03385nas a2200541   4500000000100000008004100001260001300042653001000055653000900065653002300074653001700097653002000114653001800134653001600152653003000168653002000198653001900218653001100237653001100248653001600259653002100275653001900296653001900315653001800334653001500352653001200367653002800379653002600407653003700433653000900470653001600479653002500495653002000520653002900540653003200569100001300601700002000614700001100634700001400645700001500659700001800674700001600692245021100708300001100919490000700930520189200937022001402829       2000                            d  c2000 Mar10aAdult10aAged10aBacterial Proteins10aCD56 Antigen10aCells, Cultured10aChaperonin 6010aChaperonins10aCytotoxicity, Immunologic10aDown-Regulation10aDrug Synergism10aFemale10aHumans10aImmune Sera10aInterferon-gamma10aInterleukin-1010aInterleukin-1210aInterleukin-410aInterphase10aleprosy10aLeukocytes, Mononuclear10aLymphocyte Activation10aMajor Histocompatibility Complex10aMale10aMiddle Aged10aMycobacterium leprae10aProtein Binding10aT-Lymphocytes, Cytotoxic10aTumor Necrosis Factor-alpha1 aAleman M1 aDe La Barrera S1 aFink S1 aFiniasz M1 aFarina M H1 aPizzariello G1 aSasiain M D00aInterleukin-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.  a262-700 v513 a<p>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.</p>  a0300-9475