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J Thorac Cardiovasc Surg 1995;110:1037-1046
© 1995 Mosby, Inc.
CARDIAC AND PULMONARY REPLACEMENT |
Supported by grants from the Caisse Régionale d'Assurance Maladie d'Ille de France (CRAMIF) and the Fondation de L'Avenir.
Received for publication Nov. 7, 1994. Accepted for publication Feb. 22, 1995. Address for reprints: Paolo Macchiarini, MD, Department of Thoracic and Vascular Surgery and Heart-Lung Transplantation, Hopital Marie-Lannelongue, Paris-Sud University, 133, Ave. de la Resistance, 92350 Le Plessis-Robinson, France.
Abstract
We investigated the effects of allograft perfusion with a preservative technique and of combined thyrotracheoesophageal implantation on airway epithelium of long segments of thyrotracheal grafts allotransplanted on their own vascular pedicles into immunosuppressed pigs. Four groups of five animals each underwent heterotopic (into the neck) thyrotracheal (group 1) and thyrotracheoesophageal (group 2) and orthotopic thyrotracheal (group 3) and thyrotracheoesophageal (group 4) allotransplantation. Allograft revascularization included (1) interposition of donor right subclavian artery—incorporating the inferior thyroid artery—to recipient right carotid artery (end-to-end fashion) and (2) end-to-side anastomosis of donor anterior vena cava to recipient right external jugular vein. All thyrotracheoesophageal blocks were harvested after inferior thyroid artery perfusion with 4° C Euro-Collins solution. The overall lengths of tracheal and esophageal grafts were 10.7±2.7 cm and 13.4±3.6 cm, respectively. In the heterotopic groups, all allografts were viable and histologically normal at postmortem examination and the incidence and severity of airway ischemia and rejections (at equal residual levels of cyclosporine) were not different between groups 1 and 2. In the orthotopic groups, the first two pigs died of airway collapse with histologically normal grafts. In the remaining pigs, temporary airway stenting was inserted and allografts remained viable and histologically intact for their entire length 30 days after transplantation. Transplanted tracheal smooth muscles had concentration-dependent contractions and relaxations similar to those of nontransplanted (native) tracheas. This study documents the feasibility of allotransplanting long tracheal and esophageal segments on their own vascular pedicles and demonstrates that allograft preservation and thyrotracheoesophageal transplantation are equally effective in minimizing airway ischemia. Thyrotracheoesophageal transplantation does not enhance recipient alloimmune response compared with thyrotracheal transplantation alone. (J THORACCARDIOVASCSURG1995;110:1037-46)
Successful clinical tracheal allotransplantation is still in its experimental infancy because of the lack of a surgical technique enabling harvest and reimplantation of the fragile tracheal vascular network. 
1 We recently developed a heterotopic model for direct revascularization and venous drainage of thyrotracheal allografts in immunosuppressed pigs. All grafts appeared histologically normal at postmortem examination, but early and transient airway ischemia occurred mostly into the posterior tracheal wall. 2 The mechanism underlying these ischemic phenomena was attributed to the absence of donor treatment with preservative 3,4 and section of esophageal arteries nourishing the posterior tracheal wall.
Accordingly, we hypothesized that donor treatment with a perfusate would minimize the sensitivity of airway epithelium to reimplantation response after transplantation, and that the vascular supply of the posterior tracheal wall could be increased without unbalancing recipient's alloimmune response by engrafting the esophagus. Single and combined tracheal and thyrotracheoesophageal allotransplantation were therefore performed first in a heterotopic and then in an orthotopic pig model. Surgical, histologic, and immunologic findings are presented.
MATERIALS AND METHODS
Animals
Twenty young Large White pigs of both sexes, weighing 15 to 30 kg, were used in this study. They were divided into four groups of five animals each: heterotopic tracheal (group 1) and tracheoesophageal (group 2) and orthotopic tracheal (group 3) and tracheoesophageal (group 4) allotransplantation. All received care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH Publication No. 85-23, revised 1985). Donors and recipients were matched only for weight.
