Since integrin-b-6 is only strongly upregulated at 4½ months after radiation exposure, "a tempting question to ask was what would happen if we blocked TGF-b and integrin-b-6 only during a short period before the onset of fibrosis," Dr. Cheng commented.
To test this hypothesis, the team used two approaches to block TGF-b signaling: an anti-integrin-b-6 monoclonal antibody (6.3G9, Biogen Idec) and a soluble TGF-b type 2 receptor, which sequesters active TGF-b.Irradiated wild-type mice were injected with a control antibody, with the anti-integrin antibody 6.3G9 (0.3, 1, or 10 mg/kg per week), or with the soluble receptor, starting 16 weeks after radiation.
At 26 weeks, the control mice had marked fibrosis; fibrosis in mice treated with the anti-integrin antibody was reduced in a dose-dependent manner, and fibrosis in mice treated with the soluble receptor was lower as well.
"Taken together, these findings suggest that inhibiting late TGF-b signaling can prevent the formation of radiation-induced fibrosis," Dr. Cheng said.
The investigators next evaluated the safety of TGF-b inhibition. "One concern about inhibiting TGF-b is that the total, complete loss of TGF-b function and integrin-b-6 function can cause lymphocytic inflammmation in the lung," Dr. Cheng explained.
To assess this outcome, broncho-alveolar lavage was performed in treated mice at 28 weeks to measure lymphocytes and neutrophils.Results showed that the 10-mg dose of the anti-integrin-b-6 antibody was associated with lymphocytic inflammation, but the 1-mg dose and the soluble receptor were not.
No survival increase