Experimental transplantation
Combination treatment with FTY720 and CTLA4IgG preserves the respiratory epithelium and prevents obliterative disease in a murine airway model

https://doi.org/10.1016/S1053-2498(01)00775-6Get rights and content

Abstract

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.

Conclusion

Combination treatment with FTY720 and CTLA4IgG may prevent obliterative airway disease.

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)

  • T. Uyama et al.

    Late airway changes caused by chronic rejection in rat lung allografts

    Transplantation

    (1992)
  • M.I. Hertz et al.

    Obliterative bronchiolitis after lung transplantationa fibroproliferative disorder associated with platelet-derived growth factor

    Proc Natl Acad Sci U S A

    (1992)
  • M.I. Hertz et al.

    Reproduction of the obliterative bronchiolitis lesion after heterotopic transplantation of mouse airways

    Am J Pathol

    (1993)
  • G.A. al-Dossari et al.

    Experimental large-animal model of obliterative bronchiolitis after lung transplantation

    Ann Thorac Surg

    (1994)
  • A. Yamada et al.

    Blocking the CD28-B7 T-cell costimulatory pathway abrogates the development of obliterative bronchiolitis in a murine heterotopic airway model

    Transplantation

    (2000)
  • H. Reichenspurner et al.

    Obliterative airway disease after heterotopic tracheal xenotransplantation in a concordant rodent modelpathogenesis and treatment

    Transplant Proc

    (1996)
  • A. Boehler et al.

    Lymphocytic airway infiltration as a precursor to fibrous obliteration in a rat model of bronchiolitis obliterans

    Transplantation

    (1997)
  • J.M. Charpin et al.

    Peaks of transforming growth factor-beta mRNA in alveolar cells of lung transplant recipients as an early marker of chronic rejection

    Transplantation

    (1998)
  • R.E. Girgis et al.

    Risk factors for the development of obliterative bronchiolitis after lung transplantation

    J Heart Lung Transplant

    (1996)
  • B.F. Adams et al.

    The role of respiratory epithelium in a rat model of obliterative airway disease

    Transplantation

    (2000)
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