Mutant TIRAP Gene Polymorphism Is Associated with Outcomes in HLA Genoidentical Bone Marrow Transplants Recipients with Leukemia.
Authors: Rocha Vanderson , Porcher Raphael , Kabbara Nabil , de Latour Regis Peffault , Robin Marie , Chaves Wagnara , Rodrigues Celso A. , Bittencourt Henrique , Tavela Marli , Devergie Agnes , Ribaud Patricia , Gluckman Eliane , Socie Gerard , Zago Marco Antonio 
Published: October 2019

Abstract
Toll-like receptors (TLRs) and members of their signaling pathway are important in the initiation of the innate immune response to a wide variety of pathogens. The adaptor protein TIRAP, mediates downstream signaling of TLR2 and TLR4. A leucine (Leu) substitution at position 180 serine (Ser) of TIRAP was shown to protect from infections. We hypothesized that the incidence of infections and outcome after bone marrow transplantation (BMT) could be influenced by the TIRAP gene polymorphisms. Genotyping for TIRAP at Ser180 was performed in 107 donor/recipients pairs: 64% of recipients and 63% of donors were homozygote wild type (wt) Ser180/Ser180, 20% and 19% were Ser180/Leu180 and 17% and 18% Leu180/Leu180. Severe bacterial (pneumonia, septicemia and septic shock), viral or invasive fungal infections during 180 days after BMT, TRM (transplant related mortality), acute GVHD and survival were studied retrospectively. An allogeneic HLA-identical BMT was performed in 107 patients (median age was 35 years), with acute (n=39) or chronic Leukemia (n=68). Conditioning regimen consisted of Busulfan+Cyclophosphamide±others (BU-CY) in 73 (68%) patients and TBI+CY in 15 (14%) or TBI+Melphalan in 17 (16%). GVHD prophylaxis consisted of CsA+MTX in 94%. Median follow-up time was 77 months (18–147). Cumulative incidence of neutrophil recovery was 94%. Acute GVHD (II-IV) was observed in 42%, and chronic GVHD in 50 out of 98 at risk. Estimate 5-year survival was 54%. The cumulative incidence of any first infection by day 180 was 56%, being 28% for at least one bacterial infection, 39% for viral infection and 12% for invasive fungal infection (8 invasive aspergillosis, 4 disseminated candidiosis and 1 disseminated Malassezia furfur fungal infection). TRM cumulative incidence at 1 year was 35%. Recipient’s TIRAP gene polymorphisms were not associated with outcome. However, patients transplanted from a mutant TIRAP donor (Leu/Ser or Leu/Leu) had a trend to lower incidence of fungal infections (p=0.08); lower incidence of acute GVHD (p=0.03), decreased TRM (p=0.02) and improved overall survival (p=0.02). In a multivariate analysis, adjusting for other prognostic factors, TIRAP donor polymorphisms were associated with decreased TRM (HR=0.49, p=0.02): TRM at 1 year was 43% when donors were wt (Ser/Ser) as compared to 20% when donors were mutants. There was also a trend to decreased incidence of acute GVHD in patients with a mutant TIRAP donor as compared to the others (30% versus 49%; HR 1.88 p=0.06) and better overall survival (67% versus 44%, respectively HR 1.82; p=0.07). Recipients of bone marrow (BM) from wt TIRAP donors seemed to die more frequently from infection (1 yr cumulative incidence 21% vs 8%, p=0.07). In conclusion, the presence of a Leu substitution at position 180 in the TIRAP gene of BM donors decreases the incidence of TRM in HLA-identical BMT, probably reflecting better immune reconstitution and protection against infections. This finding can help defining better surveillance and prophylaxis of bacterial infections in BMT recipients from donors with the wt TIRAP (Ser/Ser) genotype.