Low-Dose Interleukin-2 Therapy: Effects in Chronic Renal Allograft Dysfunction.

Abstract

Immune modulating therapies gain increasing importance in treatment of patients with autoimmune diseases and organ transplantation. Daily low-dose interleukin-2 therapy has been shown to expand regulatory T-cells with clinical improvement in patients with HCV-induced vasculitis or chronic graft-versus-host disease. Here, we studied safety, immunologic effects, and impact on chronic allograft dysfunction of the administration of low-dose interleukin-2 in kidney transplant recipients (KTRs) with end-stage allograft dysfunction. 3 KTRs with chronic renal allograft dysfunction who were refractory to conventional therapy, and who were receiving triple-drug maintenance immunosuppression, received one course of interleukin-2 (1.5 million IU per day) for 5 days, followed by repetition at week 3. Safety and effectiveness of the treatment were evaluated by monitoring lymphocyte subpopulations, gene expression profiles of 13 selected tolerance-associated genes, and the development of HLA- and non-HLA-antibodies. CMV-specific, BKV-specific and alloreactive T-cells were measured using an interferon-γ Elispot assay. No serious adverse events were observed. Interleukin-2 therapy didn't induce effector T-cell activation, acute cellular or antibody-medicated rejection, or reactivation of latent viruses as CMV or BKV. We observed an improvement of allograft function in all KTRs after 2 courses of interleukin-2 with a reduction of serum creatinine levels from 4.37 to 3.35, 4.44 to 3.39, and 2.88 to 2.09mg/dl. However, all KTRs showed a return to baseline serum creatinine levels after discontinuation of interleukin-2 therapy. Administration of low-dose interleukin-2 was followed by an increase in the percentage of CD4+CD25+FOXP3+ Tregs [maximum value ÷ baseline value × 100 = 350%]. Low-dose IL-2 had minimal effects on other T-cell subpopulations, NK-cells, or B-cells. Gene expression patterns of FOXP3 and MAN1a1 were upregulated by interleukin-2 therapy. Low-dose interleukin-2 therapy was safe and led to expansion of regulatory T-cells and temporary improvement of allograft function in KTRs with chronic renal allograft dysfunction.