Increased Expression of Erythropoiesis Inhibiting Cytokines (IFN-γ, TNF-α, IL-10, and IL-13) by T Cells in Patients Exhibiting a Poor Response to Erythropoietin Therapy

Abstract

ABSTRACT. Resistance to recombinant human erythropoietin occurs in a small but important proportion of hemodialysis patients. This may be due to increased immune activation because pro-inflammatory cytokines inhibit erythropoiesisin vitro. Using FACScan flow cytometry, the proportion of PMA/ionomycin-stimulated T cells expressing cytokinesex vivowas compared in 18 poor responders to erythropoietin, 14 good responders to erythropoietin, and 14 normal controls. CD4+T cells from poor responders expressed more interferon-γ (IFN-γ; 19 ± 6%) compared with good responders (11 ± 6%,P< 0.001) and controls (12 ± 6%,P< 0.01). Similarly, CD4+T cells from poor responders expressed more tumor necrosis factor-α (TNF-α; poor responders: 51 ± 19%versusgood responders: 27 ± 15% [P< 0.01] and controls: 30 ± 19% [P< 0.01]). CD4+expression of IL-10 was also enhanced (poor responders: 1.6 ± 1.1%versusgood responders: 0.7 ± 0.6% [P< 0.05] and controls: 0.5 ± 0.2% [P< 0.01]). Likewise, CD4+expression of interleukin-13 (IL-13) was increased (poor responders: 4.4 ± 4.2%versusgood responders: 1.6 ± 1.7% [P< 0.05] and controls: 1.6 ± 1.5% [P< 0.05]). CD8+T cells from poor responders also showed enhanced expression of cytokines. For IFN-γ, poor responder expression was 48 ± 20% compared with 31 ± 17% (P< 0.05) for good responders and 23 ± 15% (P< 0.01) for controls. TNF-α expression for poor responders was 41 ± 21%versus25 ± 14% for good responders (P< 0.05) and 21 ± 15% for controls (P< 0.01). IL-10 expression for poor responders was 2.0 ± 1.2% (good responders: 0.7 ± 0.6% [P< 0.01]; controls: 0.5 ± 0.2% [P< 0.001]). These data indicate that T cells from poor responders are in an enhanced activation state possibly as a result of chronic inflammation. In the absence of any other cause (such as iron deficiency), the overproduction of cytokines may account for hyporesponsiveness to erythropoietic therapy in patients with renal failure. E-mail: angela.redrup@kcl.ac.uk