Animals were medicated with intramuscular ketamine hydrochloride (25 mg/kg) and anesthetized with intravenous sodium pentobarbital (25 mg/kg). After orotracheal intubation, anesthesia was maintained with inhaled halothane and the animals' lungs were ventilated (Laboz Ventilator; Laboz Inc., Pau, France) with an equal gas mixture of oxygen and protoxide at a tidal volume of 250 ml and a rate of 20 breaths/min. Jugular and femoral venous catheters were placed for infusion of crystalloid solutions, and adequacy of ventilation and oxygenation was assessed by means of arterial blood gas analysis and pulse oximetry.
Harvesting and preservation technique
The fundamental principle for harvesting long segments of tracheal grafts is to preserve as much as possible their vascular supply provided by the right inferior thyroid artery (Fig. 1), a branch of the right subclavian artery. 2 Briefly, after completion of a median cervicosternotomy, dissection included two basic components. (1) Venous; all subclavian, jugular, vertebral, first intercostal and mammary veins were isolated and ligated distally on both sides, the right and left azygos veins were isolated and ligated at their confluence into the anterior vena cava (AVC), and the AVC and posterior vena cava were isolated and encircled. (2) Arterial; the first intercostal, axillary, vertebral, and carotid arteries were isolated on both sides and encircled. The internal mammary arteries were dissected and ligated on each side.
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2 and was placed in cold(4° C) storage with EC.
Implantation technique
To avoid an upper sternotomy, extensive dissection of the anterior mediastinum, and manipulation of the phrenic and recurrent laryngeal nerves, we simplified our original technique of implantation. 2 Operation was accomplished through a median cervicotomy alone, and revascularization of the grafts was made after (1) excision of the cervical thymus gland and the underlying sternohyoid and sternothyroid muscles, (2) isolation and encirclement with tourniquets of the right external jugular vein, and (3) isolation of the proximal and distal right carotid artery. On completion of these steps, the pigs were heparinized (5 mg/kg) and the recipient's right carotid artery was crossclamped with small bulldog clamps at its origin and distally before its entrance into the cranium and divided. The donor's subclavian artery was then interposed between the proximal and distal recipient's right carotid stumps by an end-to-end 6-0 polypropylene (Prolene) continuous anastomosis. The clamps were then released, allowing the graft to reperfuse, after injection of 240 mg intravenous methylprednisolone acetate. Thereafter the recipient's right external jugular vein was clamped and anastomosed to the donor's AVC with an end-to-side 7-0 Prolene suture. During implantation, allograft hypothermia was further maintained by topical application of cold saline solution.
Implantation of the trachea and esophagus differed in heterotopic and orthotopic allotransplantation. In the heterotopic groups, the esophagus was peeled off over its entire length as close as possible to its muscular layer in pigs belonging to group 1 and was left in place in pigs of Group 2. Thereafter, the proximal and distal grafts orifices were, depending on the site and geometry of the vascular sutures, anastomosed either in a transverse or perpendicular position to the adjacent skin with 2-0 polyglactin (Vicryl; Ethicon) interrupted sutures.
In the orthotopic tracheal group, the operative steps were as follows: (1) dissection of recipient's thyroid gland (to expose the anterior surface of the cervical trachea), (2) dissection of the cervical trachea (from the level of the second tracheal ring above to the right upper lobe takeoff below), and (3) mobilization of the cervicothoracic trachea (by opening the pretracheal fascia up to the carina; special care was taken to maintain the dissection close to the outer tracheal surface to avoid extensive lateral skeletonization of the unresected trachea and injury to both recurrent laryngeal nerves), (4) division of the recipient's proximal trachea (below the second cartilaginous ring), (5) division of the recipient's distal trachea (two lateral traction sutures were placed in the distal tracheal wall); (6) insertion of a cross-field endotracheal tube into the distal tracheal segment to obtain ventilation; (7) dissection of the posterior wall of the trachea form the esophagus (before complete transection of the airway, the original orotracheal tube was withdrawn and its tip was secured with silk sutures), (8) interposition of the donor's to the recipient's trachea by means of an end-to-end proximal anastomosis first with a continuous 4-0 polydioxanone (PDS; Ethicon) suture on the posterior tracheal wall and interrupted 3-0 Vicryl sutures on the cartilaginous wall, the knots of which were tied outside. After completion, the original orotracheal tube was guided back through the glottis and inserted into the distal trachea, and the distal anastomosis was made in the manner described previously.
