Cytokine Gene Polymorphisms and Severe Acute Graft-Versus-Host Disease (grade ≥II) After Allogeneic Hematopoietic Stem Cell Transplantation From HLA Identical Siblings
Authors: Dubois Valérie , Sobh Mohamad , Morisset Stéphane , Labussière-Wallet Hélène , Detrait Marie Y. , Rey Sylvie , Mollet Isabelle , Ducastelle Sophie , Barraco Fiorenza , Chelghoum Youcef , Thomas Xavier , Nicolini Franck E. , Michallet Mauricette 
Published: October 2019

Abstract
Abstract 4180
Graft-versus-host disease (GvHD) is one of the most important complications after allogeneic hematopoietic stem cell transplantation (HSCT) and influences morbidity and mortality, even when the donor is a human leucocyte antigen (HLA)-matched sibling. Polymorphisms at genes coding for several proinflammatorycytokines and for their related receptors or receptor inhibitors are involved in this complication.
To assess the role of cytokine gene polymorphisms on acute GvHD (aGVHD), we analysed 189 pairs of donor and recipients transplanted from HLA identical sibling for malignant hematological diseases between 2000 and 2007, using a non T depleted graft after a myeloablativeor a reduced intensity conditioning regimen.

Material and methods:
The median age of the recipients at transplantation was 43.4 years (1–68). Two third of the patients received bone marrow before myelo-ablative conditioning regimen and the median delay between diagnosis and transplantation was 9 months (1–76).
Five different polymorphisms from 3 cytokine genes were analyzed: IL-10 –592C/A, -819C/T and -1082G/A, IL-1b -511A/G and TGFb1 –509C/T.
All the pairs were studied for each gene polymorphism using the Taqman technology as previously described (Malkki2007). Each kit contains several primers pairs for amplification and two allele-specific probes, each of them conjugated with a different fluorescent marker. After amplification, analysis was driven on a Roche LC480 platform. The interpretation of the final results was performed using allelic discrimination specific software.
In our study, the frequencies of the TGFb1, IL1b, and IL-10 genotypes in recipients and donors were almost equal, and were consistent with previously reported results for the Caucasoid population and with the NCBI SNP databases.

Results:
Univariate analysis found a significant negative impact of donor genotypes carrying IL1b A allele (p=0,02) or IL10–592 A allele (p=0,03) on aGvHD.
We did not find any effect associated with IL10–819 and -1082 polymorphisms, but as previously described (Lin 2003), the presence of IL10 A-T-A haplotype in the donor, significantly increased the risk of aGVHD (p=0.043). We performed a multivariate analysis on aGVHD incidence taking into account TGFb1–509, IL-10–592 and IL1bpolymorphisms, together with other known risk factors.
A higher incidence of aGVHD was found in pairs where donor has an IL1b A allele (HR 4,16 - p=0,0031) and increased when the donor is A/A (HR>15 – p=0,0091). For IL10–592, the impact of the A allele was found different when carried by the donor (higher risk of aGVHD, HR 3,52 – p=0,00083) or the recipient (lower risk of aGVHD, HR 0,48 – p=0,024), but this effect seems only significant in pairs where donor did not carry any A allele (rec AC × don CC – HR 0.2 – p=0.05). Donor with TGFb1–509 T allele was found to have a significant lower risk of aGVHD (HR 0,42 – p=0,02). (table 1).
The role of the cytokine cascade in the physiopathology of GVHD is well established. Our study documents the possible role of IL-1b, TGFb1and IL10 gene polymorphisms in this setting.
A proven association of cytokine gene polymorphisms with acute GVHD would enable the clinician to modify the therapeutic strategy and enhance the outcomes.

Disclosures:
Nicolini: Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.