Seeding of recipient-originated epithelial cells attenuates epithelial to mesenchymal transition in rat tracheal allotransplantation.

OBJECTIVE: The specific role and mechanism of epithelium in the progression of obliterative airway disease (OAD) after tracheal allotransplantation remain poorly understood. In this study, we used rat heterotopic tracheal transplantation to investigate the mechanism of epithelial cell seeding during the process of OAD. STUDY DESIGN: Prospective, basic science. SETTING: Research laboratory. SUBJECTS AND METHODS: In total, 120 Sprague Dawley (SD) rats and 90 Wistar rats were used. Tracheas from SD rats were implanted into SD rats (syngeneic, n = 30) or Wistar rats (allogeneic, n = 30), and SD rat tracheas (seeded with Wistar rat-derived epithelial cells 6 days after transplantation) were transplanted into Wistar rats (seeded allogeneic, n = 30). Grafts were harvested at 7, 14, or 30 days after transplantation for histologic, quantitative reverse transcriptional polymerase chain reaction or Western blot analyses. RESULTS: Syngrafts retained normal histologic structures, while the corresponding allografts demonstrated less ciliated epithelia and more lumenal occlusion. Seeding of epithelial cells ameliorated the histologic changes, reduced the expression of epithelial to mesenchymal transition (EMT)-related transcriptional factors and mesenchymal markers, and dampened the expression of transforming growth factor ß1 (TGF-ß1) and phosphorylation of smad3. CONCLUSION: Seeding of recipient epithelial cells inhibits the progression of OAD by attenuating EMT via TGF-ß-Smad signaling in rat heterotopic tracheal allografts. Clinically, the injection of recipient-originated epithelial cells might provide new insights into the treatment for OAD after tracheal allotransplantation.

Interplay between immune responses to HLA and non-HLA self-antigens in allograft rejection.

Recent studies strongly suggest an increasing role for immune responses against self-antigens (Ags) which are not encoded by the major histocompatibility complex in the immunopathogenesis of allograft rejection. Although, improved surgical techniques coupled with improved methods to detect and avoid sensitization against donor human leukocyte antigen (HLA) have improved the immediate and short term function of transplanted organs. However, acute and chronic rejection still remains a vexing problem for the long term function of the transplanted organ. Immediately following organ transplantation, several factors both immune and non immune mechanisms lead to the development of local inflammatory milieu which sets the stage for allograft rejection. Traditionally, development of antibodies (Abs) against mismatched donor HLA have been implicated in the development of Ab mediated rejection. However, recent studies from our laboratory and others have demonstrated that development of humoral and cellular immune responses against non-HLA self-Ags may contribute in the pathogenesis of allograft rejection. There are reports demonstrating that immune responses to self-Ags especially Abs to the self-Ags as well as cellular immune responses especially through IL17 has significant pro-fibrotic properties leading to chronic allograft failure. This review summarizes recent studies demonstrating the role for immune responses to self-Ags in allograft immunity leading to rejection as well as present recent evidence suggesting there is interplay between allo- and autoimmunity leading to allograft dysfunction.

The effects of CD28 superagonist antibody in rat obliterative airway disease / 中国免疫学杂志

Objective:To investigate the effects of superagonistic CD28~- specific monoclonal antibody JJ316 (supCD28 MAb) on preferentially expanded rat CD4~+CD25~+Treg (Treg) cells in vivo and its applicability in obliterative airway disease (OAD).Methods:The heterotopic tracheal transplantation model in rats was used.One group received mIgG-treatment(0.5 mg/rat) as control.The experimental group was treated with supCD28 Mab(0.5 mg/rat) via intraperitoneal injection on the day of transplantation.The changes of Treg cell population in cervical lymph nodes were monitored by flow cytometry after 7 days.Tracheas were harvested after 21 days for further histologic evaluation.Results:SupCD28 MAb administration was revealed with a significant increase in the CD4~+CD25~+ T and CD4~+Foxp3~+ T cells population in cervical lymph nodes compared to treatment with mIgG group on day 7 after transplantation,[8.5%±3.4% and 11.5%±2.7% (P<0.05 vs mIgG group)in the supCD28 Mab group,1.8%±1.9% and 3.2%±2.1% in the mIgG group,respectively].Furthermore,the allografts from animals treated with supCD28 MAb were significantly less airway obliteration and destruction of the epithelium compared with that of control group animals on day 21 after transplantation.Conclusion:SupCD28 MAb targets expansion of Treg cells and attenuates airway lumen obliteration in rat obliterative airway disease.