Genetics of allogeneic hematopoietic cell transplantation. Role of HLA matching, functional variation in immune response genes

Abstract

Successful outcome following hematopoietic stem cell transplantation (HSCT) is ultimately determined by the ability to achieve sustained engraftment and immune reconstitution, control of graft-versus-host disease (GVHD), and in patients with hematological malignancy the complete eradication of abnormal or malignant cells. GVHD, which can be a serious and fatal complication, is an immune reaction that is initiated by donor T cells in response to recipient alloantigens. Genetic variation in both patient and donor can significantly affect transplant outcome by causing disparity for transplant antigens, and by altering the function of immune response genes that control cellular activation and inflammation. Genetic variation can modulate the intensity of the alloimmune response, the risk of transplant-related organ toxicity and mortality, and may also affect the development of tolerance and the reconstitution of the immune system following HSCT.

Impact of highly conserved HLA haplotype on acute graft-versus-host disease

“…Genetic variants of tumor necrosis factor-␣ gene located in the HLA region might influence the risk of developing GVHD. 27,28 In addition, TAP1/TAP2 and LMP2/ LMP7 genes encode subunit components of the proteasomes implicated in the processing of class I HLA-bound peptides, 29,30 and polymorphisms of these genes may affect antigen presentation on recipient tissues, leading to different susceptibility to GVHD. However, they probably do not explain the observed effects of haplotypes; correlations of each haplotype with known SNPs in these genes are generally weak, although DЈ among these alleles is high (Ͼ 0.98).…”

Glutathione transferase-A2 S112T polymorphism predicts survival, transplant-related mortality, busulfan and bilirubin blood levels after allogeneic stem cell transplantation

“…3,4 Much attention has been paid to the relationship between genetic variation at innate immunity loci and GVHD. 5 Until now, studies on genetic polymorphisms on HSCT have generated contrasting data, likely due to insufficient sample size, selection biases, patient and treatment heterogeneity. 2 Hematopoietic stem cell transplantation is a systemic stress: the achievement of a favorable HSCT outcome is achieved via the successful functioning of multiple stress response systems, and is likely to be affected by genetic variability over a large array of loci.…”

Single nucleotide polymorphisms and outcome risk in unrelated mismatched hematopoietic stem cell transplantation: an exploration study

“…It is thought that a large proportion of risk for adverse outcomes after hematopoietic stem cell transplantation (HSCT) is genetic, attributed to HLA matching, 1 killer-immunoglobulin-like receptor matching, 2,3 minor histocompatibility antigens, 4,5 and non-HLA gene polymorphisms. 6 Whereas the degree of HLA mismatching exerts the strongest genetic effect on risks, such as acute and chronic GVHD, relapse, and survival, non-HLA polymorphisms in immune response genes, such as cytokines, at least modify these risks, as shown in studies that have shown light on the pathobiology of HSCT, 7,8 and the relation of cytokine gene polymorphisms, 6,9,10 with gene expression and biologic effects.…”