Abstract
Natural killer (NK) cells play a central role in the innate immune system. In allogeneic stem cell transplantation (alloSCT), alloreactive NK cells derived by the graft are discussed to mediate the elimination of leukemic cells and dendritic cells in the patient and thereby to reduce the risk for leukemic relapses and graft-versus-host reactions. The alloreactivity of NK cells is determined by various receptors including the activating CD94/NKG2C and the inhibitory CD94/NKG2A receptors, which both recognize the non-classical human leukocyte antigen E (HLA-E). Here we analyze the contribution of these receptors to NK cell alloreactivity in 26 patients over the course of the first year after alloSCT due to acute myeloid leukemia, myelodysplastic syndrome and T cell Non-Hodgkin-Lymphoma. Our results show that NK cells expressing the activating CD94/NKG2C receptor are significantly reduced in patients after alloSCT with severe acute and chronic graft-versus-host disease (GvHD). Moreover, the ratio of CD94/NKG2C to CD94/NKG2A was reduced in patients with severe acute and chronic GvHD after receiving an HLA-mismatched graft. Collectively, these results provide evidence for the first time that CD94/NKG2C is involved in GvHD prevention.
Highlights
Allogeneic hematopoietic stem cell transplantation can be an effective adoptive cellular immunotherapy for the treatment of otherwise incurable leukemia
Compared to 16 patients without or with only mild acute graft-versus-host disease (GvHD), the proportions of natural killer (NK) cells expressing the activating CD94/NKG2C receptor pair are significantly reduced in 10 patients experiencing severe aGvHD grade II–IV after Allogeneic hematopoietic stem cell transplantation (alloSCT) (p = 0.005)
For cGvHD, the proportions of CD94/NKG2A bearing NK cells are significantly reduced in patients suffering from extended cGvHD compared to patients with no or only mild cGvHD independently, whether the patients received a graft from an HLA-identical (p = 0.001) or HLA-mismatched donor (p = 0.0009)
Summary
Allogeneic hematopoietic stem cell transplantation (alloSCT) can be an effective adoptive cellular immunotherapy for the treatment of otherwise incurable leukemia. The limitations of alloSCT are graft-versus-host disease (GvHD), infections, and leukemia relapses. These adverse clinical outcomes crucially depend on the immune reconstitution in the host. In this context it is noteworthy that natural killer (NK) cells are the first donor-derived lymphocyte population that recovers after alloSCT [1]. Normal NK cell counts are generally observed within the first month after alloSCT regardless of the graft source, several months are required to acquire the immunophenotypic and functional characteristics of NK cells found in healthy donors. Reconstituting NK cells exhibit a more immature phenotype expressing the inhibitory natural killer group two A (NKG2A) receptor at around 90% compared to around 50% in healthy donors [2,3]. During the NK development and peripheral maturation, the CD56dim NK cells lose NKG2A expression but up-regulate the expression of the activating NKG2C receptor, killer cell inhibitory immunoglobulin-like receptors (KIRs) and CD57 [4,5]
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