A Recessive Gene Variant in TGFB1 in the Donor Influences the Acute Graft Versus Host Disease Development and Impacts in the Outcome After Allogeneic Stem Cell Transplantation (Allo-SCT),
Authors: Martin-Antonio Beatriz , Romero Damià , Espigado Ildefonso , Gallardo David , Bosch Anna , Buno Ismael , Martinez-Laperche Carolina , Jimenz-Velasco Antonio , De La Camara Rafael , Brunet Salut , Nieto Jose B , Román Jose , Suarez-LLedo Maria , Fernandez-Avilés Francesc , Martinez Carmen , Rovira Montserrat , Urbano-Ispizua Alvaro 
Published: October 2019

Abstract
Abstract 4080
After allogeneic stem cell transplantation (allo-SCT) inflammatory cytokines and other innate immune proteins interact leading to a differentiation of donor lymphocytes which will increase the inflammatory response initiating the acute graft versus host disease (aGvHD). In this cytokine storm, TGF-β is a pleiotropic cytokine with dual roles presenting beneficial and detrimental effects after allo-SCT. Depending on its interaction with other cytokines, TGF-β will inhibit differentiation of Th1 cells and cytotoxic T lymphocytes (CTLs), and will promote expansion and maintenance of T-reg cells lowering the development of aGvHD, or it will activate Th17 lymphocyte differentiation increasing aGvHD development. Previously, we found that a recessive gene variant (AA) in TGFB1 in the promoter region was associated with higher incidence of aGVHD when present in the donor in a cohort of 99 adult donor-patients pairs who underwent HLA identical sibling allo-SCT. We aimed to validate this previous association in a multicentre study consisting of 490 adults donor-patients pairs who underwent HLA identical sibling allo-SCT. All patients were diagnosed with hematological malignancies. Median age was 45 (range, 16–69), 33% were in advanced phase of disease, and 38% received a reduced intensity conditioning regimen. Association results showed that recessive AA gene variant in TGFB1 when present either in the donor or in the patient, or in both, was associated with higher aGvHD grades III-IV (19% vs 11%, p=0.039; and 22% vs 12%, p=0.049; and 22% vs 12%, p=0.04, respectively). This variant in the donor also impacted in a higher transplant related mortality (42% vs 27%, p=0.019), influencing in both, a lower disease free survival (33% vs 44%, p=0.03, OR=1.5, p=0.03) and lower overall survival (43% vs 52%, p=0.011, OR=1.4, p=0.049). Further, we performed functional studies in 180 blood donors analyzing the expression of Th1/Th2 cytokines after phytohemagglutinin (PHA) and cytomegalovirus exposure to find out if the presence of this variant influenced in the inflammatory response. We found that recessive AA gene variant in TGFB1 was associated with higher IFNγ production (1265 pg/mL vs 1365 pg/mL vs 1471 pg/mL, p=0.02, respectively, for GG dominant variant, GA heterozygous variant, and AA recessive variant). Finally, we performed real time PCR at basal levels in blood donors to find out if this variant was associated with a differential expression of TGFB1, and we observed a non significant reduction of the expression in the recessive AA variant compared to the dominant GG variant. It is well known that increased IFNγ serum levels are associated with the severity of aGVHD and that IFNγ is crucial during the development of aGvHD initiating the proinflammatory response. These results indicate the importance of genetic variability in the cells of the donor in TGFB1 in the development of GvHD and the possible role of this variant in the IFNγ production. The knowledge of this variant in the donor might help to the prevention of aGvHD after allo-SCT.

Disclosures:
No relevant conflicts of interest to declare.