In recipients undergoing orthotopic tracheoesophageal transplantation, the anterior aspect of the esophagus was exposed after transection of the trachea with the preceding steps. Thereafter, the esophagus was (1) dissected free over a length of approximately 13 cm, with great care taken to maintain its lateral vascular supply, (2) freed from the prevertebral plane, and (3) transected transversely (approximately 1 to 2 cm away from the tracheal transections, avoiding the overlapping of the tracheal and esophageal anastomoses). The esophageal lumens were scrubbed with povidine-iodine solution and the donor's esophagus was then anastomosed proximally and distally with a one-layer interrupted suture of 2-0 Vicryl. After completion, the donor's trachea was interposed to the recipient's trachea in the manner described previously. Once the tracheal and esophageal anastomoses were completed, grafts were revascularized as previously described. The right sternothyroid muscle, preserved before implantation, was pedicled and interposed between the lower tracheal anastomosis and the right carotid artery to avoid arterial erosion. In all recipients, a central venous catheter was placed through a jugular vein and the cervical incision was closed with a two-layer 2-0 Vicryl suture after a single drainage of the cervical region.
Postransplantation management
Animals received intravenous cephalothin (500 mg/daily), oral acetylsalicylic acid (100 mg/daily), prednisolone (40 mg, days 1 and 3 after operation) and low–molecular weight heparin (0.2 ml subcutaneously) for the first 10 postoperative days. They were immunosuppressed with intramuscular cyclosporine (5 to 10 mg/kg per day) to maintain plasma concentrations of 200 to 250 ng/ml and with oral azathioprine (2.5 mg/kg/daily). 2 Rejections were intentionally not treated. The first dose of cyclosporine was given three hours before induction of anaesthesia. Animals were placed in cages and fed standard laboratory pig food and water ad libitum.
Postransplant monitoring
Fiberoptic examinations and tracheal and esophageal biopsies were performed routinely at postransplant days 2, 5, and 7. Exocrine tracheal allograft function was assessed by determining the presence of mucous secretions within the tracheal conduit. Animals receiving heterotopic allotransplantation were killed with intravenous 26% pentobarbital sodium (0.5 ml/kg) at a set time of 14 days after transplantation. This interval was selected because our previous experience suggested that new ischemic lesions were unlikely to occur after this period of investigation. 2 Animals receiving orthotopic allotransplantation were killed 30 days after transplantation; grafts were then removed for evaluation of their patency and final histology. Patency of tracheal allografts was expressed as a proportional cross-sectional area (CSA) of the most stenotic site in the graft to the third ring below the distal anastomosis of recipient's trachea. The CSA was calculated as follows 5 :
CSA = (a/2)x(b/2)x
where a was the transverse and bwas the sagittal diameter. Vascular patency was evaluated by means of premortem angiography.
Histopathologic studies
Biopsy and postmortem specimens were immediately fixed in Bouin's solution and in 10% buffered formalin, respectively. After embedding in paraffin, 5 µm thick sections were stained with hematoxylin and eosin and assessed histologically in a blinded fashion. The status of the thyroid gland was evaluated by investigating the presence or absence of follicular atrophy for ischemia and lymphoid infiltrates for rejection. Nonspecific tracheal and esophageal epithelial lesions were defined as alterations of differentiation or presence of squamous metaplasia (trachea), ulceration, and necrosis. These lesions were interpreted according to (1) the absence of inflammation (ischemia), (2) presence of lymphocytic infiltrates in the lamina propria (rejection), or (3) presence of polynuclear cell infiltrates into the lamina propria, mucopurulent debris, or germs (primary or secondary infection).
The trophic condition of the tracheal and esophageal allograft walls was scored according to the following arbitrary semiquantitative 0 to 4 scale: 0, normal wall; 1, isolated lesions of the epithelium; 2, ischemic necrosis with or without hemorrhage of the lamina propria; 3, ischemic necrosis of the submucosae; and 4, ischemic necrosis of the cartilage (trachea) or muscularis (esophagus). A scoring system for grading the severity of tracheal, esophageal, thyroid gland, and vascular (inferior thyroid artery) rejection was used (Table I).
