NEW STRATEGIES FOR EARLY DIAGNOSIS OF HEART ALLOGRAFT-REJECTION

Background. Allograft rejection is mediated by T cells that recognize allogeneic major histocompatibility complex (MHC) molecules via the di rect and indirect pathway, The direct pathway involves T cells that re act against MHC/peptide complexes expressed on the surface of donor an tigen-presenting cells (APCs), in contrast, T cells involved in the in direct pathway recognize peptides derived from processing and presenta tion of allogeneic MHC molecules by self (recipient) APCs, To explore the relative contribution of these two pathways to rejection, we have evaluated the response of peripheral blood T cells from 50 heart trans plant recipients against donor APCs (direct recognition) and against s elf APCs pulsed with synthetic peptides corresponding to the hypervari able region of the mismatched HLA-DR antigens of the donor (indirect r ecognition). Methods. T cell reactivity against donor APCs was quantit ated by measuring the expression of CD69 on allostimulated CD3(+)LDA1( +) cells. Reactivity to synthetic allopeptides was determined in limit ed dilution assays. Results. Serial studies of the kinetics of direct and indirect recognition showed that both pathways contribute to early acute rejection episodes, Primary rejection was accompanied invariabl y by indirect recognition of a dominant allopeptide, Intermolecular sp reading of T cell epitopes was observed during recurrent rejections, E nhanced recognition of donor alloantigens via the direct pathway was f ound predominantly during early rejection episodes, A single form of a llorecognition was shown to occur in some rejection episodes. Conclusi ons. Monitoring of the direct and indirect pathway of allorecognition provides a reliable method for prediction and differential diagnosis o f acute rejection of heart allografts.