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J. Exp. Med.,
Volume 189, Number 12, June 21, 1999 1855-1862
By
From the Divisions of * Hematology and Clinical Immunology and This study investigated the role of natural killer (NK) cells as effectors of an immune response
against autologous cells modified by gene therapy. T lymphocytes were transduced with
LXSN, a retroviral vector adopted for human gene therapy that carries the selectable marker
gene neo, and the autologous NK response was evaluated. We found that (i) infection with
LXSN makes cells susceptible to autologous NK cell-mediated lysis; (ii) expression of the neo
gene is responsible for conferring susceptibility to lysis; (iii) lysis of neo-expressing cells is
clonally distributed and mediated only by NK clones that exhibit human histocompatibility leukocyte antigen (HLA)-Bw4 specificity and bear KIR3DL1, a Bw4-specific NK inhibitory
receptor; and (iv) the targets are cells from HLA-Bw4+ individuals. Finally, neo peptides anchoring to the Bw4 allele HLA-B27 interfered with KIR3DL1-mediated recognition of HLA-B27, i.e., they triggered NK lysis. Moreover, neo gene mutations preventing translation of two
of the four potentially nonprotective peptides reduced KIR3DL1+ NK clone-mediated autologous lysis. Thus, individuals expressing Bw4 alleles possess an NK repertoire with the potential to eliminate autologous cells modified by gene therapy. By demonstrating that NK cells can
selectively detect the expression of heterologous genes, these observations provide a general
model of the NK cell-mediated control of viral infections.
Internal Medicine and Oncological
Sciences, Department of Clinical and Experimental Medicine, University of Perugia, 06100 Perugia, Italy
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