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2 Unlabeled monoclonal antibodies were the following: (1) anti-CD2, (2) anti-CD4, (3) anti-CD8, and (4) anti-CD25.
Pharmacologic studies on tracheal smooth muscles
Trachea rings from orthotopic transplanted and nontransplanted (native) tracheas were obtained when the animals were killed. Control tracheas were freshly obtained during other experimental procedures. Rings were carefully dissected and gently cleaned from all other tracheal layers and were maintained between an isometric force transducer and a fixed-wire support in a 10 ml isolated organ chamber containing Krebs solution at 37° C. The Krebs-Henseleit solution in the organ bath consisted of 118 mmol/L sodium chloride, 4.7 mmol/L potassium chloride, 1.5 mmol/L calcium chloride, 25 mmol/L sodium bicarbonate, 1.1 mmol/L magnesium sulfate, 1.2 mmol/L potassium phosphate, and 5.6 mmol/L glucose. The solution was gassed with 95% oxygen and 5% carbon dioxide. The organ chambers were washed every 15 minutes by exchanging the bathing Krebs solution. Changes in isometric tension were recorded on a chart recorder. During a 90-minute equilibration period, resting force was kept at 1.5 g. At equilibration, a cumulative concentration response curve to carbachol (10-8 to10-4 mol/L final concentration) was produced. Isoproterenol was then added cumulatively (10-9 to 1.5 10-5 mol/L) to promote muscle relaxation. Changes in force were measured from isometric recordings and expressed in grams. The maximal responses to carbachol or isoproterenol and the concentration of agonist yielding 50% of maximal response were interpolated from the individual concentration-effect curves. Relaxation was expressed as the percentage of decrease in tension of carbachol-elicited constriction.
Statistical analysis
Data are expressed as mean ± standard deviation or standard error of n observations. Statistical analysis was performed with the Mann-Whitney test or one-way analysis of variance (repeated measures) with Fisher's protected least significance difference, Sheffe's F-test, and Dunnett's t test for multiple comparison. All analyses were performed with a software package (STATISTICA, STATSOFT, Paris, France). The a priori level of statistical significance was accepted at p < 0.05.
RESULTS
All animals survived operation. The original vascular supply always originated from the right inferior thyroid artery. The overall mean ischemic time, tracheal length, esophageal length, and recipient carotid artery clamping time were 183 ± 45.1 minutes, 10.7 ± 2.7 cm, and 13.4 ± 3.6 cm, and 22.1 ± 4.3 minutes, respectively. None of the pigs had injury of either recurrent laryngeal nerve or postoperative neurologic deficits related to carotid artery manipulation. All animals receiving heterotopic transplants were in good condition when they were killed. The first two animals receiving orthotopic transplants died 5 and 2 days after grafting of airway collapse with histologically normal grafts; accordingly, in all subsequent animals a modified silicone T-tube (Axion, Aubagne, France) was inserted into the interposed tracheal lumen at the end of operation and its vertical limb protruded through the cervical wound. The tube was surgically removed a mean of 4.5 ± 1.3 days after transplantation.
Heterotopic transplantation
The overall lengths of the engrafted trachea and esophagus was 12.5 ±2.7 and 15.8 ± 2.8 cm, respectively. The operative differences between the two groups are listed in Table II. As shown, tracheal grafts belonging to group 2 were significantly longer than those of group 1. All vascular anastomoses were patent at premortem angiography. Graft surveillance showed the following: (1) Exocrine graft function started 2.2 ± 0.4 (group 1) and 1.2 ± 0.4 (group 2) days after transplantation (p = 0.03). (2) In both groups, early ischemic lesions of tracheal grafts were located exclusively at the levels of the tracheocutaneous and tracheoesophagocutaneous anastomoses (Tables III and IV). (3) The overall incidence (n = 7, 35% vs n = 3, 15%; p = 0.15) and severity (0.4 ± 0.5 vs 0.2 ± 0.5; p = 0.26) of ischemic lesions were lower in tracheoesophageal than tracheal allografts. (3) No graft had permanent bacterial colonization. (4) At postmortem evaluation, all thyroid and esophageal grafts appeared histologically normal; all tracheal grafts appeared histologically normal except at the level of tracheocutaneous anastomoses (n = 2) and tracheoesophagocutaneous anastomoses (n = 1) where ischemic lesions of the epithelium were recorded.
