NKG2D gene polymorphism has a significant impact on transplant outcomes after HLA-fully-matched unrelated bone marrow transplantation for standard risk hematologic malignancies

Abstract

BackgroundNKG2D, an activating and co-stimulatory receptor expressed on natural killer cells and T cells, plays pivotal roles in immunity to microbial infections as well as in cancer immunosurveillance. This study examined the impact of donor and recipient polymorphisms in the NKG2D gene on the clinical outcomes of patients undergoing allogeneic T-cell-replete myeloablative bone marrow transplantation using an HLA-matched unrelated donor. Design and MethodsThe NKG2D polymorphism was retrospectively analyzed in a total 145 recipients with hematologic malignancies and their unrelated donors. The patients underwent transplantation following myeloablative conditioning; the recipients and donors were matched through the Japan Marrow Donor Program. ResultsIn patients with standard-risk disease, the donor NKG2D-HNK1 haplotype, a haplotype expected to induce greater natural killer cell activity, was associated with significantly improved overall survival (adjusted hazard ratio, 0.44; 95% confidence interval, 0.23 to 0.85; p=0.01) as well as transplant related mortality (adjusted hazard ratio, 0.42; 95% confidence interval, 0.21 to 0.86; p=0.02), but had no impact on disease relapse or the development of grade II-IV acute graft-versus-host disease or chronic graft-versus-host disease. The NKG2D polymorphism did not significantly influence the transplant outcomes in patients with high-risk disease. ConclusionsThese data suggest an association between the donor HNK1 haplotype and better clinical outcome among recipients, with standard-risk disease, of bone marrow transplants from HLA-matched unrelated donors.

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

“…Current evidence suggests that in addition to HLA matching, genetic diversity among donors and recipients, including cytokine genes, innate immunity genes and pharmacogenetic polymorphisms, affect the success of transplantation by regulating alloimmune responses. [2][3][4][5] Optimal donor T lymphocyte proliferation, differentiation and acquisition of effector functions play a critical role in alloimmune reactivity, and their ability to detect non-self-antigens can lead to GVHD or contribute to the prevention of relapse and infections after transplantation. CD28, inducible co-stimulator (ICOS) and cytotoxic Tlymphocyte antigen 4 (CTLA-4) belong to the same family of T-cell co-stimulatory molecules.…”

A single nucleotide polymorphism of IL-17 gene in the recipient is associated with acute GVHD after HLA-matched unrelated BMT

“…2 Previous investigations have revealed that several single-nucleotide polymorphisms (SNPs), which impact on individual immune response to infections and inflammatory reactions are associated with SCT outcomes including the risk of acute GVHD. [3][4][5][6][7][8][9][10][11][12] IL-17, also known as IL-17A, is the hallmark cytokine of a new T-helper subset termed Th17. [13][14][15][16] gdT cells, macrophages and neutrophils are sources of IL-17 as well.…”

A single-nucleotide polymorphism of the Fcγ receptor type IIIA gene in the recipient predicts transplant outcomes after HLA fully matched unrelated BMT for myeloid malignancies

“…2 Previous investigations have revealed that several single-nucleotide polymorphisms (SNPs) that effect individual immune response to infections and inflammatory reactions are associated with transplant outcomes. [3][4][5][6][7][8][9] Fcg receptor type IIIA (FCGR3A), a low-affinity receptor capable of interaction with complexed or monomeric IgG, is expressed on neutrophils, eosinophils, natural killer cells, macrophages, monocytes, DC, gd-positive T cells and keratinocytes. [10][11][12][13] FCGR3A mediates Ab-dependent cell-mediated cytotoxicity, phagocytosis, cytokine production and regulation of Ig production.…”