GVHD prevents NK-cell-dependent leukemia and virus-specific innate immunity

被引：31

作者：

Bunting, Mark D. ^{[1
]}

Varelias, Antiopi ^{[1
,2
]}

Souza-Fonseca-Guimaraes, Fernando ^{[3
,4
,5
,6
]}

Schuster, Iona S. ^{[7
,8
]}

Lineburg, Katie E. ^{[9
]}

Kuns, Rachel D. ^{[1
]}

Fleming, Peter ^{[7
,8
]}

Locke, Kelly R. ^{[1
]}

Huntington, Nicholas D. ^{[4
,5
]}

Blazar, Bruce R. ^{[10
,11
]}

Lane, Steven W. ^{[2
,12
,13
]}

Tey, Siok-Keen ^{[1
,2
,12
,13
]}

MacDonald, Kelli P. A. ^{[9
]}

Smyth, Mark J. ^{[2
,3
]}

Degli-Esposti, Mariapia A. ^{[7
,8
]}

Hill, Geoffrey R. ^{[1
,2
,13
]}

机构：

[1] Queensland Inst Med Res, Berghofer Med Res Inst, Dept Immunol, Bone Marrow Transplantat Lab, Brisbane, Qld, Australia

[2] Univ Queensland, Sch Med, Brisbane, Qld, Australia

[3] QIMR Berghofer Med Res Inst, Dept Immunol, Immunol Canc & Infect Lab, Brisbane, Qld, Australia

[4] Walter & Eliza Hall Inst Med Res, Mol Immunol Div, Parkville, Vic, Australia

[5] Univ Melbourne, Dept Med Biol, Melbourne, Vic, Australia

[6] Univ Melbourne, Fac Med Dent & Hlth Sci, Melbourne, Vic, Australia

[7] Univ Western Australia, Ctr Ophthalmol & Visual Sci, Immunol & Virol Program, Crawley, WA, Australia

[8] Lions Eye Inst, Ctr Expt Immunol, Nedlands, WA, Australia

[9] QIMR Berghofer Med Res Inst, Dept Immunol, Antigen Presentat & Immunoregulat Lab, Brisbane, Qld, Australia

[10] Univ Minnesota, Mason Canc Ctr, Minneapolis, MN USA

[11] Univ Minnesota, Dept Pediat, Div Blood & Marrow Transplantat, Minneapolis, MN USA

[12] QIMR Berghofer Med Res Inst, Dept Immunol, Gordon & Jessie Gilmour Leukemia Res Lab, Brisbane, Qld, Australia

[13] Royal Brisbane & Womens Hosp, Brisbane, Qld, Australia

来源：

BLOOD | 2017年 / 129卷 / 05期

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; ACUTE MYELOID-LEUKEMIA; RELAPSE RISK EVIDENCE; NATURAL-KILLER-CELLS; T-CELLS; DENDRITIC CELLS; GRAFT; CYTOMEGALOVIRUS; RECONSTITUTION;

D O I：

10.1182/blood-2016-08-734020

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Allogeneic bone marrow transplantation (allo-BMT) is a curative therapy for hematological malignancies, but is associated with significant complications, principally graftversus- host disease (GVHD) and opportunistic infections. Natural killer (NK) cells mediate important innate immunity that provides a temporal bridge until the reconstruction of adaptive immunity. Here, we show that the development of GVHD after allo-BMT prevented NK-cell reconstitution, particularly within the maturing M1 and M2 NK-cell subsets in association with exaggerated activation, apoptosis, and autophagy. Donor T cells were critical in this process by limiting the availability of interleukin 15 (IL-15), and administration of IL-15/IL-15Ra or immune suppression with rapamycin could restore NK-cell reconstitution. Importantly, the NK-cell defect induced by GVHD resulted in the failure of NK-cell-dependent in vivo cytotoxicity and graft-versus-leukemia effects. Control of cytomegalovirus infection after allo-BMT was also impaired during GVHD. Thus, during GVHD, donor T cells compete with NK cells for IL-15 thereby inducing profound defects in NK-cell reconstitution that compromise both leukemia and pathogen-specific immunity.

引用

页码：630 / 642

页数：13

共 59 条

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