Tracheal Transplantation Research Articles

Application of aortic allograft in trachea transplantation

The use of tracheal implants for tracheal reconstruction remains a challenge in thoracic medicine due to the complex structure of the trachea in mammalian organisms, including smooth muscles, cartilage, mucosa, blood vessels, cilia, and other tissues, and the difficulty in achieving tracheal regeneration using implants from either allografts or synthetic biomaterials. This project used the Lee-Sung strain pig, a swine breed local to Taiwan, as the experimental subject. The aorta of the pig was harvested, decellularized to form the scaffold, and transplanted into the trachea of allogeneic pigs together with growth factors. Postoperative physiological function and tissue changes were observed. The postoperative physiological parameters of the LSP were monitored, and they were sacrificed after a certain period to observe the pathological changes in the tracheal epithelial cells and cartilages. Overall, six LSP tracheal transplantations were performed between March 4, 2020, and March 10, 2021. These included aortic patch anastomosis for pig 1 and aortic segmental anastomosis for pigs 2-6. The shortest and longest survival periods were 1 day and 147 days, respectively. Excluding the pig that survived for only 1 day due to a ruptured graft anastomosis, all other subjects survived for over 1 month on average. In this study, we grafted a decellularized porcine aorta into a recipient pig with a tracheal defect. We found cryopreservation of the allogeneic aorta transplantation was a feasible and safe method for the management of airway disease, and immunosuppressants were unnecessary during the treatment course.

Investigation of the In Vitro and In Vivo Biocompatibility of a Three-Dimensional Printed Thermoplastic Polyurethane/Polylactic Acid Blend for the Development of Tracheal Scaffolds.

Tissue-engineered polymeric implants are preferable because they do not cause a significant inflammatory reaction in the surrounding tissue. Three-dimensional (3D) technology can be used to fabricate a customised scaffold, which is critical for implantation. This study aimed to investigate the biocompatibility of a mixture of thermoplastic polyurethane (TPU) and polylactic acid (PLA) and the effects of their extract in cell cultures and in animal models as potential tracheal replacement materials. The morphology of the 3D-printed scaffolds was investigated using scanning electron microscopy (SEM), while the degradability, pH, and effects of the 3D-printed TPU/PLA scaffolds and their extracts were investigated in cell culture studies. In addition, subcutaneous implantation of 3D-printed scaffold was performed to evaluate the biocompatibility of the scaffold in a rat model at different time points. A histopathological examination was performed to investigate the local inflammatory response and angiogenesis. The in vitro results showed that the composite and its extract were not toxic. Similarly, the pH of the extracts did not inhibit cell proliferation and migration. The analysis of biocompatibility of the scaffolds from the in vivo results suggests that porous TPU/PLA scaffolds may facilitate cell adhesion, migration, and proliferation and promote angiogenesis in host cells. The current results suggest that with 3D printing technology, TPU and PLA could be used as materials to construct scaffolds with suitable properties and provide a solution to the challenges of tracheal transplantation.

MiR-27a-3p alleviates lung transplantation-induced bronchiolitis obliterans syndrome (BOS) via suppressing Smad-mediated myofibroblast differentiation and TLR4-induced dendritic cells maturation

BackgroundBronchiolitis obliterans syndrome (BOS), induced by a chronic rejection, remains a significant obstacle for end-stage lung diseases after lung transplantation. We have previously determined that the small non-coding mRNA (miRNA) miR-27a-3p maintained the immature state of dendritic cells (DCs) via the interleukin 10 (IL-10)-dependent regulatory pathway. Such status helped in preventing rejection and alleviating BOS. The present study explored mechanisms how miR-27a-3p may suppress the fibrosis as well as the maturation of DCs, ultimately attenuating BOS in vitro and in vivo. Methods/ResultsIn our tracheal transplantation mouse model, the expression of Smad2, Smad4, and αSMA were significantly decreased in the miR-27a-3p-transfected DCs (p < 0.0001, p = 0.0006, and p = 0.0002 respectively). Moreover, the expression of fibrosis markers (α-SMA, collagen I, and Fn) were potently inhibited in the miR-27a-3p-transfected NIH-3 T3 cells (p < 0.0001, p = 0.00148, and p < 0.0001 respectively). At the same time, reversed results were observed in the inhibitor group (p = 0.0002, p < 0.0001, and p < 0.0001 respectively), indicating that miR-27a-3p could directly inhibit myofibroblast differentiation. Furthermore, in the tracheal transplanted mice, the population of Treg cells was significantly decreased (p < 0.0001). In contrast, Th17 cells were down-regulated in the miR-27a-3p-transfected DCs group (p < 0.0001), accompanied by the decreased IL-17 levels (p = 0.0007) and the induction of TGF-β1 and IL-10 (p < 0.0001 and p = 0.0016 respectively). Further mechanistic studies indicated that miR-27a-3p altered the maturation of DCs by targeting TLR4 and IRAK (p < 0.0001 and p = 0.0002 respectively). ConclusionsOur study suggests that miR-27a-3p selectively blocked the TGF-β1/Smad pathways to suppress the myofibroblast differentiation and targeted the TRL4/IRAK4 pathway to restrain DCs maturation, thus attenuating BOS. Our findings suggest that miR-27a-3p is a potential active molecule on BOS management after lung transplantation.

