Reduced Incidence of Severe Acute GVHD in Patients Transplanted from Donors with IL23R (Arg381Gln) Gene Variant.

Background. Recently, a gene polymorphism of the IL23R gene (Arg381Gln), which is a subunit of the receptor of the pro-inflammatory cytokine interleukin-23, was found to be strongly associated with Crohn’s disease (Duerr et al.Science 2006). The exchange of arginine with glutamine at position 381 of IL23R causes a blockade of the IL-23 signaling pathway, which confers strong protection against Crohn’s disease. Because IL-23 activity is participated in autoimmune diseases, we hypothesized that it might also be important in the development of GVHD reaction post allogeneic transplantation.

Methods .Here we evaluated 401 patients with their donors for the occurrence of the IL23R gene variant (Arg381Gln, 1142 G>A) by real-time PCR who underwent allogeneic transplantation.

Results. We analyzed the IL23 gene variant 1142 G>A in a cohort of 221 transplant recipients and their HLA-identical sibling donors and in a second cohort of 186 transplant recipients and their HLA- identical unrelated donors. A heterozygous Arg381Gln gene variant was found in 13,1% of patients and in 11,3% of donors. The donor’s IL-23R genotype was significantly associated with a reduced risk of severe acute GVHD in both cohorts for patients after transplant. Analysis of all 407 transplant recipients showed that IL-23R (1142G>A, Arg381Gln) genotype of the donor were associated with a decreased risk of grade II-IV acute GVHD (31.6% compared to 51.0%, p=0.02) and severe acute GVHD III or IV (3.91% compared 23.4%, p=0.003). Death in remission was significantly lower in patients transplanted from donors with variante of IL23-R (11.7% versus 27.7%, p=0.028), whereas overall survival or relapse rates were not influenced significantly by the IL-23R genotype. The multivariate analysis including factors which influence the occurrence of severe acute GVHD as disease stage, age of patients (>or <40 years, gender constellation of recipient and donor, graft source, HLA-status (HLA-identical versus non-identical), donor constellation (sibling versus unrelated) confirmed that the gene variant of IL23R at the donor site confers protection against the occurrence of acute GVHD grade II-IV or severe acute GVHD grade III-IV. The association of IL23R mutation to GVHD was stronger than NOD2 mutations.

Conclusions. The results presented here suggest that IL-23 signaling pathway may play an important role in development of acute GVHD after transplant. Blockade of IL-23 signaling could be a rational therapeutic strategy for GVHD.