LONGITUDINAL-STUDY OF IN-VITRO CD4-HELPER CELL-FUNCTION IN RECENTLY TRANSPLANTED RENAL-ALLOGRAFT PATIENTS UNDERGOING TAPERING OF THEIR IMMUNOSUPPRESSIVE DRUGS( T)

Three distinct T helper activation pathways contribute to interleukin- 2 production by human peripheral blood mononuclear cells following in vitro stimulation with HLA alloantigens in a mixed lymphocyte reaction . These pathways involve both CD4+ and CD8+ T helper cells, as well as self and allogeneic antigen-presenting cells. The pathways are differ entially susceptible to cyclosporine in vitro, with the CD4+ T helper cell and selfAPC (CD4 approximately sAPC) pathway being the most sensi tive. Furthermore, these pathways are differentially susceptible to im munosuppressive drugs in renal allograft patients, and by functional a nalysis of these pathways we have identified patients who are at incre ased risk for rejection of their kidney allografts. The present report provides a longitudinal study of the functional T helper cell status of recently transplanted renal allograft recipients undergoing taperin g of their immunosuppressive drugs by testing the ability of recipient PBMC to generate IL-2 in response to pathway-specific stimuli. This s tudy provides evidence that IL-2 generation by T helper pathways is dy namic, fluctuating independently of the commonly followed clinical par ameters used to assess graft function and degree of immunosuppression. Significantly, the function of the CD4 approximately sAPC activation pathway correlates with risk of acute rejection. As such, we suggest t hat periodic assessment of pathway specific T helper function is a mor e sensitive index for the detection of subtherapeutic dosing of immuno suppressives-and, in particular, for assessing cyclosporine maintenanc e requirements. Monitoring of pathway specific activity with appropria te cyclosporine dosing adjustments might prevent the initiation of the rejection process and reduce a major source of late graft failure.