Vaccination-based immunotherapy to target profibrotic cells in liver and lung

Fibrosis is the final path of nearly every form of chronic disease, regardless of the pathogenesis. Upon chronic injury, activated, fibrogenic fibroblasts deposit excess extracellular matrix, and severe tissue fibrosis can occur in virtually any organ. However, antifibrotic therapies that target fibrogenic cells, while sparing ho-meostatic fibroblasts in healthy tissues, are limited. We tested whether specific immunization against endog-enous proteins, strongly expressed in fibrogenic cells but highly restricted in quiescent fibroblasts, can elicit an antigen-specific cytotoxic T cell response to ameliorate organ fibrosis. In silico epitope prediction re-vealed that activation of the genes Adam12 and Gli1 in profibrotic cells and the resulting "self-peptides"can be exploited for T cell vaccines to ablate fibrogenic cells. We demonstrate the efficacy of a vaccination approach to mount CD8+ T cell responses that reduce fibroblasts and fibrosis in the liver and lungs in mice. These results provide proof of principle for vaccination-based immunotherapies to treat fibrosis.

Comprehens Canc Ctr Zurich
Univ Hosp Zurich
Medical University of South Carolina
Hop Europeen Georges Pompidou
Inst Stem Cell Sci & Regenerat Med InStem
Eidgenössische Technische Hochschule Zürich
Institut National de la Sante et de la Recherche Medicale (INSERM)
Veterinärmedizinische Universität Wien
Universität Zürich
Jichi Medical University
Department of Biotechnology (DBT) India
Inst Mol Canc Res
Swiss Federal Institutes of Technology Domain
Assistance Publique Hopitaux Paris (APHP)