Association of TLR4 mutations and the risk for acute GVHD after HLA-matched-sibling hematopoietic stem cell transplantation

Lipopolysaccharide (LPS) has been implicated in the pathogenesis of graft-v ersus-host disease (GVHD). The toll-like receptor (TLR)-4 has been recently identified as a major receptor for LPS. Mutations of TLR4 have been associ ated with LPS hyporesponsiveness. We hypothesized that TLR4 mutations reduc e the risk of acute GVHD in allogeneic marrow transplant recipients. In a p reliminary study to determine the frequency of TLR4 mutations and their pos sible association with GVHD, we tested 237 patients and their HLA-identical sibling donors for 2 TLR4 polymorphisms. All patients received methotrexat e 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 pro bability (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% confi dence interval [CI], 0.25-1.60; P = .16). When a mutation was present in th e donor, the adjusted odds ratio was 0.88 (95% CI, 0.36-2.17; P = .40). Whe n 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 e ither donor or recipient, 4 (16.7%) developed gram-negative bacteremia. Amo ng 213 patients without mutations, 14 (6.6%) developed gram-negative bacter emia (P = .09). The data indicate that a reduced risk of acute GVHD is asso ciated with TLR4 mutations and that TLR4 mutations may increase the risk fo r gram-negative bacteremia. However, these associations are not statistical ly significant in recipients of HLA-matched sibling marrow transplants who are prophylactically treated for infections and GVHD. A much larger study p opulation would be needed to confirm the role of LPS in the pathogenesis of GVHD in humans.