Nuclear factor-kappaB inducing kinase is required for graft-versus-host disease.
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.
Sánchez-Valdepeñas
Carmen
C
Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid, Madrid, Spain.
Casanova
Lucía
L
Colmenero
Isabel
I
Arriero
Mar
M
González
Africa
A
Lozano
Nieves
N
González-Vicent
Marta
M
Díaz
Miguel A
MA
Madero
Luís
L
Fresno
Manuel
M
Ramírez
Manuel
M
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
D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase
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