Polarization of T-helper lymphocytes toward the Th2 phenotype in uremic patients

T-helper (Th) lymphocytes consist of Th1 and Th2 subsets. Th1 cells are eff ectors of cell-mediated immunity and secrete interferon-gamma (IFN-gamma), which recruits new Th1 cells in cooperation with interleukin-12 (IL-12; pro duced by monocytes) and inhibits Th2 differentiation. Th2 cells produce IL- 4 and IL-10, which inhibit IFN-gamma secretion and cell immunity. We invest igated whether the impaired immune response in uremia is associated with an altered balance of Th1/Th2. Peripheral-blood mononuclear cells (PBMCs) wer e collected from patients with chronic renal failure (CRF) on conservative treatment (CRF patients), patients with end-stage renal disease (ESRD) on r egular hemodialysis therapy (ESRD-HD patients), and healthy controls (CON). CD4(+) cells were Isolated from PBMCs by negative selection using a magnet ic labeling system. PBMCs and purified CD4(+) cells were cultured In Iscove 's medium and Iscove's medium plus mitogens (phytohemagglutinin and lipopol ysaccharide). IFN-gamma, IL-12, IL-4, and IL-10 were measured in supernatan t. The constitutive release of IL-4 and IL-10 by PBMCs and CD4(+) cells of CRF and ESRD-HD patients was increased by five to eight times in comparison with CON (P < 0.001). Constitutive IFN-gamma release by PBMCs of ESRD-HD p atients was undetectable, although they secreted an increased amount of IL- 12. Mitogen-stimulated release of IFN-gamma by PBMCs and CD4(+) cells of CR F and ESRD-HD patients was blunted (average PBMCs: CON, 115.8 pg/2 x 10(6) cells; CRF, 81.8 pg/2 x 10(6) cells; ESRD-HD, 9.3 pg/2 X 10(6) cells; CD4() cells: CON, 358.0 pg/5 x 10(5) cells; CRF, 165.4 pg/5 x 10(5) cells; ESRD -HD, 43.5 pg/5 x 10(5) cells). The ability of PBMCs of ESRD-HD patients to secrete IFN-gamma was recovered after IL-4 and IL-10 neutralization. Uremia is associated with a prevalence of Th1 over Th2 cells and a configuration of cytokine network that depresses cell-mediated immunity. (C) 2001 by the National Kidney Foundation, Inc.