title: Combined inhibition of c-Abl and PDGF receptors for prevention and treatment of murine sclerodermatous chronic graft-versus-host disease.
abstract: Chronic graft-versus-host disease (cGvHD) is a common complication of allogeneic bone marrow transplantation, and has a major effect on the long-term prognosis. The molecular mechanisms underlying cGvHD have been only partially revealed, and molecular targeted therapies have not yet been established for clinical use. We examined the effects of the combined inhibition of the Abelson kinase (c-Abl) and platelet-derived growth factor receptors (PDGFR) in experimental sclerodermatous cGvHD. Treatment using imatinib or nilotinib abolished the aberrant activation of c-Abl and PDGFR and protected against experimental cGvHD. Preventive therapy using imatinib or nilotinib inhibited the development of sclerodermatous cGvHD. Clinical features such as weight loss, alopecia, and skin ulcers, and histologic features with dermal thickening and accumulation of collagen were significantly reduced in mice that received imatinib or nilotinib therapy, but not in mice that received prednisone therapy. Of note, imatinib and nilotinib were also effective for treatment of experimental cGvHD that had already been clinically manifested. In summary, the combined inhibition of c-Abl and PDGFR is effective for prevention and treatment of experimental sclerodermatous cGvHD. Considering the high morbidity associated with cGvHD, the lack of efficient molecular therapies for clinical use, and first positive signals from uncontrolled studies of imatinib, combined inhibition of c-Abl and PDGFR might be a promising future strategy for treatment of sclerodermatous cGvHD.
authors.affiliation: Department of Internal Medicine III, University of Erlangen-Nuremberg, Germany.
authors.forename: Pawel
authors.initials: P
authors.lastname: Zerr
authors.forename: Alfiya
authors.initials: A
authors.lastname: Distler
authors.forename: Katrin
authors.initials: K
authors.lastname: Palumbo-Zerr
authors.forename: Michal
authors.initials: M
authors.lastname: Tomcik
authors.forename: Stefan
authors.initials: S
authors.lastname: Vollath
authors.forename: Clara
authors.initials: C
authors.lastname: Dees
authors.forename: Friederike
authors.initials: F
authors.lastname: Egberts
authors.forename: Ilaria
authors.initials: I
authors.lastname: Tinazzi
authors.forename: Francesco
authors.initials: F
authors.lastname: Del Galdo
authors.forename: Oliver
authors.initials: O
authors.lastname: Distler
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Bernd M
authors.initials: BM
authors.lastname: Spriewald
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
mesh_terms: D000818:Animals; D001549:Benzamides; D002908:Chronic Disease; D020405:Dermis / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D005355:Fibrosis; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor; D016315:Proto-Oncogene Proteins c-abl; C498826:nilotinib