Critical Care and Postoperative Management of the First Human Long Segment Orthotopic Tracheal Transplantation.

The recipient required reconstruction of a long segment tracheal defect from a previous prolonged intubation. A male donor was chosen for a female recipient to enable analysis of the reepithelialization kinetics using fluorescence in situ hybridization to analyze the source of the new ciliated epithelium. Transplant ICU at the Mount Sinai Hospital, New York, NY. The female recipient was previously intubated for an asthma exacerbation and subsequently developed long segment tracheal stenosis and failed conventional management including dilatation, stenting, and six major surgical procedures rendering her chronically tracheostomy-dependent. The male donor suffered a massive subarachnoid hemorrhage and was subsequently pronounced brain dead. Organ procurement occurred after obtaining appropriate consent from the patient's family. The patient received a deceased donor tracheal allograft that included the thyroid gland, parathyroid glands, and the muscularis of the cervical and thoracic esophagus. Triple therapy immunosuppression (tacrolimus, mycophenolate mofetil, and a corticosteroid taper) was maintained. The patient was initially managed postoperatively with deep sedation on ventilator via armored/reinforced endotracheal tube placed through a small tracheostomy located along the superior tracheal anastomosis. Serial bronchoscopies were performed for graft assessment, pulmonary toilet, and biopsies, which initially showed acute inflammatory changes but no features of acute allograft rejection. A euthyroid state was maintained but hypercalcemia developed. The ICU management of this first long segment orthotopic tracheal transplant required a multidisciplinary approach involving critical care, otolaryngology, transplant surgery, interventional pulmonary, endocrinology, 1:1 nursing throughout the recipient's transplant ICU stay, and respiratory therapy that resulted in the successful establishment of a viable tracheal airway and heralded the end of chronic tracheostomy dependence.

(195) Psychosocial Considerations and Role of Consultation Liaison Psychiatry in Care of Sole Recipient of Tracheal Transplant

(195) Psychosocial Considerations and Role of Consultation Liaison Psychiatry in Care of Sole Recipient of Tracheal Transplant

Vascularized Tracheal Transplantation: A Twenty Month Follow Up.

Tracheal transplantation has been considered the ideal option for the reconstruction of long-segment circumferential tracheal defects. Our group developed a technique for vascularized single-staged tracheal transplantation. Twenty months ago, we performed the first-in-human tracheal transplantation. Herein, we report a twenty-month follow-up. The recipient presented with a 9.0 cm airway tracheal stenosis and complete cricoid stenosis. The patient previously failed six major conventional surgical procedures. Prior to transplantation, the patient's airway was maintained with an extended tracheostomy and stent. The patient experienced repeated life-threatening airway obstruction because of mucous plugging and obstructive granulation tissue. In January 2020 the patient underwent a single-staged tracheal transplantation treated with triple-therapy immunosuppression. Organ rejection was monitored with endoscopic tracheoscopy, narrow-band imaging, free-cell DNA assessment, and histological and cytogenetic analysis of tracheal biopsies. Mucociliary function was assessed with dye motility studies. Twenty months following transplantation, there has been no evidence of acute or chronic rejection. Since day 60, there has been no detectable free cell DNA, a surrogate marker for immune-mediated allograft rejection. Fluorescence in situ hybridization (FISH) cytogenetics demonstrated that the donor trachea was repopulated with recipient epithelium establishing a chimeric allograft. Narrow-band imaging demonstrates a well-vascularized epithelial mucosa and bronchoscopic biopsies demonstrate normal ciliated epithelial architecture and viable epithelial lining with functional ciliated epithelium. The patient has resumed a normal life without a stent or tracheostomy and has returned to work. Twenty months after single-staged vascularized tracheal transplantation, the trachea is functional and the patient breathes without the need for a tracheostomy or stent. Single-staged long-segment tracheal transplantation is a viable option for tracheal defects that are not amenable to conventional reconstructive techniques. 4 Laryngoscope, 133:1839-1845, 2023.

