Tracheal transplantation without immunosuppressive therapy in a rabbit model

Objectives: Tracheal transplantation raises 2 major issues: the lack of an individualized vascular pedicle, which impedes immediate revascularization of the graft, as in solid organ transplantation, and immune rejection with the need for immunosuppressive therapy, strictly contraindicated in malignancies. Given that respiratory epithelium plays an essential role in the immune response of tracheal allografts, we have investigated the epithelium-denuded-cryopreserved tracheal allograft in a rabbit model. Methods: Eleven adult female New Zealand rabbits served as donors of tracheas that were denuded of their epithelium and then cryopreserved. During the first phase of the study, 13 males were used as recipients. Following graft wrap using a lateral thoracic fascial flap, long allograft segments (10/12 tracheal rings) were implanted under the skin. During the second phase of the study, tracheal transplantation was performed in 14 male recipients receiving: (i) long allograft segment with prior heterotopic revascularization; (ii) average allograft segment (6-8 tracheal rings) or (iii) short allograft segment (4-5 tracheal rings), with single-stage orthotopic revascularization by graft wrap with the strap muscles. Bronchoscopic follow-up was performed. No immunosuppressive therapy was administered. Results: After heterotopic transplantation allografts displayed satisfactory tubular morphology up to Day 91 provided that an endoluminal tube was inserted. After orthotopic transplantation, four animals were sacrificed from Day 33 to Day 220. The survival time of other recipients was 0 to 47 days (mean 19.6±16.7.3 days). Aside from 3 animals that died from complications, all allograft segments had satisfactory stiffness, were well vascularized, showed varying levels of neoangiogenesis and inflammatory infiltration devoid of lymphocytes, and showed evidence of only low levels of apoptosis suggestive of minimal rejection. Cartilage rings exhibited calcification deposits increasing over time, ensuring graft stiffness. After orthotopic transplantation, varying degrees of fibroblastic proliferation originating from the lamina propria was observed in the lumen of allografs and evolved over time into collagenized fibrosis in animals surviving over 45 days. Epithelial regeneration was constantly observed. Intense fibroblastic proliferation led to stenosis mainly in animals receiving long and average allograft segments.Conclusion: We have demonstrated satisfactory neoangiogenesis, immune tolerance and strain abilities of the epithelium-denuded-cryopreserved tracheal allograft in heterotopy despite the absence of immunosuppressive drugs, and then the feasibility of orthotopic transplantation with such allografts. Similar studies need, however, to be conducted in bigger mammals before considering clinical applications.