Antitransforming growth factor-beta antibody 1D11 ameliorates normal tissue damage caused by high-dose radiation.
OBJECTIVE
The aim of this study was to determine whether a neutralizing transforming growth factor-beta (TGFbeta) antibody can prevent radiation (RT) induced lung injury.


METHODS
Fractionated and sham right lung irradiation in Fischer 344 rats was delivered to assess the radioprotective effect of the antibodies. Animals were divided into the following groups: (1) control (sham RT, control antibody 13C4); (2) RT (800cGy x 5)+13C4); (3) RT + 0.1 mg/kg 1D11 anti-TGFbeta antibody; and (4) RT + 1 mg/kg 1D11 antibody. Antibodies were intraperitoneally administered immediately after the last fraction of RT. Animals were sacrificed at 6 and 26 weeks after irradiation. Lungs were assessed for histologic changes, activation of macrophages, expression/activation of TGFbeta and its signal transduction pathway.


RESULTS
At 6 weeks post-RT, there was a significant reduction in macrophage accumulation (p = 0.041), alveolar wall thickness (p = 0.0003), and TGF-beta activation (p = 0.032) in animals receiving 1.0 mg/kg 1D11 vs. in the control group. However, at 6 weeks, the low dose of 1D11 antibody (0.1 mg/kg) failed to produce any significant changes. At 6 months post-RT, radioprotection is apparent for the group receiving 1.0 mg/kg 1D11, with activated macrophages (p = 0.037), alveolar wall thickness (p = 0.0002), TGFbeta activation (p = 0.002) and its signal transduction proteins (p < 0.05) compared with the control group.


CONCLUSIONS
Administration of a single dose of 1.0 mg/kg of the anti-TGFbeta antibody 1D11 resulted in decreased morphologic changes, inflammatory response, and reduced expression and activation of TGFbeta 6 weeks and 6 months after 40 Gy to the right hemithorax. Targeting the TGFbeta pathway may be a useful strategy to prevent radiation-induced lung injury.
Anscher
Mitchell S
MS
Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA. ansch001@notes.duke.edu
Thrasher
Bradley
B
Rabbani
Zahid
Z
Teicher
Beverly
B
Vujaskovic
Zeljko
Z
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D005260:Female; D008168:Lung / Q000528:radiation effects*; D011829:Radiation Dosage; D011833:Radiation Injuries, Experimental / Q000517:prevention & control*; D017564:Radiation Pneumonitis / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology* / Q000378:metabolism
D000906:Antibodies; D011837:Radiation-Protective Agents; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D016212:Transforming Growth Factor beta