Impact of HLA-G 14-bp polymorphism in sibling related hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is a standard curative therapy offered to patients with various malignant and non-malignant disorders. Post-transplant outcome is influenced by infections, graft-vs-host disease and conditioning related toxicity. Since GvHD is the most common cause of morbidity and mortality in HSCT recipients, identifying biomarkers for prediction of GvHD is important to improve transplant outcomes. Non-classical human leukocyte antigen (HLA) class I molecule, HLA-G has been identified as a key mediator of tolerance. Analogically, this molecule could be implicated in the immunomodulation of various diseases and in transplantation. The 3′untranslated region(3′UTR), particularly the 14-bp insertion/deletion polymorphismin exon 8, influences the HLA-G expression. Presence of 14 bpinduces alternate splicing and decreased production of sHLA-G which influences allograft acceptance in allotransplantation. This study was performed on 29 recipients who underwent HLA-identical sibling HSCT at our centre and 90 ethnically matched healthy controls. The 14-bp polymorphism in the exon 8 – 3′UTRof the HLA-G gene and serum soluble HLA-G levels (pre-transplant and post-transplant day 30, day 60 and at time of GvHD) were evaluated. Allo-activation status and regulatory T cell (Treg) frequency was assessed at the time points mentioned above. Of the 29 recipients, 27.6% patients manifested GvHD (n=8), four each had acute GvHD and chronic GvHD. A comparison of HLA-G 14-bp allele polymorphism revealed presence of insertion (+14 bp) in higher percentage of recipients(57%vs50.6% in controls) and+14 bp allele was also more fre-quent in the cohort that developed GvHD in comparison to those that did not develop GvHD (62.5%vs54%). Genotype analysis revealed presence of+/+14 bp genotype in 36% recipients,whereas only 26% controls carried this genotype. Nearly 48%of controls were 14-bp heterozygous (−/+). Among the recipients carrying−/−14-bp genotype, which leads to high sHLA-Glevels, the majority did not develop GvHD (87.5%). It is likely that higher sHLA-G levels may have influenced the alloreactiv-ity and inhibited manifestation of GvHD. In addition, solubleHLA-G levels correlated with the 14-bp polymorphism and were decreased in patients at the time of GvHD compared with their pre-transplant levels. Treg frequency was also decreased at thetime of GvHD. Our preliminary findings indicate that HLA-G might have influenced the outcome of HSCT in our study cohort and studies on larger cohorts may be more informative to under-stand if HLA-G can serve as an important predictor of transplant outcome.