Genetic variations in T-cell activation and effector pathways modulate alloimmune responses after allogeneic hematopoietic stem cell transplantation in patients with hematologic malignancies

Abstract

Background: Recently, several important polymorphisms have been identified in T-cell activation and effector pathway genes and have been reported to be associated with inter-patient variability in alloimmune responses. The present study was designed to assess the impact of these genetic variations on the outcomes of allogeneic hematopoietic stem cell transplantation.

Design and methods: We first investigated ten single nucleotide polymorphisms in six genes, CD28, inducible co-stimulator, cytotoxic T-lymphocyte antigen 4, granzyme B, Fas and Fas ligand, in 138 pairs of patients and their unrelated donors and a second cohort of 102 pairs of patients and their HLA-identical sibling donors.

Results: We observed that patients receiving stem cells from a donor with the cytotoxic T-lymphocyte antigen 4 gene CT60 variant allele (AA genotype) had a reduced incidence of grades II-IV acute graft-versus-host disease; however, they experienced early cytomegalovirus infection and relapsed more frequently, which suggested an interaction between the donor cytotoxic T-lymphocyte antigen 4 gene CT60 AA genotype and reduced T-cell alloreactivity. Furthermore, an unrelated donor with the granzyme B +55 variant genotype (AA) was an independent risk factor for development of grades II-IV acute graft-versus-host disease (P=0.024, RR=1.811). Among patients with acute myelogenous leukemia, those with the Fas -670 TT genotype were at higher risk of relapse (P=0.003, RR=3.823). The presence of these susceptible alleles in the donor and/or patient resulted in worse overall survival (54.9% versus 69.5%, P=0.029).

Conclusions: Our data suggest that genotype analysis of T-cell activation and effector pathway genes can be used for risk assessment for patients with hematologic malignancies before hematopoietic stem cell transplantation.

Figure 1.

The capacity for T-cell alloimmune reactivity stratified according to the donors' CTLA-4 CT60 genotype. Cumulative incidence of grades II to IV aGVHD (A), early CMV infection in the URD transplantation cohort (B), early CMV infection in the sibling transplantation cohort (C) and relapse in AML patients (D).

Figure 2.

Cumulative incidence of grades II to IV aGVHD stratified according to the donors' granzyme B +55 genotypes

Figure 3.

Cumulative incidence of relapse in AML patients stratified according to the patients' Fas -670 genotypes.

Figure 4.

Overall survival of patients stratified according to the donors' CTLA-4 CT60 genotype, donors' granzyme B +55 genotype and patients' Fas -670 genotype.