Reepithelialization of Orthotopic Tracheal Allografts Prevents Rejection after Withdrawal of Immunosuppression

Abstract

Prior work has demonstrated that immunosuppressed orthotopic tracheal allografts undergo progressive reepithelialization over a 48-day period with recipient-derived tracheal epithelium. We hypothesized that reepithelialization of tracheal allografts would prevent rejection after withdrawal of immunosuppression. BALB/c murine tracheal grafts were transplanted orthotopically into either syngeneic or allogeneic C57/BL6 recipients. The recipients were either not immunosuppressed, immunosuppressed with cyclosporine A (10 mg/kg per day) continuously, or immunosuppressed for 48 days and then withdrawn from immunosuppression. The grafts were assessed for acute and chronic rejection 10 days and 50 days after immunosuppression withdrawal. The immunosuppressed allograft recipients maintained a ciliated epithelium acutely and chronically after immunosuppression withdrawal. Ten days after immunosuppression withdrawal, there was a mild cellular infiltrate, which resolved 50 days after withdrawal. Electron microscopy, lymphocyte subpopulation assays, and lamina propria analysis demonstrated that immunosuppression withdrawal did not result in tracheal allograft rejection. In vitro and in vivo assessments did not demonstrate evidence of systemic or local immune tolerance. We conclude that reepithelialization of orthotopic tracheal allografts with recipient-derived mucosa prevents rejection of allograft segments. Tracheal transplantation may require only transient immunosuppression, which can be withdrawn after tracheal reepithelialization.

Single-stage long-segment tracheal transplantation

“…Cytogenomics performed on biopsies from the distal third of the allograft on day thirty demonstrated progressive re-epithelialization with recipient mucosa. On day 86, the recipient epithelium within the donor graft increased to 75.3% meeting the criteria for chimerism; a phenomenon that was observed in experimental allografts 18,19 (Figure 6). At the time of this submission, we are performing twice monthly transtracheal endoscopy in the clinic.…”

“…Rodent and canine transplantation models demonstrate that immediately following tracheal transplantation, the ischemic‐sensitive ciliated columnar epithelium partially sloughs 17 and donor and recipient basal cells repopulate the graft reestablishing functional ciliated epithelium 18,19 . Post‐transplant biopsies in this patient demonstrate a similar pattern of mucosal sloughing followed by basal cell differentiation and cilia repopulation.…”

“…The failure to reestablish mucociliary transport results in stasis of secretions and life-threatening airway obstruction. Tracheal transplantation is the only reconstructive option that accomplishes these objectives.Rodent and canine transplantation models demonstrate that immediately following tracheal transplantation, the ischemic-sensitive ciliated columnar epithelium partially sloughs17 and donor and recipient basal cells repopulate the graft reestablishing functional ciliated epithelium 18,19. Post-transplant biopsies in this patient demonstrate a similar pattern of mucosal sloughing followed by basal cell differentiation and cilia repopulation.…”

“…We believe that blood flow to the tracheal allograft relies on distinct arterial and venous connections included in the esophageal musculature. This vascular network, supplied by the inferior thyroid artery, may be important to ensuring adequate a phenomenon that was observed in experimental allografts 18,19 (Figure 6). At the time of this submission, we are performing twice monthly transtracheal endoscopy in the clinic.…”

Human Tracheal Transplantation

“…31,32 The reepithelialization of the allograft segment with recipient-derived epithelium seems to evade rejection. 33 In this regard, the tracheal allograft is unique in its ability to achieve chimerism, a potentially desirable state.…”