title: Cellular and molecular basis of haploidentical hematopoietic stem cell transplantation in the successful treatment of high-risk leukemias: role of alloreactive NK cells.
abstract: Natural killer (NK) cells are involved in innate immune responses and play a major role in tumor surveillance and in defense against viruses. Human NK cells recognize human leukocyte antigen (HLA) class I molecules via surface receptors [killer immunoglobulin-like receptor (KIR) and NKG2A] delivering signals that inhibit NK cell function and kill HLA class I-deficient target cells, a frequent event in tumors or virus-infected cells. NK cell triggering is mediated by activating receptors that recognize ligands expressed primarily on tumors or virus-infected cells. NK cells play also a key role in the cure of high-risk leukemias. Thus, donor-derived "alloreactive" NK cells are fundamental effectors in adult acute myeloid leukemia and in pediatric acute lymphoblastic leukemia patients undergoing haploidentical hematopoietic stem cell transplantation (HSCT). Alloreactive NK cells mediate killing of leukemia cells and patient's dendritic cell, thus preventing respectively leukemic relapses and graft-vs-host responses. Cytofluorimetric analysis of KIRs expressed by NK cells allows to define the size of the alloreactive NK subset and the selection of the best potential donor. Recently, it has been shown that also the expression of activating KIRs, in particular the (C2-specific) KIR2DS1, may contribute to donor NK alloreactivity. It has also been established a correlation between the size of the alloreactive NK cell population and the clinical outcome. Notably, the alloreactive NK cells derived from donor's hematopoietic stem cells are generated and persist in patients over time. The high survival rates of patients undergoing haploidentical HSCT highlight an important new reality in the setting of allograft performed to cure otherwise fatal leukemias. Novel approaches are in progress to further improve the clinical outcome based on the infusion of donor alloreactive NK cells either as a component of the transplanted cell population or as in vitro expanded NK cells.
authors: Department of Pediatric Hematology/Oncology, Istituto Di Ricovero e Cura a Carattere Scientifico, Ospedale Pediatrico Bambino Gesù Rome, Italy ; Università di Pavia Pavia, Italy.
authors: Franco
authors: F
authors: Locatelli
authors: Daniela
authors: D
authors: Pende
authors: Maria C
authors: MC
authors: Mingari
authors: Alice
authors: A
authors: Bertaina
authors: Michela
authors: M
authors: Falco
authors: Alessandro
authors: A
authors: Moretta
authors: Lorenzo
authors: L
authors: Moretta
keywords: NK alloreactivity; acute lymphoblastic leukemia; acute myeloid leukemia; graft-vs-host disease; haploidentical hemopoietic stem cell transplantation; killer Ig-like receptors; natural killer cells
references: Blood. 2008 Aug 1;112(3):708-10
references: 18502829
references: Blood. 2009 Mar 26;113(13):3119-29
references: 18945967
references: Adv Immunol. 1994;55:341-80
references: 7508176
references: J Exp Med. 1997 Dec 1;186(11):1809-18
references: 9382880
references: Eur J Immunol. 2001 Jan;31(1):233-42
references: 11265639
references: Blood. 2012 Mar 15;119(11):2665-74
references: 22180440
references: J Clin Oncol. 2010 Feb 20;28(6):955-9
references: 20085940
references: Immunol Rev. 2008 Aug;224:58-69
references: 18759920
references: Nat Immunol. 2006 Dec;7(12):1334-42
references: 17057721
references: Biol Blood Marrow Transplant. 2010 Apr;16(4):533-42
references: 19961944
references: J Exp Med. 2003 Aug 18;198(4):557-67
references: 12913096
references: J Immunol. 2001 Aug 15;167(4):1877-81
references: 11489965
references: Nat Genet. 2002 Aug;31(4):429-34
references: 12134147
references: Science. 1999 Jul 30;285(5428):730-2
references: 10426994
references: J Exp Med. 1998 Sep 7;188(5):953-60
references: 9730896
references: Blood. 2011 Jan 20;117(3):764-71
references: 20889923
references: EMBO J. 2004 Jan 28;23(2):255-9
references: 14685277
references: N Engl J Med. 2006 Apr 27;354(17):1813-26
references: 16641398
references: Blood. 2009 Sep 24;114(13):2667-77
references: 19553639
references: J Exp Med. 1999 Mar 1;189(5):787-96
references: 10049942