Inhibiting S100A8/A9 attenuates airway obstruction in a mouse model of heterotopic tracheal transplantation

Although bronchiolitis obliterans syndrome (BOS) is a major cause of death after lung transplantation, an effective drug therapy for BOS has not yet developed. Here, we assessed the effectiveness of a neutralizing anti-S100 calcium binding protein (S100) A8/A9 antibody against BOS. A murine model of heterotopic tracheal transplantation was used. Mice were intraperitoneally administered control IgG or the S100A8/A9 antibody on day 0 and twice per week until they were sacrificed. Tissue sections were used to evaluate the obstruction ratio, epithelium-preservation ratio, α-smooth muscle actin (SMA)-positive myofibroblast infiltration, and luminal cell death. Quantitative reverse transcriptase-polymerase chain reaction analysis was performed to analyze the mRNA-expression levels of collagen, inflammatory cytokines, and chemokines on days 7, 14, and 21. The anti-S100A8/A9 antibody significantly improved the obstruction ratio and epithelium-preservation ratio, with less α-SMA-positive myofibroblast infiltration compared to the control group. Antibody treatment reduced the type-III collagen: type-I collagen gene-expression ratio. The antibody also significantly suppressed the number of dead cells in the graft lumen. The expression levels of tumor growth factor β1 and C–C motif chemokine 2 on day 21, but not those of interleukin-1β, interleukin-6, and tumor necrosis factor α, were significantly suppressed by S100A8/A9 antibody treatment. These findings suggest that S100A8/A9 may be a potential therapeutic target for BOS after lung transplantation.

Mediastinitis after a cryopreserved allograft tracheal transplant treated by transposition of the major omentum.

A 56-year-old female presented with an extended adenoid cystic carcinoma of the entire trachea. She underwent a 12-cm fully-circumferential tracheal replacement by a cryopreserved aortic allograft(CAA) stented by a silicon prosthesis to prevent airway collapse. A muscle flap was used to provide neovascularization and prevent fistulization to mediastinal structures. Post-surgery mediastinitis was detected three weeks after surgery and reoperation was performed. A partial allograft necrosis with stent exposure was found. Major omentum transposition allowed neo-trachea coverage, preventing air-leak, providing antibiotics delivery and mediastinal infection treatment. Six months after surgery the patient is alive. Follow-up bronchoscopy showed a satisfactory allograft revascularization.

Early reperfusion with hemoglobin vesicles into tracheal subepithelial capillaries in a mouse tracheal transplant model.

Hemoglobin vesicles (HbVs), liposomes containing concentrated hemoglobin extracted from outdated human red blood cells (RBC), are artificial oxygen carriers with a small particle size. To evaluate the reperfusion of capillaries with HbVs in a tracheal transplant model and compare it with that of RBC. Isogenic mice were used as donors and recipients in a parallel trachea transplant model. Both ends of the donor trachea were anastomosed end-laterally to the recipient trachea to form in parallel. After transplantation, 0.3 mL of HbV solution (Hb concentration, 10 g/dL) was administered via the tail vein. The recipients were euthanized 1, 4, 6, and 8 h after surgery (n = 5 in each group). The tracheas were harvested, and tracheal subepithelial capillaries (SEC) reperfusion was histologically evaluated. A significant number of particles defined as HbV by electron microscopy were observed in the SEC of the grafted tracheas 4 h after the transplant surgery and HbV administration when no RBC were found in the SECs. The number increased 6 and 8 h later. Our findings suggest that HbVs, which are smaller than RBC, can reperfuse the capillaries of grafts earlier than RBCs after transplantation and contribute to the oxygenation of transplanted tissues.

Skin-derived epithelial lining facilitates orthotopic tracheal transplantation by protecting the tracheal cartilage and inhibiting granulation hyperplasia.

