NK Cells Mediate Reduction of GVHD by Inhibiting Activated, Alloreactive T Cells While Retaining GVT Effects

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2010 Mar 18

PMID 20233969

Citations 195

Authors

Janelle A Olson

Dennis B Leveson-Gower

Saar Gill

Jeanette Baker

Andreas Beilhack

Robert S Negrin

Affiliations

Soon will be listed here.

Abstract

Natural killer (NK) cells suppress graft-versus-host disease (GVHD) without causing GVHD themselves. Our previous studies demonstrated that allogeneic T cells and NK cells traffic similarly after allogeneic bone marrow transplantation (BMT). We therefore investigated the impact of donor NK cells on donor alloreactive T cells in GVHD induction. Animals receiving donor NK and T cells showed improved survival and decreased GVHD score compared with controls receiving donor T cells alone. Donor T cells exhibited less proliferation, lower CD25 expression, and decreased interferon-gamma (IFN-gamma) production in the presence of NK cells. In vivo, we observed perforin- and Fas ligand (FasL)-mediated reduction of donor T cell proliferation and increased T cell apoptosis in the presence of NK cells. Further, activated NK cells mediated direct lysis of reisolated GVHD-inducing T cells in vitro. The graft-versus-tumor (GVT) effect was retained in the presence of donor NK cells. We demonstrate a novel mechanism of NK cell-mediated GVHD reduction whereby donor NK cells inhibit and lyse autologous donor T cells activated during the initiation of GVHD.

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References

Cerwenka A, Bakker A, McClanahan T, Wagner J, Wu J, Phillips J . Retinoic acid early inducible genes define a ligand family for the activating NKG2D receptor in mice. Immunity. 2000; 12(6):721-7. DOI: 10.1016/s1074-7613(00)80222-8. View

Nishimura R, Baker J, Beilhack A, Zeiser R, Olson J, Sega E . In vivo trafficking and survival of cytokine-induced killer cells resulting in minimal GVHD with retention of antitumor activity. Blood. 2008; 112(6):2563-74. PMC: 2532819. DOI: 10.1182/blood-2007-06-092817. View

Diefenbach A, Jamieson A, Liu S, Shastri N, Raulet D . Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages. Nat Immunol. 2001; 1(2):119-26. DOI: 10.1038/77793. View

Su H, Nguyen K, Salazar-Mather T, Ruzek M, Dalod M, Biron C . NK cell functions restrain T cell responses during viral infections. Eur J Immunol. 2001; 31(10):3048-55. DOI: 10.1002/1521-4141(2001010)31:10<3048::aid-immu3048>3.0.co;2-1. View

Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik W, Tosti A . Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002; 295(5562):2097-100. DOI: 10.1126/science.1068440. View

Carayannopoulos L, Naidenko O, Fremont D, Yokoyama W . Cutting edge: murine UL16-binding protein-like transcript 1: a newly described transcript encoding a high-affinity ligand for murine NKG2D. J Immunol. 2002; 169(8):4079-83. DOI: 10.4049/jimmunol.169.8.4079. View

Edinger M, Cao Y, Verneris M, Bachmann M, Contag C, Negrin R . Revealing lymphoma growth and the efficacy of immune cell therapies using in vivo bioluminescence imaging. Blood. 2002; 101(2):640-8. DOI: 10.1182/blood-2002-06-1751. View

Kim Y, Sachs T, Asavaroengchai W, Bronson R, Sykes M . Graft-versus-host disease can be separated from graft-versus-lymphoma effects by control of lymphocyte trafficking with FTY720. J Clin Invest. 2003; 111(5):659-69. PMC: 151899. DOI: 10.1172/JCI16950. View

Diefenbach A, Hsia J, Hsiung M, Raulet D . A novel ligand for the NKG2D receptor activates NK cells and macrophages and induces tumor immunity. Eur J Immunol. 2003; 33(2):381-91. DOI: 10.1002/immu.200310012. View

10.

Rabinovich B, Li J, Shannon J, Hurren R, Chalupny J, Cosman D . Activated, but not resting, T cells can be recognized and killed by syngeneic NK cells. J Immunol. 2003; 170(7):3572-6. DOI: 10.4049/jimmunol.170.7.3572. View

11.

Edinger M, Hoffmann P, Ermann J, Drago K, Fathman C, Strober S . CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med. 2003; 9(9):1144-50. DOI: 10.1038/nm915. View

12.

Cao Y, Wagers A, Beilhack A, Dusich J, Bachmann M, Negrin R . Shifting foci of hematopoiesis during reconstitution from single stem cells. Proc Natl Acad Sci U S A. 2003; 101(1):221-6. PMC: 314166. DOI: 10.1073/pnas.2637010100. View

13.

Reddy P . Pathophysiology of acute graft-versus-host disease. Hematol Oncol. 2004; 21(4):149-61. DOI: 10.1002/hon.716. View

14.

Yokoyama W, Kim S, French A . The dynamic life of natural killer cells. Annu Rev Immunol. 2004; 22:405-29. DOI: 10.1146/annurev.immunol.22.012703.104711. View

15.

Verneris M, Karimi M, Karami M, Baker J, Jayaswal A, Negrin R . Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells. Blood. 2004; 103(8):3065-72. DOI: 10.1182/blood-2003-06-2125. View

16.

Panoskaltsis-Mortari A, Price A, Hermanson J, Taras E, Lees C, Serody J . In vivo imaging of graft-versus-host-disease in mice. Blood. 2004; 103(9):3590-8. DOI: 10.1182/blood-2003-08-2827. View

17.

Mowat A . Antibodies to IFN-gamma prevent immunologically mediated intestinal damage in murine graft-versus-host reaction. Immunology. 1989; 68(1):18-23. PMC: 1385499. View

18.

Ferrara J, Deeg H . Graft-versus-host disease. N Engl J Med. 1991; 324(10):667-74. DOI: 10.1056/NEJM199103073241005. View

19.

Dickinson A, Sviland L, Dunn J, Carey P, Proctor S . Demonstration of direct involvement of cytokines in graft-versus-host reactions using an in vitro human skin explant model. Bone Marrow Transplant. 1991; 7(3):209-16. View

20.

Olson J, Zeiser R, Beilhack A, Goldman J, Negrin R . Tissue-specific homing and expansion of donor NK cells in allogeneic bone marrow transplantation. J Immunol. 2009; 183(5):3219-28. PMC: 2880476. DOI: 10.4049/jimmunol.0804268. View