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Regulation of the NK Cell Alloreactivity to Bone Marrow Cells by the Combination of the Host NK Gene Complex and MHC Haplotypes¹

Koho Iizuka^2,*, Anthony A. Scalzo^,, Hong Xian^* and Wayne M. Yokoyama^*,

^* Department of Medicine, Rheumatology Division and Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110; and Immunology and Virology Program, Centre for Ophthalmology and Visual Science, University of Western Australia and Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, Australia

Host NK cells can reject MHC-incompatible (allogeneic) bone marrow cells (BMCs), suggesting their effective role for graft-vs leukemia effects in the clinical setting of bone marrow transplantation. NK cell-mediated rejection of allogeneic BMCs is dependent on donor and recipient MHC alleles and other factors that are not yet fully characterized. Whereas the molecular mechanisms of allogeneic MHC recognition by NK receptors have been well studied in vitro, guidelines to understand NK cell allogeneic reactivity under the control of multiple genetic components in vivo remain less well understood. In this study, we use congenic mice to show that BMC rejection is regulated by haplotypes of the NK gene complex (NKC) that encodes multiple NK cell receptors. Most importantly, host MHC differences modulated the NKC effect. Moreover, the NKC allelic differences also affected the outcome of hybrid resistance whereby F₁ hybrid mice reject parental BMCs. Therefore, these data indicate that NK cell alloreactivity in vivo is dependent on the combination of the host NKC and MHC haplotypes. These data suggest that the NK cell self-tolerance process dynamically modulates the NK cell alloreactivity in vivo.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health (to W.M.Y.). K.I. was supported by a fellowship from the Eastern Missouri Chapter of the Arthritis Foundation. W.M.Y. is an investigator of the Howard Hughes Medical Institute. A.A.S. was supported by a National Health and Medical Research Council Senior Research Fellowship.

² Address correspondence to Dr. Koho Iizuka at the current address, Department of Medicine, Center for Immunology and Cancer Center, University of Minnesota, Minneapolis, MN 55455. E-mail address: iizuk001{at}umn.edu

³ Abbreviations used in this paper; BMC, bone marrow cell; β₂m, β₂-microglobulin; BMT, bone marrow transplantation; BM, bone marrow; NKC, NK gene complex; ASGM, asialo GM1 Ab.