Long-segment tracheal defects caused by tumours, inflammation or trauma can cause serious damage to the quality of life of patients. Although many novel neotracheas have been constructed, the therapeutic effect of orthotopic transplantation was compromised mainly because of the lack of an epithelial lining in those neotracheas. In this study, we aimed to investigate the therapeutic function of skin-derived epithelial lining for orthotopic tracheal transplantation. Strips of auricular cartilage with fixed interval were interrupted sutured on a silicone tube to mimic the cartilage rings of the native trachea. Neotrachea in the with epithelium group retained the unilateral skin as the epithelial lining in the lumen, whereas the neotrachea in the without epithelium group consisted solely of cartilage strips. After revascularized in the sternohyoid muscle, 2-cm-long tracheal defects were made and were reconstructed using these neotracheas. Our results showed that the skin-derived epithelial lining simultaneously protected the engineered tracheal cartilage and inhibited granulation hyperplasia in the tracheal lumen; further, compared with the without epithelium group, the group with epithelium showed a marked improvement in the tracheal lumen patency and the survival rate of rabbits. Our study provides a critical cue for improvements in the repair of tracheal defects via skin-derived epithelial lining and may significantly advance the clinical translation of tissue-engineered trachea.

Macrophage Lysosomal Alkalinization Drives Invasive Aspergillosis in a Mouse Cystic Fibrosis Model of Airway Transplantation.

Cystic fibrosis (CF) lung transplant recipients (LTRs) exhibit a disproportionately high rate of life-threatening invasive aspergillosis (IA). Loss of the cystic fibrosis transmembrane conductance regulator (CFTR-/-) in macrophages (mφs) has been associated with lyosomal alkalinization. We hypothesize that this alkalinization would persist in the iron-laden post-transplant microenvironment increasing the risk of IA. To investigate our hypothesis, we developed a murine CF orthotopic tracheal transplant (OTT) model. Iron levels were detected by immunofluorescence staining and colorimetric assays. Aspergillus fumigatus (Af) invasion was evaluated by Grocott methenamine silver staining. Phagocytosis and killing of Af conidia were examined by flow cytometry and confocal microscopy. pH and lysosomal acidification were measured by LysoSensorTM and LysotrackerTM, respectively. Af was more invasive in the CF airway transplant recipient compared to the WT recipient (p < 0.05). CFTR-/- mφs were alkaline at baseline, a characteristic that was increased with iron-overload. These CFTR-/- mφs were unable to phagocytose and kill Af conidia (p < 0.001). Poly(lactic-co-glycolic acid) (PLGA) nanoparticles acidified lysosomes, restoring the CFTR-/- mφs’ ability to clear conidia. Our results suggest that CFTR-/- mφs’ alkalinization interacts with the iron-loaded transplant microenvironment, decreasing the CF-mφs’ ability to kill Af conidia, which may explain the increased risk of IA. Therapeutic pH modulation after transplantation could decrease the risk of IA.

Whole-organ deceased donor tracheal allograft transplantation for the treatment of refractory tracheal stenosis: a case report

Tracheal stenosis involving &gt;5 cm of trachea is debilitating for patients, impedes their quality of life and may even become life-threatening. Large, open defects often result in these patients because of multiple failed tracheal resections and endoscopic dilatations. Tracheal transplantation has been proposed as a curative solution, but revascularization of the trachea as an allograft has generally been considered prohibitively challenging due to a tenuous blood supply. We report a multidisciplinary effort resulting in the first vascularized, single-stage, deceased donor tracheal allograft transplantation in a woman with long-segment tracheal stenosis.

Current aspects of the diagnosis and treatment of adenoid cystic carcinoma of the trachea and larynx: a literature review

This review discusses current aspects of the diagnosis and treatment of adenoid cystic carcinoma of the trachea and larynx. It describes different variants of surgical treatment, radiotherapy, combination therapy, endotracheal interventions using endoscopic techniques and physical methods, grafting, tracheal transplantation, complications, and oncological and functional treatment outcomes. We also analyze clinical aspects of adenoid cystic carcinoma of the larynx, most common tumor location, difficulties associated with morphological verification, and controversial issues related to surgery volume, considering that this disease is rare and clinical experience is often insufficient.

Tracheal transplantation and reconstruction: state of the problem

Trachea is one of the most difficult organs for transplantation because of its segmental blood supply is provided by vessels which are too small for microvascular anastomosis. An effective vascular supply and, respectively, microcirculation is fundamental for successful transplantation of this organ. The possibility of using bioprosthesis for tracheal replacement is under investigation. Only few groups of researchers over the world have developed their own techniques of tracheal transplantation, but at present time the problem is not resolved. This review describes past and current researches in the field of tracheal transplantation and reconstruction.

