CD28 BLOCKADE ALTERS CYTOKINE MESSENGER-RNA PROFILES IN CARDIAC TRANSPLANTATION

Background. T-cell response to alloantigen is dependent on T-cell rece ptor activation and costimulation through the CD28 receptor because T- cell receptor activation alone is insufficient for optimal immune resp onse. The CD28 receptor on helper T cells interacts with its ligand B7 on activated B cells-macrophages as costimulus to support T-cell acti vity. CTLA4Ig is a recombinant inhibitor of CD28 receptor activation. In. vivo studies with a rat major histocompatibility complex mismatch heterotopic cardiac transplant model demonstrate that CTLA4Ig prolongs cardiac allograft survival. This CTLA4Ig survival benefit is enhanced with prior donor-specific antigen exposure. Methods. To investigate C TLA4Ig mechanisms, we examined the differential expression of B7 and c ytokine mRNAs for interferon-gamma (IFN-gamma), interleukin-2 (IL-2) I L-4, and IL-10 (Th1 or Th2 activation) in cardiac allografts after tre atment with CTLA4Ig and donor-specific antigen exposure versus convent ional immunotherapy (cyclosporine, cyclophosphamide or antilymphocyte serum). In the above major histocompatibility complex mismatch model, hearts (on day 5 after transplantation at peak rejection) had cytokine mRNA expression determined by semiquantitative reverse transcriptase polymerase chain reaction. Results. Inhibition of B7 expression was ob served in CTLA4Ig animals. Expression of IL-2 and IFN-gamma was near u ndetectable in CTLA4Ig and cyclophosphamide rats but was only moderate ly reduced by cyclosporine and antilymphocyte serum. IL-4 mRNA express ion was reduced equally in all animals. Finally, IL-IO levels were unc hanged by CTLA4Ig but were decreased by other therapies. Conclusions. The beneficial effect of CTLA4Ig, inhibiting expression of B7, alters Th2 cytokines IL-2 and IFN-gamma, with a resultant predominant IL-10 d riven, Th2 tolerogenic response.