Increased expression of erythropoiesis inhibiting cytokines (IFN-gamma, TNF-alpha, IL-10, and IL-13) by T cells in patients exhibiting a poor response to erythropoietin therapy.
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 erythropoiesis in vitro. Using FACScan flow cytometry, the proportion of PMA/ionomycin-stimulated T cells expressing cytokines ex vivo was 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-gamma (IFN-gamma; 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-alpha (TNF-alpha; poor responders: 51 +/- 19% versus good 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% versus good 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% versus good 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-gamma, 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-alpha expression for poor responders was 41 +/- 21% versus 25 +/- 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.
Cooper
Angela C
AC
Department of Renal Medicine, GKT School of Medicine, King's College Hospital, Bessemer Road, London SE5 9PJ, UK. angela.redrup@kcl.ac.uk
Mikhail
Ashraf
A
Lethbridge
Mark W
MW
Kemeny
D Michael
DM
Macdougall
Iain C
IC
D000328:Adult; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D016022:Case-Control Studies; D002455:Cell Division; D002469:Cell Separation; D016207:Cytokines / Q000378:metabolism; D004920:Erythropoiesis; D004921:Erythropoietin / Q000627:therapeutic use*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation; D007371:Interferon-gamma / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000378:metabolism; D018793:Interleukin-13 / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000378:metabolism; D015759:Ionomycin / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011994:Recombinant Proteins / Q000627:therapeutic use; D015203:Reproducibility of Results; D013601:T-Lymphocytes / Q000378:metabolism*; D013997:Time Factors; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000806:Angiotensin-Converting Enzyme Inhibitors; D016207:Cytokines; D018793:Interleukin-13; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin; D016753:Interleukin-10; D015847:Interleukin-4; D015759:Ionomycin; D007371:Interferon-gamma