FK778 and tacrolimus prevent the development of obliterative airway disease after heterotopic rat tracheal transplantation.
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FK778 and tacrolimus prevent the development of obliterative airway disease after heterotopic rat tracheal transplantation. / Deuse, Tobias; Schrepfer, Sonja; Koch-Nolte, Friedrich; Haddad, Munif; Schwedhelm, Edzard; Böger, Rainer; Schäfer, Hansjörg; Detter, Christian; Reichenspurner, Hermann.
in: J HEART LUNG TRANSPL, Jahrgang 24, Nr. 11, 11, 2005, S. 1844-1854.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - FK778 and tacrolimus prevent the development of obliterative airway disease after heterotopic rat tracheal transplantation.
AU - Deuse, Tobias
AU - Schrepfer, Sonja
AU - Koch-Nolte, Friedrich
AU - Haddad, Munif
AU - Schwedhelm, Edzard
AU - Böger, Rainer
AU - Schäfer, Hansjörg
AU - Detter, Christian
AU - Reichenspurner, Hermann
PY - 2005
Y1 - 2005
N2 - BACKGROUND: The effectiveness of the novel immunosuppressive agent FK778 and of tacrolimus to prevent the development of obliterative airway disease (OAD) was investigated in an animal model. METHODS: Tracheae from Brown-Norway donors were heterotopically transplanted in the greater omentum of Lewis rats. Recipients were treated for 28 days with FK778 (5 or 20 mg/kg), tacrolimus (1 or 4 mg/kg) or combination regimens at varying doses (5 + 1 mg/kg, 10 + 2 mg/kg or 20 + 4 mg/kg). Grafts were harvested and processed for histologic and immunohistochemical evaluation. Lymphocyte surface antigen expression was quantified and in vitro smooth muscle cell (SMC) proliferation assays were performed. RESULTS: In untreated recipients, very large amounts of infiltrating CD4+, CD8+ and ED1+ mononuclear cells were observed in the peritracheal region with epithelial loss and complete luminal obliteration. Granulation tissue consisted of alpha-actin-positive cells and collagen-rich fibrosis. FK778 and tacrolimus as well as combination regimens of both agents dose-dependently inhibited peritracheal infiltration and luminal obliteration. Only tacrolimus-treated recipients showed preserved luminal epithelial coverage with airway goblet cells, whereas, in animals that received FK778, no epithelium was found. Both agents equally suppressed in vivo lymphocyte CD25 expression. Only FK778-treated animals were completely free of adverse drug side effects. FK778 but not tacrolimus showed potent anti-proliferative effects on SMC in vitro. CONCLUSIONS: Although both agents proved effective to prevent OAD development, histology revealed major differences. The anti-proliferative potency of FK778 on SMC may be an important mechanism of action. Combination regimens showed favorable drug interaction and allowed dose reduction of both agents to achieve maximal immunosuppressive efficacy.
AB - BACKGROUND: The effectiveness of the novel immunosuppressive agent FK778 and of tacrolimus to prevent the development of obliterative airway disease (OAD) was investigated in an animal model. METHODS: Tracheae from Brown-Norway donors were heterotopically transplanted in the greater omentum of Lewis rats. Recipients were treated for 28 days with FK778 (5 or 20 mg/kg), tacrolimus (1 or 4 mg/kg) or combination regimens at varying doses (5 + 1 mg/kg, 10 + 2 mg/kg or 20 + 4 mg/kg). Grafts were harvested and processed for histologic and immunohistochemical evaluation. Lymphocyte surface antigen expression was quantified and in vitro smooth muscle cell (SMC) proliferation assays were performed. RESULTS: In untreated recipients, very large amounts of infiltrating CD4+, CD8+ and ED1+ mononuclear cells were observed in the peritracheal region with epithelial loss and complete luminal obliteration. Granulation tissue consisted of alpha-actin-positive cells and collagen-rich fibrosis. FK778 and tacrolimus as well as combination regimens of both agents dose-dependently inhibited peritracheal infiltration and luminal obliteration. Only tacrolimus-treated recipients showed preserved luminal epithelial coverage with airway goblet cells, whereas, in animals that received FK778, no epithelium was found. Both agents equally suppressed in vivo lymphocyte CD25 expression. Only FK778-treated animals were completely free of adverse drug side effects. FK778 but not tacrolimus showed potent anti-proliferative effects on SMC in vitro. CONCLUSIONS: Although both agents proved effective to prevent OAD development, histology revealed major differences. The anti-proliferative potency of FK778 on SMC may be an important mechanism of action. Combination regimens showed favorable drug interaction and allowed dose reduction of both agents to achieve maximal immunosuppressive efficacy.
M3 - SCORING: Zeitschriftenaufsatz
VL - 24
SP - 1844
EP - 1854
JO - J HEART LUNG TRANSPL
JF - J HEART LUNG TRANSPL
SN - 1053-2498
IS - 11
M1 - 11
ER -