Nintedanib as an Anti-Fibrotic Therapy in a Mouse Model of Chronic Lung Allograft Dysfunction

<h3>Purpose</h3> Chronic lung allograft dysfunction (CLAD) is the leading cause of lung transplant failure, with 50% of patients developing it by five years post-transplant. CLAD is characterized by progressive fibrosis, and it has no effective therapies. Nintedanib is a multiple tyrosine kinase inhibitor used to treat idiopathic pulmonary fibrosis. Here we assess nintedanib's efficacy, with tacrolimus, as a potential preventative CLAD therapy in the heterotopic tracheal transplant mouse model of CLAD-like airway fibrosis. <h3>Methods</h3> We performed Balb/C (H-2^d)-to-C57BL/6 (H-2^b) transplants. To arrive at effective doses of nintedanib and tacrolimus alone, we treated nine groups of n=10 recipients with one of three doses of nintedanib (0, 25, 50mg/kg), or six doses of tacrolimus (0, 0.1, 0.25, 0.5, 1, 2mg/kg). Mice were given either drug daily for 28 days. Following sacrifice, tracheas underwent Masson-Trichrome staining and were graded for luminal fibrotic occlusion and epithelial necrosis. Kruskal-Wallis one-way analyses of variance were performed on both grades within drug treatments. <h3>Results</h3> We found that compared to the control (Fig. 1C), fibrotic occlusion was significantly reduced in nintedanib treatment groups, but that epithelial necrosis was unaffected (Fig. 1 A, B, D). In contrast, we found that high doses of tacrolimus eliminated both pathologies (Fig. 1 A, B, E). Lower doses of tacrolimus had a moderate effect on luminal occlusion, and no effect on epithelial necrosis. <h3>Conclusion</h3> Our results demonstrate nintedanib's potential as an anti-fibrotic drug in lung transplantation. Nintedanib caused a significant decrease in fibrotic occlusion, but epithelial necrosis was reduced only by tacrolimus. Based on this, we will examine the combined effects of the drugs to arrive at a treatment strategy with both immunosuppressive and antifibrotic components.

Inhibiting S100A8/A9 Attenuates Airway Obstruction in a Mouse Heterotopic Tracheal Transplantation Model

<h3>Purpose</h3> Chronic lung allograft dysfunction (CLAD) is a major cause of mortality after lung transplantation (LTx). The main pathogenesis of CLAD is fibrosis of the small airways or lung parenchyma. Neutralizing antibodies against S100A8/A9, an inflammatory protein, have been shown to inhibit lung fibrosis in mouse models. In the present study, we tested the hypothesis that S100A8/A9 antibodies suppress airway fibrosis in a mouse model. <h3>Methods</h3> A mouse heterotopic tracheal transplantation model was used. The anti-S100A8/A9 monoclonal antibody or control IgG were intraperitoneally administered twice a week. The rate of graft lumen occlusion, the positivity of the fibroblast marker α-smooth muscle actin (SMA), and mRNA expression of cytokines and chemokines were evaluated. <h3>Results</h3> The luminal obstruction ratio at day 21 was significantly higher in the treatment group than in the control group (p = 0.0023) (Fig.1A, 1B and 2A). The αSMA-positive area in submucosal layer was significantly smaller in the treatment group than in the control group (p = 0.0376) (Fig 1C, 1D and 2B). The expression levels of TGFβ (p = 0.0026) and Collagen 3a1 (p = 0.0238) at day 21 by qPCR were significantly lower in the treatment group than in the control group. Conversely, expression levels of inflammatory cytokines in the treatment group was equivalent to those in the control group. <h3>Conclusion</h3> S100A8/A9 antibody ameliorated airway obstruction by reducing collagen production of αSMA positive myofibroblast without suppression of inflammatory responses in a mouse model. The heterodimer S100A8/A9 can be a novel therapeutic target for CLAD after LTx.

