Effect of IL-2-Bax, a novel interleukin-2-receptor-targeted chimeric protein, on bleomycin lung injury.
The role of lymphocytes in the pathogenesis of lung fibrosis is not clear, but the weight of the evidence supports a pro-fibrotic effect for lymphocytes. The high-affinity interleukin-2 receptor (haIL-2R) is expressed on activated, but not quiescent, T lymphocytes. This selective expression of haIL-2R provides the basis for therapeutic strategies that target IL-2R-expressing cells. We hypothesized that elimination of activated lymphocytes by IL-2R-targeted chimeric proteins might ameliorate lung fibrosis. We investigated the effects of IL-2-Bax, a novel apoptosis-inducing IL-2R-targeted chimeric protein, on bleomycin-induced lung injury in mice. Treatment groups included (i) a single intratracheal instillation of bleomycin and twice-daily intraperitoneal injections of IL-2-Bax; (ii) intratracheal bleomycin and intraperitoneal IL-2-PE66(4Glu), an older-generation chimeric protein; (iii) intratracheal bleomycin/intraperitoneal PBS; (iv) intratracheal saline/intraperitoneal PBS. Lung injury was evaluated 14 days after intratracheal instillation by cell count in bronchoalveolar lavage (BAL) fluid, semi-quantitative and quantitative histomorphological measurements and by biochemical analysis of lung hydroxyproline. Bleomycin induced a BAL lymphocytosis that was significantly attenuated by IL-2-Bax and IL-2-PE66(4Glu). However, morphometric parameters and lung hydroxyproline were unaffected by the chimeric proteins. These results show that IL-2-Bax reduces the lymphocytic infiltration of the lungs in response to bleomycin, but this effect is not accompanied by a decrease in lung fibrosis.
Segel
Michael J
MJ
Lung Cellular and Molecular Biology Laboratory, Institute of Pulmonology, Hadassah University Hospital and Hebrew University, Hadassah Medical School, Jerusalem, Israel. msegel@tufts-nemc.org
Aqeilan
Rami
R
Zilka
Keren
K
Lorberboum-Galski
Haya
H
Wallach-Dayan
Shulamit B
SB
Conner
Michael W
MW
Christensen
Thomas G
TG
Breuer
Raphael
R
D000818:Animals; D017209:Apoptosis; D001427:Bacterial Toxins / Q000235:genetics; D001761:Bleomycin; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002452:Cell Count; D005818:Genetic Engineering; D006909:Hydroxyproline / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D007167:Immunotherapy / Q000379:methods; D007376:Interleukin-2 / Q000235:genetics*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D011658:Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*
D001427:Bacterial Toxins; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D001761:Bleomycin; D006909:Hydroxyproline