Immunotherapy Destroys Activated Fibroblasts to Reduce Fibrosis

Researchers here report on an approach to treating fibrosis via vaccination to target distinctive molecular features of activated fibroblasts, the cells that generate the scar-like deposits of excess collagen that are characteristic of fibrosis. This scarring disrupts tissue structure and function. At the present time, there are no truly effective treatments for fibrosis in the clinic, and it is a problem characteristic of old age that affects numerous vital organs, such as heart, lungs, liver, and kidneys. Approaches that can efficiently reverse the progression of fibrosis are very much needed.

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 antigen-specific 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.


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