Combination treatment with FTY720 and CTLA4IgG preserves the respiratory epithelium and prevents obliterative disease in a murine airway model.
BACKGROUND
Mouse heterotopic tracheal transplantation offers a reproducible model of obliterative bronchiolitis after lung transplantation. CTLA4IgG inhibits signaling of the CD28/B7 pathway and induces antigen-specific T-cell unresponsiveness. FTY720 induces T-cell apoptosis and sequestration of circulating mature lymphocytes. We previously found that CTLA4IgG could prevent the development of obliterative airway disease but could not preserve the respiratory epithelium of grafted tracheae. We evaluated whether treatment with either FTY720 or CTLA4IgG, or with combination FTY720 and CTLA4IgG could preserve the respiratory epithelium and inhibit the development of obliterative airway disease.


METHODS
Tracheae with main bronchi from C3H/He mice were transplanted heterotopically into BALB/C mice and harvested on Day 35. Recipient mice received either no treatment or treatment with intraperitoneal FTY720, CTLA4IgG, or the combination of the 2.


RESULTS
Either FTY720 or CTLA4IgG alone significantly inhibited the development of obliterative airway disease. However, normal ciliated columnar respiratory epithelial cells were lost in the allografts. In contrast, combination therapy preserved the respiratory epithelium of the allografted tracheae. FTY720 concentration in the tissue was very high; treatment with FTY720 inhibited mixed lymphocyte reactions and augmented T-cell apoptosis.


CONCLUSIONS
Combination treatment with FTY720 and CTLA4IgG may prevent obliterative airway disease.
Konishi
Katsuhito
K
Division of Molecular Immunology, Institute for Genetic Medicine and First Department of Surgery, Hokkaido University, Sapporo, Japan. kinishik@med.hokudai.ac.jp
Inobe
Manabu
M
Yamada
Akira
A
Murakami
Masaaki
M
Todo
Satoru
S
Uede
Toshimitsu
T
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000627:therapeutic use*; D001989:Bronchiolitis Obliterans / Q000517:prevention & control*; D060908:CTLA-4 Antigen; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride; D018796:Immunoconjugates; D007074:Immunoglobulin G / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016040:Lung Transplantation; D051379:Mice; D011183:Postoperative Complications; D011409:Propylene Glycols / Q000627:therapeutic use*; D020545:Respiratory Mucosa / Q000637:transplantation; D013110:Sphingosine / Q000031:analogs & derivatives; D014132:Trachea / Q000637:transplantation
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000069594:Abatacept; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine