NK cells in allogeneic bone marrow transplantation

Abstract

NK cells, until recently an ignored subset of lymphocytes, have begun to emerge as important cytotoxic effectors. It is now accepted that NK cells together with T cells constitute major actors in graft-versus-leukemia reaction after allogeneic bone marrow transplantation (BMT). Over the last several years the mechanisms regulating the activation of NK cells have been the subject of intense investigations encouraged by the clinical implications that these studies will have. This article provides a general overview of NK-cells biology and regulation pertinent to their function in allogeneic BMT, followed by a review of the in vivo preclinical and clinical evidence for the beneficial effect of NK cells in the adoptive immunotherapy of leukemia.

Fig. 1A–C.

Schematic general mechanism of NK cell lysis. NK cells do not lyse cells that coexpress sufficient levels of inhibitory ligands in addition to activatory ligands (A) or cells not expressing activatory ligands (B). They do lyse targets that have down-regulated or absent ligands for inhibitory receptors (C) or have up-regulated ligands for activatory receptors (for example, the stress-related molecules MICA and MICB) (D). Blocks denote inhibitory receptor/ligand pairs and pointing blocks activatory receptor/ligand pairs

Fig. 2.

Upon HLA-C ligation, KIR receptors auto-phosphorylate their cytoplasmic ITIMs (represented as a diamond in CD58) which become docking sites for SHP-1 and -2. These phosphatases dephosphorylate and inhibit Syk and ZAP-70 kinases

Fig. 3.

After HLA-E ligation, CD94/NKG2A ITIMs (represented as a diamond in NKG2A) are phosphorylated and recognized by SHP1 and 2 which then dephosphorylate activatory kinases

Fig. 4.

Activation of NKp46 leads to the activation of syk and ZAP-70 kinases through their recruitment by the phosphorylated ITAM sequences of CD3ζ and FcεRIγ. (Here ITAM sequences are represented as a diamond in CD3ζ.)