Activating and inhibitory killer immunoglobulin-like receptors (KIR) in haploidentical haemopoietic stem cell transplantation to cure high-risk leukaemias

Abstract

A number of experimental studies have shown that natural killer (NK) cells can eliminate cancer cells and the mechanisms involved in this effect have been uncovered during the last two decades. Clinical data from haploidentical haematopoietic stem cell transplantation (haplo-HSCT) revealed that NK cells were responsible for remarkably favourable effects in both adult and paediatric high-risk leukaemias. NK receptors specific for major histocompatibility complex (MHC) class I molecules, including killer immunoglobulin (Ig)-like receptors (KIR) and CD94/NKG2A, play a major role in the anti-leukaemia effect (mediating either inhibitory or activating signals). Haplo- HSCT requires a heavy conditioning regimen for the patient and the use of large numbers of T cell-depleted HSC to be grafted. After transplantation, natural killer cells develop from HSC shortly after engraftment and may include 'alloreactive' NK cells that kill leukaemic cells and prevent graft-versus-host disease (GvHD). Alloreactive NK cells are characterized by the expression of KIR that are not engaged by any of the human leucocyte antigen (HLA) class I alleles expressed by the patient. Their generation is dependent upon the existence of a KIR/HLA class I mismatch between donor and recipient. Novel important information on the function and specificity of different KIR has been obtained recently by the analysis of donor-derived alloreactive NK cells in a cohort of paediatric patients given haplo-HSCT to cure acute, high-risk leukaemias.

Figures

Fig. 1

Alloreactivity against leukaemic targets is regulated by both inhibitory and activating killer immunoglobulin (Ig)-like receptors (KIRs). Alloreactive natural killer (NK) cells express KIR and lack CD94/NKG2A [that is specific for human leucocyte antigen (HLA)-E, a class Ib molecule expressed on virtually all HLA class I+ cells]. The most common alloreactivity is mediated by the C2-specific KIR2DL1+ NK cells [21,54], which kill leukaemic targets expressing the C1/C1 specificity (a). NK cells co-expressing [50] both the C2-specific KIRD2L1 and the C1-specific KIR2DL2/3 are not alloreactive (b). As expected, NK cells expressing KIR2DL2/3 [21] do not kill C1/C1+ leukaemias; however, they frequently also display poor cytotoxicity against C2/C2+ leukaemias (c). This has been explained by the recent finding [54,67] that KIR2DL2/3 recognize not only C1 (with high affinity) but also C2 (with low affinity). However, KIR2DL2/3+ NK cells can kill C2/C2+ leukaemias provided that they also express KIR2DS1 (d) or high levels of the natural cytotoxicity receptor (NCR) activating receptors (not shown). The group of C1 alleles include: HLA-Cw1, -Cw3, -Cw7, -Cw8, -Cw12, -Cw13, -Cw14 and -Cw16. The group of C2 alleles include: HLA-Cw2, -Cw4, -Cw5, -Cw6, -Cw15, Cw*-1602, -Cw17 and -Cw18.