Inhibition of EGFR Tyrosine Kinase by Erlotinib Prevents Sclerodermatous Graft-Versus-Host Disease in a Mouse Model.
Chronic graft-versus-host disease (GVHD) follows allogeneic hematopoietic stem cell transplantation. It results from alloreactive processes induced by minor histocompatibility antigen incompatibilities leading to the activation of CD4 T cells and the development of fibrosis and inflammation of the skin and visceral organs and autoimmunity that resemble systemic sclerosis. EGFR is a ubiquitous cell receptor deeply involved in cell proliferation, differentiation, and motility. EGFR has recently been implicated in autoimmune and fibrotic diseases. Therefore, we tested whether Erlotinib, an EGFR tyrosine kinase inhibitor, can prevent sclerodermatous GVHD (Scl-GVHD). Scl-GVHD was induced in BALB/c mice by B10.D2 bone marrow and spleen cell transplantation. Transplanted mice displayed severe clinical symptoms including alopecia, fibrosis of the skin and visceral organs, vasculitis, and diarrhea. The symptoms were reversed in mice treated with Erlotinib. These beneficial effects were mediated by the decreased production of activated/memory CD4(+) T cells and the reduction in T-cell infiltration of the skin and visceral organs along with a decrease in IFN-γ and IL-13 production and autoimmune B-cell activation. The improvement provided by Erlotinib in the mouse model of Scl-GVHD supplies a rationale for the evaluation of Erlotinib in the management of patients affected by chronic GVHD.
INSERM U 1016, Institut Cochin, Université Paris Descartes Sorbonne Paris Cité, Faculté de Médecine, Paris, France; Laboratoire d'Immunologie biologique, Hôpital Cochin, AP-HP, Paris, France.
Florence
F
Morin
INSERM U 1016, Institut Cochin, Université Paris Descartes Sorbonne Paris Cité, Faculté de Médecine, Paris, France; Laboratoire d'Immunologie biologique, Hôpital Cochin, AP-HP, Paris, France.
Niloufar
N
Kavian
INSERM U 1016, Institut Cochin, Université Paris Descartes Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
Wioleta
W
Marut
INSERM U 1016, Institut Cochin, Université Paris Descartes Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
Christiane
C
Chéreau
INSERM U 1016, Institut Cochin, Université Paris Descartes Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
Olivier
O
Cerles
INSERM U 1016, Institut Cochin, Université Paris Descartes Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
Philippe
P
Grange
INSERM U 1016, Institut Cochin, Université Paris Descartes Sorbonne Paris Cité, Faculté de Médecine, Paris, France; Laboratoire d'Immunologie biologique, Hôpital Cochin, AP-HP, Paris, France.
Bernard
B
Weill
INSERM U 1016, Institut Cochin, Université Paris Descartes Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
Carole
C
Nicco
INSERM U 1016, Institut Cochin, Université Paris Descartes Sorbonne Paris Cité, Faculté de Médecine, Paris, France; Laboratoire d'Immunologie biologique, Hôpital Cochin, AP-HP, Paris, France. Electronic address: frederic.batteux@cch.aphp.fr.
Frédéric
F
Batteux
D064591:Allografts; D000704:Analysis of Variance; D000818:Animals; D001707:Biopsy, Needle; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016133:Polymerase Chain Reaction / Q000379:methods; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011897:Random Allocation; D012016:Reference Values; D012594:Scleroderma, Localized / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*
D018793:Interleukin-13; D007371:Interferon-gamma; D000069347:Erlotinib Hydrochloride; D011505:Protein-Tyrosine Kinases