TREATMENT WITH INTERLEUKIN-4 PROLONGS ALLOGENEIC NEONATAL HEART GRAFT-SURVIVAL BY INDUCING T-HELPER-2 RESPONSES

Background. The T helper (Th) 2 cytokine interleukin (IL)-4 has been i mplicated as a major regulatory cytokine for the induction of transpla nt tolerance, but few studies have examined the capacity of IL-4 to in duce tolerance. The effect of IL-4 therapy alone or with low doses of anti-CD4 monoclonal antibody (mAb) therapy on survival of fully alloge neic PVG neonatal heart graft in adult DA rats was examined. Methods. Rat recombinant (r) IL-4 was given at 30 mu g (10(4) U)/kg daily intra peritoneally for 10 days and MRC OX35 (anti-CD4, nondepleting) or MRC OX81 (anti-IL-4) was given intraperitoneally on days 0, 3, 7, and 10. Semiquantitative reverse transcriptase-polymerase chain reaction was u sed to assay mRNA for cytokine in the graft, regional node and spleen and fluorescence-activated cell sorting was used to assay alloantibody Ig isotypes, Results. Grafts in rIL-4-treated rats survived a median period of 39 days (range, 28-52 days), significantly longer than in bo th untreated and nontransfected Chinese hamster ovary-Ri supernatant-t reated controls (median, 14 days; range, 10-16 days, lD=0.009), rIL-4 treatment with a suboptimal dose of anti-CD4 mAb prolonged median surv ival to 70 days (range, 63-80 days), which was longer than rIL-4 treat ment alone or anti-CD4 mAb alone (median, 36 days; range, 30-55 days; P<0.0045). Combining MRC OX81 with MRC OX35 therapy led to earlier rej ection at a median period of 26 days (range, 20-28 days); MRC OX81 alo ne had no effect on graft survival. Alloantibody titers, especially Ig G1, were higher in rIL-4-treated animals and lower in anti-CD4 mAb-tre ated animals than in animals with normal rejection (P<0.05). IL-4 mRNA was increased in regional lymph nodes and spleen of the rIL-4-treated groups compared with all other groups, but there were no differences for IL-2, interferon-gamma, or IL-10, Conclusions. rIL-4 therapy marke dly prolonged neonatal cardiac allograft survival, and, with anti-CD4 therapy, it further prolonged survival. It induced IL-4 mRNA in lympho id tissues and enhanced alloantibody production, especially IgG1, whic h demonstrated enhanced Th2 responses, but did not affect Th1 cytokine s.