title: Interleukin-18 binding protein in acute graft versus host disease and engraftment following allogeneic peripheral blood stem cell transplants.
abstract: Dysregulation of the cytokine network plays an important role in graft-versus-host disease (GVHD). Interleukin-18 (IL-18) is an obligatory cytokine for interferon-gamma (IFN-gamma) production and IFN-gamma and sIFN-gammaR are elevated in patients with GVHD. Because IL-18 binding protein (IL-18BP) is an inhibitor of IL-18-mediated IFN-gamma production, we evaluated IL-18BP levels in patients undergoing allogeneic peripheral blood stem cell transplantation (PBSCT). IL-18BP levels were assessed in 14 patients on day -10 (before conditioning), on the day of transplant, on the day of engraftment, and during transplant-related complications. A comparison of the kinetics of IL-18BP and soluble(s) IL-6R, sIFN-gammaR, IL-18 serum levels was performed. IL-18BP levels were assessed by specific monoclonal antibodies in a double-sandwich enzyme-linked immunosorbent assay (ELISA). In all patients IL-18BP levels decreased during conditioning and increased in parallel with engraftment (p < 0.05). Accordingly, during rejection, IL-18BP serum levels remained low and similar to pretransplant levels. The mean elevation of IL-18BP detected in association to acute GVHD was significantly higher in comparison to normal engraftment (p < 0.05). A correlation between IL-18BP, sIFNgammaR, and sIL-6R serum levels was found in all patients. No correlation between IL-18 and IL-18BP serum levels was found in patients undergoing uneventful PBSCT and rejection, whereas a marked increase in both IL-18 and IL-18BP levels was detected during acute GVHD (p < 0.01). Our data suggest that the dysregulation of IL-18 and IL-18BP may be important in the pathophysiology of transplant-related complications. Furthermore, because preliminary data from our group show that IL-18 blockage ameliorates GVHD in murine models, it is inferred that these cytokines may represent potential targets in the development of new therapeutic strategies in acute GVHD.
authors.affiliation: Department of Scienze Cliniche e Biologiche Universitá di Torino, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Zecchina
authors.forename: D
authors.initials: D
authors.lastname: Novick
authors.forename: M
authors.initials: M
authors.lastname: Rubinstein
authors.forename: V
authors.initials: V
authors.lastname: Barak
authors.forename: C
authors.initials: C
authors.lastname: Dinarello
authors.forename: A
authors.initials: A
authors.lastname: Nagler
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D006023:Glycoproteins / Q000097:blood*; D006085:Graft Survival / Q000276:immunology*; D006086:Graft vs Host Disease / Q000097:blood / Q000209:etiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18 / Q000097:blood; D008297:Male; D008875:Middle Aged; D017471:Receptors, Interferon / Q000097:blood; D019947:Receptors, Interleukin-6 / Q000097:blood; D033581:Stem Cell Transplantation / Q000009:adverse effects*; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D000096743:Interferon gamma Receptor
chemical_list: D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D017471:Receptors, Interferon; D019947:Receptors, Interleukin-6; D000096743:Interferon gamma Receptor; C118370:interleukin-18 binding protein