KGF pretreatment decreases B7 and granzyme B expression and hastens repair in lungs of mice after allogeneic BMT.
We investigated keratinocyte growth factor (KGF) as a pretreatment therapy for idiopathic pneumonia syndrome (IPS) generated as a result of lung damage and allogeneic T cell-dependent inflammatory events occurring in the early peri-bone marrow (BM) transplant (BMT) period. B10.BR (H2(k)) recipient mice were transplanted with C57BL/6 (H2(b)) BM with spleen cells after lethal irradiation with and without cyclophosphamide conditioning with and without subcutaneous KGF pretreatment. KGF-pretreated mice had fewer injured alveolar type II (ATII) cells at the time of BMT and exhibited ATII cell hyperplasia at day 3 post-BMT. The composition of infiltrating cells on day 7 post-BMT was not altered by KGF pretreatment, but the frequencies of cells expressing the T-cell costimulatory molecules B7.1 and B7.2 and mRNA for the cytolysin granzyme B (usually increased in IPS) were decreased by KGF. Sera from KGF-treated mice had increases in the Th2 cytokines interleukin (IL)-4, IL-6, and IL-13 4 days after cessation of KGF administration (i.e., at the time of BMT). These data suggest that KGF hinders IPS by two modes: 1) stimulation of alveolar epithelialization and 2) attenuation of immune-mediated injury as a consequence of failure to upregulate cytolytic molecules and B7 ligand expression and the induction of anti-inflammatory Th2 cytokines in situ.
Panoskaltsis-Mortari
A
A
Department of Pediatrics, Division of Hematology-Oncology and Bone Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota 55455, USA. panos001@tc.umn.edu
Ingbar
D H
DH
Jung
P
P
Haddad
I Y
IY
Bitterman
P B
PB
Wangensteen
O D
OD
Farrell
C L
CL
Lacey
D L
DL
Blazar
B R
BR
D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D018122:B7-1 Antigen / Q000235:genetics*; D051940:B7-2 Antigen; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology*; D051526:Fibroblast Growth Factor 10; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D015870:Gene Expression / Q000276:immunology; D053804:Granzymes; D006133:Growth Substances / Q000494:pharmacology*; D006967:Hypersensitivity / Q000276:immunology; D017403:In Situ Hybridization; D018793:Interleukin-13 / Q000097:blood / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000097:blood / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D009000:Monocytes / Q000276:immunology; D011014:Pneumonia / Q000209:etiology / Q000276:immunology; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000276:immunology* / Q000648:ultrastructure; D012333:RNA, Messenger / Q000032:analysis; D012697:Serine Endopeptidases / Q000235:genetics*; D018418:Th2 Cells / Q000276:immunology; D019172:Transplantation Conditioning
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; C496454:Fgf7 protein, mouse; D051526:Fibroblast Growth Factor 10; D006133:Growth Substances; D018793:Interleukin-13; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D051523:Fibroblast Growth Factor 7; D015847:Interleukin-4; D005346:Fibroblast Growth Factors; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases