Vaccination-based immunotherapy to target profibrotic cells in liver and lung
Michal Sobecki, Jing Chen, Ewelina Krzywińska, Shunmugam Nagarajan, Fan Zheng, Eric Nelius, Josep M. Monné Rodríguez, Frauke Seehusen, Amro Hussein, Greta Moschini, Edries Yousaf Hajam, Ravi Kiran, Dagmar Gotthardt, Julien Debbache, Cécile Badoual, Tatsuyuki Sato, Takayuki Isagawa, Norihiko Takeda, Corinne Tanchot, Éric Tartour, Achim Weber, Sabine Werner, Johannes Loffing, Lukas Sommer, Veronika Sexl, Christian Münz, Carol Feghali‐Bostwick, Elena Pachera, Oliver Distler, Jess G. Snedeker, Colin Jamora, Christian Stockmann
Abstract
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 homeostatic fibroblasts in healthy tissues, are limited. We tested whether specific immunization against endogenous proteins, strongly expressed in fibrogenic cells but highly restricted in quiescent fibroblasts, can elicit an antigenspecific cytotoxic T cell response to ameliorate organ fibrosis. In silico epitope prediction revealed 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.