CYTOKINE AND ALLOANTIBODY NETWORKS IN LONG-TERM CARDIAC ALLOGRAFTS INRAT RECIPIENTS TREATED WITH RAPAMYCIN

Treatment with rapamycin (RPM) prevents accelerated rejection of (LEWx BN)F-1 cardiac allografts in LEW rats presensitized with BN skin graft s, This study analyzed the influence of RPM on cytokine (IL-2, IL-4, I L-10, and IL-12) and alloantibody networks in this model, Accelerated (24-h) rejection was associated with strong expression of intragraft I L-2 and IL-12 (p40) mRNAs, which reached maximal levels 3 to 6 h post- transplantation. IL-4 and IL-10 mRNAs were readily detectable througho ut the observation period, RPM therapy abrogated rejection at 24 h and prolonged cardiac allograft survival to about 50 days, This effect wa s correlated with a profound initial depression of IL-2 mRNA; delayed expression of IL-2 mRNA was detected in well functioning grafts at >20 days, In RPM-treated hosts, expression of IL-12 (p40) mRNA was low at the early time points (6-24 h), but prominent in long term grafts, Th e expression of both IL-4 and IL-10 mRNAs was preserved in RPM-conditi oned hosts, Immunohistologic analysis of long term allografts revealed an interstitial cellular infiltrate and areas of intimal proliferatio n within small arteries indicative of early transplant arteriosclerosi s, Analysis of cytokine proteins showed dense labeling of mononuclear and some endothelial cells for IL-4 and IL-12 (p70), but not for IL-2 or IFN-gamma. RPM treatment diminished the IgM alloantibody response i n the serum and prevented the switch from IgM to Ige alloantibody in t he early post-transplant period, However, an increase in circulating a nd intragraft IgM and, to a lesser extent, IgG, primarily of the IgG2b subclass, was evident in long term recipients, Thus, RPM treatment re duces, but does not completely inhibit, the expression of Th1-type and preserves the expression of Th2-type cytokines, The demonstration of IL-12 in long term allografts after RPM therapy may reflect late activ ation of macrophages that, coupled with the appearance of IgG2a and Ig G2b, may contribute to the ultimate chronic rejection of cardiac allog rafts.