Deficient TNF-alpha and IFN-gamma production correlates with nondetectable donor-specific cytotoxicity after clinical kidney transplantation.
BACKGROUND
We previously reported that no cytotoxic T-lymphocyte precursor frequencies (CTLpf) were found in 60% of patients on azathioprine or mycophenolate mofetil+Pred long after kidney transplantation. We questioned whether the absence of donor-specific CTLpf was associated with low levels of stimulatory Th1 (tumor necrosis factor [TNF]-alpha, interferon [IFN]-gamma) or high levels of regulatory Th2 (interleukin [IL]-4, IL-6, IL-10) cytokines.


METHODS
In this study, peripheral blood monocyte cells (PBMC) were stimulated with irradiated donor cells. After 7 days, cytokine production was determined by cytokine bead array, and CTLpf by limiting dilution assay.


RESULTS
Patients with detectable CTLpf (> or =10/10(6) PBMC) had significantly higher levels of TNF-alpha (P=0.04) and IFN-gamma (P=0.02) than patients with nondetectable CTLpf (<10/10(6) PBMC). Donor-reactive IL-4, IL-6, and IL-10 production was comparable in both patient groups. Additionally, CTLpf was positively correlated with TNF-alpha (rs=0.54, P=0.0003) and IFN-gamma (rs=0.64, P<0.0001) production.


CONCLUSIONS
The absence of donor-specific CTLp after transplantation correlates with low levels of stimulatory cytokines, not with elevated levels of regulatory cytokines.
van Besouw
Nicole M
NM
Department of Internal Medicine-Transplantation, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. n.vanbesouw@erasmusmc.nl
de Kuiper
Ronella
R
van der Mast
Barbara J
BJ
van de Wetering
Jacqueline
J
Baan
Carla C
CC
Weimar
Willem
W
D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D003602:Cytotoxicity, Immunologic; D004359:Drug Therapy, Combination; D005190:Family; D006680:HLA Antigens / Q000032:analysis; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007371:Interferon-gamma / Q000276:immunology*; D016753:Interleukin-10 / Q000097:blood; D015847:Interleukin-4 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007519:Isoantigens / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D019520:Living Donors; D009000:Monocytes / Q000166:cytology / Q000502:physiology; D011446:Prospective Studies; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000276:immunology*; D019014:fas Receptor
D000305:Adrenal Cortex Hormones; D006680:HLA Antigens; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D007519:Isoantigens; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma