in cells from multibacillary patients (MB). Anti IL-4 upregulated 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-gamma 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 binding or receptor expression of both TNF-alpha and IFN-gamma. Development of 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 from MB.