title: Nuclear factor-kappaB inducing kinase is required for graft-versus-host disease.
abstract: BACKGROUND
  Donor T lymphocytes are directly responsible for graft-versus-host disease. Molecules important in T-cell function may, therefore, be appropriate targets for graft-versus-host disease therapy and/or prophylaxis. Here we analyzed whether nuclear factor-κ B inducing kinase might have a role in graft-versus-host disease.
  
  
  METHODS
  We studied the expression of nuclear factor-κ B inducing kinase in human samples from patients with graft-versus-host disease. We also explored the effect of nuclear factor-κ B inducing kinase in a murine model of graft-versus-host disease using donor cells from aly/aly mice (deficient in nuclear factor-κ B inducing kinase) and C57BL/6 mice (control).
  
  
  RESULTS
  We detected expression of nuclear factor-κ B inducing kinase in T-lymphocytes in the pathological lesions of patients with acute graft-versus-host disease. Mice transplanted with aly/aly T lymphocytes did not develop graft-versus-host disease at all, while mice receiving C57BL/6 cells died of a lethal form of the disease. Deficiency of nuclear factor-κ B inducing kinase did not affect the engrafting ability of donor T cells, but severely impaired their expansion capacity early after transplantation, and aly/aly T cells showed a higher proportion of apoptosis than did C57BL/6 T cells. Effector T lymphocytes were the T-cell subset most affected by nuclear factor-κ B inducing kinase deficiency. We also detected lower amounts of inflammatory cytokines in the serum of mice receiving aly/aly T cells than in the serum of mice receiving C57BL/6 T cells.
  
  
  CONCLUSIONS
  Our results show that nuclear factor-κ B inducing kinase has a role in graft-versus-host disease by maintaining the viability of activated alloreactive T lymphocytes.
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Sánchez-Valdepeñas
authors.forename: Lucía
authors.initials: L
authors.lastname: Casanova
authors.forename: Isabel
authors.initials: I
authors.lastname: Colmenero
authors.forename: Mar
authors.initials: M
authors.lastname: Arriero
authors.forename: Africa
authors.initials: A
authors.lastname: González
authors.forename: Nieves
authors.initials: N
authors.lastname: Lozano
authors.forename: Marta
authors.initials: M
authors.lastname: González-Vicent
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Díaz
authors.forename: Luís
authors.initials: L
authors.lastname: Madero
authors.forename: Manuel
authors.initials: M
authors.lastname: Fresno
authors.forename: Manuel
authors.initials: M
authors.lastname: Ramírez
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D003106:Colon / Q000201:enzymology / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000201:enzymology / Q000473:pathology; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D014184:Transplantation, Homologous; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase
references.citation: Blood. 2008 Sep 1;112(5):2101-10
references.pmid: 18596226
references.citation: Blood. 2005 Aug 1;106(3):1113-22
references.pmid: 15855275
references.citation: J Exp Med. 1999 Apr 5;189(7):1073-81
references.pmid: 10190898
references.citation: J Immunol. 2000 Aug 15;165(4):1743-54
references.pmid: 10925251
references.citation: Blood. 2007 May 15;109(10):4119-26
references.pmid: 17234737
references.citation: Immunol Rev. 2003 Jun;193:70-81
references.pmid: 12752672
references.citation: Curr Opin Immunol. 2002 Jun;14(3):354-9
references.pmid: 11973134
references.citation: Blood. 2007 Apr 1;109(7):3115-23
references.pmid: 17148592
references.citation: J Exp Med. 2000 May 1;191(9):1477-86
references.pmid: 10790423
references.citation: J Immunol. 2006 Apr 15;176(8):4666-74
references.pmid: 16585559
references.citation: J Clin Invest. 2005 Jul;115(7):1848-54
references.pmid: 15937549
references.citation: Mol Med Today. 2000 Nov;6(11):441-8
references.pmid: 11074370
references.citation: Nat Rev Immunol. 2007 Jul;7(7):532-42
references.pmid: 17589543
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3503-8
references.pmid: 18292232
references.citation: J Clin Invest. 2001 Jan;107(1):7-11
references.pmid: 11134171
references.citation: J Immunol. 2006 Feb 15;176(4):2183-9
references.pmid: 16455974
references.citation: Lancet. 2009 May 2;373(9674):1550-61
references.pmid: 19282026
references.citation: J Immunol. 2003 Sep 15;171(6):2930-6
references.pmid: 12960316
references.citation: Cancer Cell. 2007 Aug;12(2):131-44
references.pmid: 17692805
references.citation: Semin Hematol. 1999 Oct;36(4 Suppl 7):95-103
references.pmid: 10595758
references.citation: Bone Marrow Transplant. 2005 Jun;35(12):1179-86
references.pmid: 15852028
references.citation: Blood. 2009 Jun 25;113(26):6603-10
references.pmid: 19411637
references.citation: J Immunol. 2002 Aug 1;169(3):1151-8
references.pmid: 12133934
references.citation: Nature. 2006 Jun 15;441(7095):890-3
references.pmid: 16778891
references.citation: Immunity. 2003 Mar;18(3):331-42
references.pmid: 12648451
references.citation: Blood. 2006 Jan 15;107(2):827-34
references.pmid: 16174760
references.citation: Bioessays. 2003 Aug;25(8):767-80
references.pmid: 12879447
references.citation: J Immunol. 2004 Feb 15;172(4):2194-200
references.pmid: 14764686
references.citation: Blood. 2008 May 15;111(10):5118-29
references.pmid: 18305221
references.citation: J Exp Med. 2003 Jun 16;197(12):1623-33
references.pmid: 12810685
references.citation: Nat Rev Immunol. 2007 May;7(5):340-52
references.pmid: 17438575
references.citation: Annu Rev Immunol. 2004;22:765-87
references.pmid: 15032596
references.citation: J Immunol. 2005 Aug 1;175(3):1651-7
references.pmid: 16034105
references.citation: J Clin Invest. 2001 Jan;107(2):135-42
references.pmid: 11160126
references.citation: Crit Rev Oncol Hematol. 2008 Apr;66(1):52-64
references.pmid: 18289867
references.citation: EMBO J. 2005 Dec 21;24(24):4279-90
references.pmid: 16341093
references.citation: J Clin Invest. 2003 Jul;112(1):101-8
references.pmid: 12840064
references.citation: Nat Rev Immunol. 2002 Oct;2(10):725-34
references.pmid: 12360211
references.citation: Cancer Cell. 2007 Aug;12(2):115-30
references.pmid: 17692804
references.citation: Nat Immunol. 2006 Jul;7(7):763-72
references.pmid: 16732290
references.citation: Curr Opin Immunol. 1995 Jun;7(3):333-42
references.pmid: 7546397
references.citation: Biochem Pharmacol. 2006 Oct 30;72(9):1161-79
references.pmid: 16970925
references.citation: Biol Blood Marrow Transplant. 2010 Feb;16(2):170-8
references.pmid: 19804837