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Panminerva Medica 2004 September;46(3):171-87


language: English

Progressive liver injury in chronic hepatitis C infection is related to altered cellular immune response and to different citokine profile

Cecere A., Marotta F., Vangieri B., Tancredi L., Gattoni A.

“F. Magrassi” Department of Clinical and Experimental Medicine, II University of Naples School of Medicine, Naples, Italy


Natural ­immune respons­es, ­both cel­lu­lar and humo­ral, are not ­capable of ter­mi­nat­ing HCV infec­tion in ­most ­patients. The aim of ­this ­study was to eval­u­ate: a) the impor­tance of the ­immune ­system in the path­o­gen­e­sis of chron­ic HCV infec­tion; b) anal­y­sis of suc­cess­ful immu­no­res­pons­es in per­sons infect­ed ­with C ­virus; c) immu­no mech­a­nisms in the pro­gres­sion of hepat­ic dam­age; d) dif­fer­ent cyto­kine pro­files ­from ­patients ­with per­sis­tent and ­self-lim­it­ed hep­a­titis C ­virus infec­tion; e) devel­op­ment of new anti­vi­ral strat­e­gies ­when ­virus is resist­ant to inter­fer­on treat­ment. The inad­e­quate T help­er1 (Th1) immu­nity as ­well as the ­weak HCV-spe­cif­ic T-­cell ­response at the ­site of inflam­ma­tion is asso­ciat­ed ­with fail­ure to ­clear the ­virus and a chron­ic ­course of dis­ease. The pro­duc­tion of inter­leu­kin 12 (IL-12) is crit­i­cal for induc­tion of Th1 immu­nity, direct­ed ­towards elim­i­na­tion of intra­cel­lu­lar patho­genes and virus­es. The ­core pro­tein of HCV ­seems to ­have a sup­pres­sive ­action on IL-12 pro­duc­tion at the tran­scrip­tion­al lev­el. The spe­cif­ic Th1 ­cell ­defect is cor­re­lated ­with insuf­fi­cient Th and CTL respons­es, and low­er pro­duc­tion of ­type 1 cyto­kine (IL-2, IFN-γ, lym­pho­kine-acti­vat­ed kill­er ­cells). Taken togeth­er, ­these ­results are prob­ably respon­sible for non-erad­i­ca­tion of HCV infec­tion. Particularly the ­effects of inter­fer­on-γ may ­include inhi­bi­tion of HCV vir­ion pro­duc­tion by an ­effect on ­viral RNA and pro­tein syn­the­sis, enhance­ment of ­immune ­lysis of HCV infect­ed ­cells, inhi­bi­tion of hepat­ic fibro­sis by an ­effect on TGF-­β, and an ­effect on HCV ­induced car­cin­o­gen­e­sis. These ­data sug­gest an HCV-relat­ed cel­lu­lar ­immune ­defect in ­patients ­with hep­a­titis C ­that can be ­restored in ­most ­patients by IL-12. New approach­es ­using a com­bi­na­tion of nucle­oside ana­logs or oth­er strat­e­gies, ­such as ­immune inter­ven­tion (DNA vac­cine, stim­u­la­tion of the Th1 ­response) or ­gene ther­a­py (anti­sense oli­go­nu­cleo­tides dom­i­nant neg­a­tive ­mutants) ­should there­fore be eval­u­at­ed in ani­mal mod­els to opti­mize the cur­rent anti­vi­ral pro­to­cols.

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