Monocyte-secreted inflammatory cytokines are associated with transplant glomerulopathy in renal allograft recipients

• Published in: Transplantation Vol. 91; no. 5; p. 552
• Main Authors: De Serres, Sacha A, Vadivel, Nidyanandh, Mfarrej, Bechara G, Grafals, Monica, DeJoseph, Maura, Dyer, Christine, Magee, Ciara N, Chandraker, Anil, Gallon, Lorenzo G, Najafian, Nader
• Format: Journal Article
• Language: English
• Published: United States 15.03.2011
• Subjects: Adult; Aged; Biopsy; CD4 Antigens - metabolism; Cells, Cultured; Cohort Studies; Cross-Sectional Studies; Female; Glomerulonephritis - epidemiology; Glomerulonephritis - immunology; Glomerulonephritis - pathology; Humans; Immunity, Innate - immunology; Incidence; Interleukin-1beta - metabolism; Interleukin-6 - metabolism; Kidney Transplantation - immunology; Kidney Transplantation - pathology; Male; Middle Aged; Monocytes - metabolism; Retrospective Studies; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - pathology; T-Lymphocytes, Regulatory - physiology; Transplantation, Homologous; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1534-6080
• DOI: 10.1097/TP.0b013e318205b3c1

Although there is ample evidence about the role of adaptive immunity in the development of chronic allograft dysfunction, little is known about the contribution of innate immunity to this process. Herein, we studied the relationship between inflammation, chronic biopsy scores, and anti-human leukocyte antigen (HLA) circulating alloantibodies in a cohort of 57 patients recruited at our center. Available biopsies (n=27) were graded for chronic lesion scores according to Banff criteria. The production of cytokines by peripheral blood mononuclear cells after 48 hr of culture under resting conditions was quantified by Luminex. Tumor necrosis factor (TNF)-α secretion assay and depletion studies were used to identify the source of these cytokines. There was a high correlation between the levels of interleukin (IL)-1β, IL-6, and TNF-α (r>0.8, P<0.001 for all correlations). The levels of these cytokines were associated with transplant glomerulopathy (IL-1β, P=0.019; IL-6, P=0.015; and TNF-α, P=0.006) but not with other chronic lesions or anti-HLA circulating alloantibodies. TNF-α was predominantly secreted by monocytes (percent of TNF-α secreting cells: 20.4±4.8 vs. 1.2±0.5 vs. 1.4±0.6 vs. 1.7±0.5 for CD14, CD4, CD8, and CD19 cells, respectively; all P<0.01 vs. CD14). The levels of all three proinflammatory cytokines were significantly reduced after monocyte depletion. Intriguingly, cytokine levels increased after ex vivo depletion of regulatory T cells (all P<0.001). Taken together, these data suggest that in vivo-activated monocytes in peripheral blood spontaneously secrete proinflammatory cytokines in renal allograft recipients with transplant glomerulopathy and seem to be under the regulation of functional regulatory T cells in this setting.