references: J Immunol. 1997 Jun 1;158(11):5237-41
references: 9164941
references: J Exp Med. 2001 Aug 6;194(3):235-46
references: 11489943
references: Bone Marrow Transplant. 2008 Jan;41(2):207-14
references: 18084331
references: J Exp Med. 2009 Jul 6;206(7):1495-503
references: 19528259
references: Int J Cancer Suppl. 1992;7:6-10
references: 1428407
references: Nat Rev Immunol. 2003 Oct;3(10):781-90
references: 14523385
references: Blood. 2010 Oct 7;116(14):2411-9
references: 20581313
references: Blood. 2004 Dec 1;104(12):3664-71
references: 15304389
references: Blood. 2012 Jan 12;119(2):399-410
references: 22096237
references: Annu Rev Immunol. 1996;14:619-48
references: 8717527
references: Science. 1995 Apr 21;268(5209):405-8
references: 7716543
references: Annu Rev Immunol. 2002;20:197-216
references: 11861602
references: Semin Hematol. 2002 Jan;39(1):48-56
references: 11799529
references: J Immunol. 2007 Jul 15;179(2):854-68
references: 17617576
references: Semin Immunol. 2000 Apr;12(2):109-19
references: 10764619
references: Cytotherapy. 2007;9(8):746-54
references: 17917892
references: Nat Med. 1995 Dec;1(12):1268-73
references: 7489407
references: Blood. 1994 Dec 1;84(11):3948-55
references: 7524753
references: N Engl J Med. 1998 Oct 22;339(17):1186-93
references: 9780338
references: Immunol Today. 1999 Aug;20(8):343-7
references: 10431152
references: J Exp Med. 1993 Oct 1;178(4):1397-406
references: 8376943
references: Blood. 2002 May 15;99(10):3661-7
references: 11986221
references: Science. 2002 Mar 15;295(5562):2097-100
references: 11896281
references: Science. 1999 Jul 16;285(5426):412-5
references: 10411505
references: J Exp Med. 1993 Aug 1;178(2):597-604
references: 8340759
references: Adv Immunol. 1987;41:333-445
references: 2891262
references: J Exp Med. 1992 Oct 1;176(4):963-71
references: 1328466
references: Immunity. 1995 May;2(5):439-49
references: 7749980
references: J Exp Med. 2009 Oct 26;206(11):2557-72
references: 19858347
references: Adv Immunol. 1989;47:187-376
references: 2683611
references: Clin Immunol. 2009 Nov;133(2):171-8
references: 19481979
references: J Exp Med. 2004 May 17;199(10):1331-41
references: 15136589
references: Annu Rev Immunol. 1999;17:875-904
references: 10358776
references: J Exp Med. 1998 Jun 15;187(12):2065-72
references: 9625766
references: J Exp Med. 1990 Dec 1;172(6):1589-98
references: 2147946
references: Immunity. 1997 Aug;7(2):273-82
references: 9285411
references: Eur J Immunol. 1994 Apr;24(4):1003-6
references: 8149950
references: J Exp Med. 1992 Mar 1;175(3):709-18
references: 1371301
references: Immunity. 1996 Jun;4(6):573-81
references: 8673704
references: Blood. 2008 Oct 15;112(8):3488-99
references: 18645039
references: Lancet. 2003 Feb 15;361(9357):553-60
references: 12598139
references: Blood. 2005 Mar 1;105(5):2066-73
references: 15536144
references: J Clin Invest. 1998 May 1;101(9):1835-42
references: 9576746
references: J Immunol. 2008 Mar 15;180(6):3969-79
references: 18322206
references: Semin Immunol. 2006 Jun;18(3):151-8
references: 16730454
references: J Immunol. 1996 May 1;156(9):3098-101
references: 8617928
references: Blood. 2005 Apr 15;105(8):3051-7
references: 15632206
references: Semin Oncol. 2012 Dec;39(6):664-73
references: 23206843
references: Blood. 1983 Feb;61(2):341-8
references: 6217853
references: J Exp Med. 1996 Aug 1;184(2):505-18
references: 8760804
references: Biol Blood Marrow Transplant. 2006 Aug;12(8):808-12
references: 16864050
references: Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3384-9
references: 17360655
references: J Exp Med. 1995 Sep 1;182(3):875-84
references: 7650491
references: Blood. 1990 Feb 1;75(3):555-62
references: 2297567
references: J Exp Med. 1997 Oct 6;186(7):1129-36
references: 9314561
references: J Immunol. 2004 Jan 1;172(1):644-50
references: 14688377
references: J Exp Med. 1995 Aug 1;182(2):605-9
references: 7629517
references: J Exp Med. 1990 Mar 1;171(3):695-714
references: 2137855
references: Blood. 2005 May 15;105(10):4135-42
references: 15687235
references: Annu Rev Immunol. 1998;16:359-93
references: 9597134
references: Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13224-9
references: 16141329
references: J Exp Med. 1999 Nov 15;190(10):1505-16
references: 10562324