Longitudinal study of in vitro CD4⁺ T helper cell function in recently transplanted renal allograft patients undergoing tapering of their immunosuppressive drugs

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 differentially susceptible to cyclosporine in vitro, with the CD4⁺ T helper cell and selfAPC (CD4~sAPC) pathway being the most sensitive. Furthermore, these pathways are differentially susceptible to immunosuppressive drugs in renal allograft patients, and by functional analysis of these pathways we have identified patients who are at increased 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 tapering of their immunosuppressive drugs by testing the ability of recipient PBMC to generate IL-2 in response to pathway- specific stimuli. This study provides evidence that IL-2 generation by T helper pathways is dynamic, fluctuating independently of the commonly followed clinical parameters used to assess graft function and degree of immunosuppression. Significantly, the function of the CD4~sAPC activation pathway correlates with risk of acute rejection. As such, we suggest that periodic assessment of pathway specific T helper function is a more sensitive index for the detection of subtherapeutic dosing of immunosuppressives-and, in particular, for assessing cyclosporine maintenance requirements. Monitoring of pathway specific activity with appropriate cyclosporine dosing adjustments might prevent the initiation of the rejection process and reduce a major source of late graft failure.