Trends in Immunology
Volume 23, Issue 9, 1 September 2002, Pages 438-444
Journal home page for Trends in Immunology

Opinion
NK cells: a lesson from mismatched hematopoietic transplantation

https://doi.org/10.1016/S1471-4906(02)02284-6Get rights and content

Abstract

The past ten years have witnessed dramatic progress in our understanding of how natural killer (NK) cells function, their role in innate defenses and their possible exploitation in therapy. This article traces the major advances in these formerly mysterious cells, from the ‘missing self’ hypothesis and the first discovery of HLA-class I-specific inhibitory receptors to a recent major breakthrough that highlighted important perspectives and major expectations regarding the cure of life-threatening leukemias. The key role of ‘alloreactive’ NK cells in eradicating acute myeloid leukemias and in preventing both graft rejection and graft-versus-host disease, might lead to a true revolution in bone marrow transplantation. Thus, it might now be possible to search for appropriate HLA class I mismatches to set NK cells in action.

Section snippets

NK cells recognize MHC molecules via inhibitory receptors

The molecular mechanisms that enable NK cells to lyze tumor cells while sparing normal cells were clarified only in recent years. First, an inverse correlation was established between the expression of surface MHC class I molecules on target cells and susceptibility to NK-cell-mediated lysis. This suggested that MHC molecules could exert a protective role, sparing normal cells from lysis. The lack of expression of self-MHC molecules, as can occur in virus-infected or tumor cells, would result

HLA class I mismatches, KIR repertoire and NK-mediated lysis of allogeneic cells

In an autologous setting, the NK-mediated lysis of self cells will occur only when self cells have lost HLA class I molecules 10., 16.. By contrast, NK cells can lyze allogeneic cells provided that these express HLA class I alleles that are not recognized by their NK inhibitory receptors. Because each KIR actually recognizes allotypic determinants that are shared by different HLA class I alleles (Table 1), an HLA-mismatch between NK cells and target cells does not necessarily lead to

NK-cell triggering and the activating NK receptors

NK-cell inactivation represents an important fail-safe mechanism to prevent the killing of normal MHC class I+ cells. As a corollary, an ‘on’ signal must be generated upon interaction of NK cells with potential target cells that is extinguished upon interaction of inhibitory receptors with MHC molecules. Such an ‘on’ signal is easily detectable whenever NK cells interact with target cells that lack MHC class I molecules. The receptors mediating NK-cell triggering in the process of natural

Haploidentical hematopoietic transplantation

Allogeneic hematopoietic transplantation might cure leukemia through two sequential mechanisms: (1) a myelo-ablative and immune suppressive radio- and/or chemotherapy-based conditioning regimen, and (2) T cells in the graft recognizing and eliminating residual leukemic cells that survive the conditioning regimen and cause relapse. Donor T cells react against host alloantigens that are expressed by normal lympho-hematopoietic and/or leukemic cells 30., 31.. As a consequence, they also mediate

Alloreactive NK cells prevent rather than cause GvHD

A relevant question arises: given such a powerful donor-versus-recipient immune reaction, why do NK cells not mediate severe GvHD? Experimental evidence suggested that NK cells predominantly attack the hematopoietic cells of the host while sparing other tissues that are common targets for T-cell-mediated GvHD. For example, in the hybrid resistance murine model, alloreactive NK cells cause rejection of BM grafts but do not appear to attack other tissues. Indeed, the hybrid mouse readily

Conclusions and future perspectives

The remarkable effects of NK-cell alloreactivity on the transplantation outcomes of AML patients deserve some comments. It is of note that most of our patients had undergone at least three complete remissions or were in relapse (with a probability of survival in five years time of 5% in the absence of NK cell alloreactivity). In the presence of donor-versus-recipient NK alloreactivity, the survival rate was as high as 60% [37]. Importantly, this survival rate is considerably higher than in

Acknowledgements

The authors thank G.A. Boyd for editing the manuscript. This work was supported by grants from: Associazione Italiana per la Ricerca sul Cancro; Fondazione Italiana per la Ricerca sul Cancro; Istituto Superiore di Sanità; Ministero della Salute; Ministero dell'Università e della Ricerca Scientifica e Tecnologica (MURST); MURST 5%–CNR Biotechnology program 95/95; Consiglio Nazionale delle Ricerche; Progetto Finalizzato Biotecnologie and Translational Research Grant from the Leukemia & Lymphoma

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