title: Association of TLR4 mutations and the risk for acute GVHD after HLA-matched-sibling hematopoietic stem cell transplantation.
abstract: Lipopolysaccharide (LPS) has been implicated in the pathogenesis of graft-versus-host disease (GVHD). The toll-like receptor (TLR)-4 has been recently identified as a major receptor for LPS. Mutations of TLR4 have been associated with LPS hyporesponsiveness. We hypothesized that TLR4 mutations reduce the risk of acute GVHD in allogeneic marrow transplant recipients. In a preliminary study to determine the frequency of TLR4 mutations and their possible association with GVHD, we tested 237 patients and their HLA-identical sibling donors for 2 TLR4 polymorphisms. All patients received methotrexate and cyclosporine for GVHD prophylaxis. One or more mutants were detected in 10.8% of patients and 10.6% of donors. Multivariable logistic regression models were used to analyze the association between TLR4 mutations and probability (1-sided) of GVHD. The odds ratio (adjusted for advanced disease, total body irradiation dose, and patient age) for development of grades II to IV GVHD when a mutation was present in the recipient was 0.63 (95% confidence interval [CI], 0.25-1.60; P = .16). When a mutation was present in the donor, the adjusted odds ratio was 0.88 (95% CI, 0.36-2.17; P = .40). When a mutation was present in both recipient and donor, the odds ratio was 0.72 (95% CI, 0.22-2.32; P = .29). Among 24 patients with TLR4 mutations in either donor or recipient, 4 (16.7%) developed gram-negative bacteremia. Among 213 patients without mutations, 14 (6.6%) developed gram-negative bacteremia (P = .09). The data indicate that a reduced risk of acute GVHD is associated with TLR4 mutations and that TLR4 mutations may increase the risk for gram-negative bacteremia. However, these associations are not statistically significant in recipients of HLA-matched sibling marrow transplants who are prophylactically treated for infections and GVHD. A much larger study population would be needed to confirm the role of LPS in the pathogenesis of GVHD in humans.
authors.affiliation: Department of Medicine, Duke University, Durham, North Carolina, USA.
authors.forename: E
authors.initials: E
authors.lastname: Lorenz
authors.forename: D A
authors.initials: DA
authors.lastname: Schwartz
authors.forename: P J
authors.initials: PJ
authors.lastname: Martin
authors.forename: T
authors.initials: T
authors.lastname: Gooley
authors.forename: M T
authors.initials: MT
authors.lastname: Lin
authors.forename: J W
authors.initials: JW
authors.lastname: Chien
authors.forename: J A
authors.initials: JA
authors.lastname: Hansen
authors.forename: J G
authors.initials: JG
authors.lastname: Clark
mesh_terms: D016470:Bacteremia / Q000235:genetics; D015331:Cohort Studies; D029721:Drosophila Proteins; D005787:Gene Frequency; D005820:Genetic Testing; D006086:Graft vs Host Disease / Q000139:chemically induced / Q000209:etiology / Q000235:genetics*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006650:Histocompatibility Testing; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology; D009154:Mutation; D009679:Nuclear Family; D016017:Odds Ratio; D011446:Prospective Studies; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000502:physiology; D012307:Risk Factors; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014184:Transplantation, Homologous / Q000009:adverse effects
chemical_list: D029721:Drosophila Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors