IFNgamma differentially controls the development of idiopathic pneumonia syndrome and GVHD of the gastrointestinal tract.
Although proinflammatory cytokines are key mediators of tissue damage during graft-versus-host disease (GVHD), IFNgamma has previously been attributed with both protective and pathogenic effects. We have resolved this paradox by using wild-type (wt), IFNgamma(-/-), and IFNgammaR(-/-) mice as donors or recipients in well-described models of allogeneic stem cell transplantation (SCT). We show that donor-derived IFNgamma augments acute GVHD via direct effects on (1) the donor T cell to promote T helper 1 (Th1) differentiation and (2) the gastrointestinal (GI) tract to augment inflammatory cytokine generation. However, these detrimental effects are overwhelmed by a protective role of IFNgamma in preventing the development of idiopathic pneumonia syndrome (IPS). This is the result of direct effects on pulmonary parenchyma to prevent donor cell migration and expansion within the lung. Thus, IFNgamma is the key cytokine differentially controlling the development of IPS and gastrointestinal GVHD after allogeneic SCT.
Burman
Angela C
AC
Queensland Institute of Medical Research, 300 Herston Road, Herston, QLD 4006, Australia.
Banovic
Tatjana
T
Kuns
Rachel D
RD
Clouston
Andrew D
AD
Stanley
Amanda C
AC
Morris
Edward S
ES
Rowe
Vanessa
V
Bofinger
Helen
H
Skoczylas
Renae
R
Raffelt
Neil
N
Fahy
Olivier
O
McColl
Shaun R
SR
Engwerda
Christian R
CR
McDonald
Kelli P A
KP
Hill
Geoffrey R
GR
D000208:Acute Disease; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D005260:Female; D005767:Gastrointestinal Diseases / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D041981:Gastrointestinal Tract / Q000276:immunology / Q000473:pathology; D006086:Graft vs Host Disease / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007371:Interferon-gamma / Q000172:deficiency / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011014:Pneumonia / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D033581:Stem Cell Transplantation; D013577:Syndrome; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D014184:Transplantation, Homologous
D007371:Interferon-gamma