Experimental transplantationCombination treatment with FTY720 and CTLA4IgG preserves the respiratory epithelium and prevents obliterative disease in a murine airway model
Section snippets
Animals
Eight to 10-week-old female BALB/C, C3H/He, and C57BL/6 mice were purchased from Japan SLC Co., (Shizuoka, Japan). They were housed under specific, pathogen-free conditions in the animal facility at the Institute for Genetic Medicine, Hokkaido University.
Transplantation and treatment regimen
Heterotopic tracheal transplantation from the donor C3H/He to the recipient BALB/C was performed as previously described.8 Briefly, each donor mouse was exsanguinated, and the neck and chest cavity were exposed using an anterior mid-line
FTY720 inhibited development of obliterative airway disease
We evaluated the degree of obliterative lesions and the condition of tracheal epithelium and summarized them in Table I. Figure 1 shows the representative histology. Isografts (n = 5) harvested at Day 35 after transplantation were histologically normal, preserving respiratory epithelium without any obliterative lesion, as expected (Figure 1, A and B). Allografts without treatment harvested at Day 35 (n = 5, Group 4) showed almost complete obliteration of the lumens by fibroblastic tissue and
Discussion
The development of OB is a common complication that seriously hinders long-term survival of patients with lung transplantation and is considered one cause of chronic rejection; its cause and pathogenesis are not yet known. Hertz et al6 first described using the murine model of heterotopic tracheal transplantation to analyze OB. In this model, attempts were made to analyze the underlying mechanisms and inhibit the development of obliterative airway disease.3, 4, 5, 6, 7, 8, 9 Preserving
Acknowledgments
The authors thank Yoshitomi Pharmaceutical Co., producers of FTY720, for technical support and especially thank Kyoko Sawai, Dr. Hiroaki Mizuta, and Dr. Noriyuki Arima for measuring FTY720 concentrations.
References (41)
- et al.
Potential role of dendritic cells in bronchiolitis obliterans in heart-lung transplantation
Ann Thorac Surg
(1990) - et al.
Preclinical evaluation of a new immunosuppressive agent, FTY720
Clin Biochem
(1998) - et al.
Signal-transduction cascades as targets for therapeutic intervention by natural products
Trends Biotechnol
(1998) - et al.
Effects of the immunosuppressive drugs CsA and FK506 on intracellular signalling and gene regulation
Immunobiology
(1997) - et al.
Molecular mechanisms of action of new xenobiotic immunosuppressive drugstacrolimus (FK506), sirolimus (rapamycin), mycophenolate mofetil and leflunomide
Curr Opin Immunol
(1996) Rapamune (RAPA, rapamycin, sirolimus)mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression
Clin Biochem
(1998)- et al.
Induction of selective cell death targeting on mature T-lymphocytes in rats by a novel immunosuppressant, FTY720
Immunopharmacology
(1996) - et al.
Evidence that FTY720 induces T cell apoptosis in vivo
Immunopharmacology
(2000) - et al.
A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts. International Society for Heart and Lung Transplantation
J Heart Lung Transplant
(1993) - et al.
The bronchial epitheliuma potential allogeneic target for chronic rejection after lung transplantation
J Heart Lung Transplant
(1996)
Late airway changes caused by chronic rejection in rat lung allografts
Transplantation
Obliterative bronchiolitis after lung transplantationa fibroproliferative disorder associated with platelet-derived growth factor
Proc Natl Acad Sci U S A
Reproduction of the obliterative bronchiolitis lesion after heterotopic transplantation of mouse airways
Am J Pathol
Experimental large-animal model of obliterative bronchiolitis after lung transplantation
Ann Thorac Surg
Blocking the CD28-B7 T-cell costimulatory pathway abrogates the development of obliterative bronchiolitis in a murine heterotopic airway model
Transplantation
Obliterative airway disease after heterotopic tracheal xenotransplantation in a concordant rodent modelpathogenesis and treatment
Transplant Proc
Lymphocytic airway infiltration as a precursor to fibrous obliteration in a rat model of bronchiolitis obliterans
Transplantation
Peaks of transforming growth factor-beta mRNA in alveolar cells of lung transplant recipients as an early marker of chronic rejection
Transplantation
Risk factors for the development of obliterative bronchiolitis after lung transplantation
J Heart Lung Transplant
The role of respiratory epithelium in a rat model of obliterative airway disease
Transplantation
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Early administration of FTY720 prevents chronic airway as well as vascular destruction in experimental rat lung transplantation
2013, Transplantation ProceedingsThe need for a new animal model for chronic rejection after lung transplantation
2011, Transplantation ProceedingsCitation Excerpt :As reviewed by McDyer10 and Hele et al,11 this model has been used extensively to study OB. Several treatment options have been, more or less effectively, tested: Cyclosporine (CsA),12 Rapamycin,13 FTY720 plus CTLA4, immunoglobulin (Ig)G,14 gene therapy with interleukin (IL)-10,15 and more recently Pirfenidone16 and PX3.102.17 The role of chimerism remains controversial; initially it was associated with rejection,18,19 but combining bone marrow transplantation (BMT) with anti–CD-40 ligand antibody treatment attenuated rejection.19
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2006, Thoracic Surgery ClinicsCitation Excerpt :Pharmacokinetic studies have shown FTY720 to operate in a synergistic manner with cyclosporine, without the nephrotoxicity or the use of a similar metabolism pathway. In a murine model of tracheal transplantation, FTY720, in combination with cytotoxic T-lymphocyte antigen 4-immunoglobulin G (CTLA4IgG, an immunoglobulin capable of blocking the costimulatory pathway of T-lymphocyte activation), preserved respiratory epithelium of allografted tracheas, prevented obliteration of the airway, and promoted T-lymphocyte apoptosis [63]. If these effects manifest clinically, then this compound holds great promise for clinical lung transplantation.
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