TLR9 but Not NOD2/CARD15 Gene Polymorphism Influence Outcome in AML-Patients Transplanted From HLA-Identical Sibling Donors.

We evaluated in a homogenous group of 101 AML-patients after non-T-cell depleted, myeloablative transplantation from HLA-identical sibling donors the role of gene polymorphism of TLR1, TLR4,TLR9, IL23R, and NOD2 on the outcome of transplant. TLR9 and NOD2 are part of the innate immune system, which are able to recognize and bind to the so-called pathogen-associated molecular patterns (PAMPs) from invading pathogens. They induce a rapid innate immune response to microbial invaders and thereby also an activation of the adoptive immune system. TLR9 is activated by DNA containing unmethylated CpG motifs and produces potent Th1-type innate and adaptive immune responses. NOD2 was reported to influence the outcome of transplant.

Here we evaluated the genotype of 101 AML-patients with their donors for the occurrence of the TLR1, TLR4 (A1063G and C1363T), TLR9 (T1237C and T1486C), IL23R (G1142A) and NOD2 by real-time PCR who underwent allogeneic transplantation.

Gene variants of the NOD2 gene at patients and donors side were observed in 8.8% of the patients. The CC gene variant of TLR9 -1486 occurred in 19.1% of patients.

In our retrospective analyzed study we found that the TLR9 gene variant was the only polymorphism that influenced the outcome of transplant. The estimate for 5-year overall survival (OS) in patients with the CC gene variant of TLR9 at (T1486C) was 74.6% ± 11.1% compared to 45.2% ± 6.0% (p<0.01) in patients with TC/TT of TLR9 gene variants. No influence on 5-year OS was seen for gene polymorphisms of NOD2 or IL23R in this study group. Patients with TLR9 CC gene variant at 1486 or NOD2 gene variants (at recipient and donor side) had a lower rate of leukemic relapse at 5-year post transplant 24.6% ±10.4% versus 44.4 ± 6.6% for TLR9 [p<0.10], and 25% ± 15.3% versus 39.7% ± 7.7% NS). 5-year TRM was lowest in patients with CC gene variant of TLR9 with 7.7% versus 23.7%. Surprisingly also patients with NOD2 gene variant at donor and recipient side hade a reduced 5-year TRM compared to patients with wild-type of NOD2. Acute GVHD grade 2-4 was higher (although not significant) in patients with NOD2 gene variants (recipient and donor side) with 57.1% versus 39.3%. In contrast to NOD2, patients with the gene variant of TLR9 had a no difference in the incidence of acute GVHD grade 2-4 with 22.8% versus 33.1% demonstrating that the lower estimate for relapse risk in patient with TLR9 gene variant was not associated with increased GVHD.

The results presented here suggest that the CC gene variant of TLR at 1483 is a strong marker for outcome of transplant, whereas NOD2 gene variants had no influence on the overall survival. The role of NOD2 in transplant must be further evaluated. The gene variant of TLR9 might be helpful in patients planning a transplant as a prognostic positive factor.

No relevant conflicts of interest to declare.