Hypoxic preconditioning improves the survival and pro-angiogenic capacity of transplanted human umbilical cord mesenchymal stem cells via HIF-1α signaling in a rat model of bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is a serious chronic respiratory disease that predominates in the neonatal period. Currently, efficacious and effective specific treatments are lacking. Mesenchymal stem cells (MSCs) transplantation has emerged as a promising option for treating BPD. However, the lower cell survival rate limits its therapeutic efficacy. Hypoxic preconditioning is a direct and effective strategy for promoting MSCs survival, proliferation, and paracrine secretion in the recipient after transplantation, which is greatly important to tissue engineering. We investigated whether hypoxia-pretreated MSCs (HPMSCs) confer superior benefit in an experimental BPD rat model. Neonatal Sprague-Dawley rats were exposed to 80–85% O2 for 14 days. Before tracheal transplantation, the MSCs were pretreated for 48 h with deferoxamine, a chemical hypoxia-mimicking agent. In vitro, the HPMSCs reduced the apoptosis rare, caspase-3 expression, and reactive oxygen species (ROS) generation and promoted proliferation, hypoxia inducible factor-1α (HIF-1α) expression, VEGF secretion, and human umbilical vein endothelial cell tube formation (p < 0.05). In vivo, the HPMSCs restored alveolar structure and lung function, ameliorated pulmonary hypertension, increased vessel density in the BPD rat model (p < 0.05). This work demonstrates for the first time that HPMSCs could have a markedly improved therapeutic effect in BPD, presenting a new potential strategy for the clinical implementation of stem cell biotechnology.

Bioinspired carbon monoxide delivery using artificial blood attenuates the progression of obliterative bronchiolitis via suppression of macrophage activation by IL-17A

Carbon monoxide (CO) is expected to attenuate the progression of obliterative bronchiolitis (OB), which is a serious complication after lung transplantation. However, issues in terms of feasible exogenous CO supply, such as continuousness and safety, remain unsolved. Here, we applied nano red blood cells, namely hemoglobin vesicles (Hb-V), as a CO cargo based on the biomimetic concept and investigated the therapeutic potential of CO-loaded Hb-V on OB in orthotopic tracheal transplant model mice. The CO-loaded Hb-V was comprised of negatively charged liposomes encapsulating carbonylhemoglobin with a size of ca. 220 nm. The results of histological evaluation showed that allograft luminal occlusion and fibrosis were significantly ameliorated by treatment with CO-loaded Hb-V compared to treatment with saline, cyclosporine, and Hb-V. The therapeutic effects of CO-loaded Hb-V on OB were due to the suppression of M1 macrophage activation in tracheal allografts, resulting from decreased IL-17A production. Furthermore, the expression of TNF-α and TGF-β in tracheal allografts was decreased by CO-loaded Hb-V treatment but not saline and Hb-V treatment, indicating that CO liberated from CO-loaded Hb-V inhibits epithelial-mesenchymal transition. These findings suggest that CO-loaded Hb-V exerts strong therapeutic efficacy against OB via the regulation of macrophage activation by IL-17A and TGF-β-driven epithelial-mesenchymal transition.

Single-stage long-segment tracheal transplantation

Tracheal transplantation has been envisioned as a viable option for reconstruction of long-segment tracheal defects. We report the first human single-stage long-segment tracheal transplantation. Narrow-band imaging and bronchoscopic biopsies demonstrate allograft vascularization and viable epithelial lining. The recipient was immunosuppressed with Tacrolimus, Mycophenolate mofetil, and corticosteroids. Six months after transplantation, the trachea is both functional and the patient is breathing without the need of a tracheostomy or stent.

Recipient bone marrow-derived IL-17 receptor A-positive cells drive allograft fibrosis in a mouse intrapulmonary tracheal transplantation model

IL-17A is implicated in the pathogenesis of chronic lung allograft dysfunction, which limits survival after lung transplantation. While many cells express the IL-17 receptor A (IL-17RA) which is the main receptor for IL-17A, the cellular targets of IL-17A in development of post-transplant fibrosis are unknown. The purpose of this study was to determine whether IL-17RA expression by donor or recipient structural or bone marrow (BM) cells is required for the development of allograft fibrosis in a mouse intrapulmonary tracheal transplantation (IPTT) model. BM chimeras were generated using C57BL/6 and IL-17RA-knockout mice. After engraftment, allogeneic IPTTs were performed using the chimeric and BALB/c mice as donors or recipients. This allowed us to assess the effect of IL-17RA deficiency in recipient BM, recipient structural, donor BM, or donor structural compartments separately. Tracheal grafts, the surrounding lung, and mediastinal lymph nodes were assessed 28 days after IPTT. Only recipient BM IL-17RA deficiency resulted in attenuation of tracheal graft obliteration. In the setting of recipient BM IL-17RA deficiency, T cells and neutrophils were decreased in mediastinal lymph nodes. Additionally, recipient BM IL-17RA deficiency was associated with increased B220+PNAd+ lymphoid aggregates, consistent with tertiary lymphoid organs, in proximity to the tracheal allograft. In this IPTT model, recipient BM-derived cells appear to be the primary targets of IL-17RA signaling during fibrotic obliteration of the tracheal allograft.