Therapeutic targeting of CC ligand 21 or CC chemokine receptor 7 abrogates pulmonary fibrosis induced by the adoptive transfer of human pulmonary fibroblasts to immunodeficient mice.
Idiopathic interstitial pneumonias (IIPs) are a collection of pulmonary fibrotic diseases of unknown etiopathogenesis. CC chemokine receptor 7 (CCR7) is expressed in IIP biopsies and primary fibroblast lines, but its role in pulmonary fibrosis was not previously examined. To study the in vivo role of CCR7 in a novel model of pulmonary fibrosis, 1.0 x 10(6) primary fibroblasts grown from idiopathic pulmonary fibrosis/usual interstitial pneumonia, nonspecific interstitial pneumonia, or histologically normal biopsies were injected intravenously into C.B-17 severe combined immunodeficiency (SCID)/beige (bg) mice. At days 35 and 63 after idiopathic pulmonary fibrosis/usual interstitial pneumonia fibroblast injection, patchy interstitial fibrosis and increased hydroxyproline were present in the lungs of immunodeficient mice. Adoptively transferred nonspecific interstitial pneumonia fibroblasts caused a more diffuse interstitial fibrosis and increased hydroxyproline levels at both times, but injected normal human fibroblasts did not induce interstitial remodeling changes in C.B-17SCID/bg mice. Systemic therapeutic immunoneutralization of either human CCR7 or CC ligand 21, its ligand, significantly attenuated the pulmonary fibrosis in groups of C.B-17SCID/bg mice that received either type of IIP fibroblasts. Thus, the present study demonstrates that pulmonary fibrosis is initiated by the intravenous introduction of primary human fibroblast lines into immunodeficient mice, and this fibrotic response is dependent on the interaction between CC ligand 21 and CCR7.
Pierce
Elizabeth M
EM
Associate Professor, Immunology Program, Department of Pathology, University of Michigan Medical School, Room 4057, BSRB, 109 Zina Pitcher Pl., Ann Arbor, MI 48109-0602, USA.
Carpenter
Kristin
K
Jakubzick
Claudia
C
Kunkel
Steven L
SL
Flaherty
Kevin R
KR
Martinez
Fernando J
FJ
Hogaboam
Cory M
CM
D019264:Adoptive Transfer / Q000009:adverse effects* / Q000379:methods; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D007275:Injections, Intravenous; D018793:Interleukin-13 / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D016133:Polymerase Chain Reaction; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D000911:Antibodies, Monoclonal; C515478:CCL21 protein, human; C515370:CCR7 protein, human; C515479:Ccl21c protein, mouse; C515371:Ccr7 protein, mouse; D054421:Chemokine CCL21; D019742:Chemokines, CC; D016207:Cytokines; D016326:Extracellular Matrix Proteins; D018793:Interleukin-13; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; C070959:Ccl6 protein, mouse; D006909:Hydroxyproline