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Table V), eight (8/20, 40%) occurred synchronously in the tracheal and esophageal grafts, and three were dyssynchronous esophageal rejection only. The residual levels of cyclosporine were not significantly different (p = 0.2) between groups 1 (243.04 ± 119.75 µg/ml) and 2 (204.4 ± 112.2 µg/ml). The blood CD4+/CD8+ lymphocyte ratio was significantly higher (p = 0.01) in pigs with (0.876 ± 0.1) than without (0.57 ± 0.16) rejection.
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Table VI). The outcomes of these two types of allotransplantation are depicted in Table VII. Except for the two pigs that died of airway collapse, these animals underwent open tracheal graft biopsy at the time of removal of the T-tube, and all showed histologically normal tracheal walls. All vascular anastomoses were patent when the animals were killed. All tracheal and esophageal grafts were viable and histologically intact for their entire length 30 days after transplantation (Fig. 2). Only one tracheal graft showed a clinically asymptomatic stenosis of the distal site of the tracheal anastomosis. Maximal smooth muscle contraction and relaxation responses did not differ among transplanted, native, and control tracheas (Fig. 3).
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DISCUSSION
Presently available techniques of circumferential resection and primary reconstruction have greatly expanded the indications for operation and dramatically improved the quality of survival for both children and adults with benign and malignant diseases involving up to 50% of tracheal length. 6,7 Unfortunately, many patients have more extensive diseases, for which complex operations are currently under investigation 8 or surgery is contraindicated because the length of the residual trachea would not permit primary reconstruction. 9 To maintain tracheal patency, these long-segment diseases necessitate repeated dilation, tracheal T-tubes, or a definitive tracheostomy, all procedures associated with some degree of compromise of normal respiration, deglutition, or phonation and social acceptability.
Because of this problem, and encouraged by the success of transplantation efforts with other organs, many investigators have evaluated replacement of the tracheal conduit. Tracheal substitution grafts have taken three forms: (1) not revascularized, 11-18 (2) indirectly revascularized, 19-22 and (3) directly revascularized. 23 Except for the study of Khalil-Marzouk, 23 these attempts had disappointing results; all long-segment tracheal grafts transplanted without their vascular pedicles became ischemic, necrotic, and infected. We recently detailed a surgical technique for direct revascularization of unpreserved long segments of tracheal allograft in immunosuppressed pigs. 2 Revascularization included interposition of the donor's subclavian artery (incorporating the origin of the inferior thyroid artery) to the recipient's subclavian artery and a single cava-caval anastomosis; grafts were then implanted heterotopically into the neck. Unlike the study of Khalil-Marzouk, 23 our results demonstrated that the thyrotracheal allografts' viability depended on both arterial and venous revascularization and that early ischemic lesions, located mainly in the posterior tracheal wall, disappeared after epithelial regeneration. In this study, we have investigated how to (1) reduce the early allograft ischemic phenomena by developing a technique of allograft preservation before extraction, (2) increase the vascular supply to the posterior tracheal wall, and (3) simplify our original demanding technique of allograft revascularization.
This technique of thyrotracheoesophageal perfusion was extrapolated from that described by LoCicero and colleagues 24 for perfusion of the bronchial circulation in donor lung procurement. We postulated that the thyrotracheoesophageal circulation could be accessed by clamping the ascending and distal thoracic aorta beyond the origin of the bronchial artery and by infusing, after distal ligation of all cervical vessels, the perfusate into a closed aortic segment incorporating the origins of the innominate and left subclavian arteries. With this technique, the perfusate circulates selectively through the right and left carotid, subclavian, and inferior thyroid arteries; the thyroid gland; the anterolateral surface of the cervicothoracic trachea up to the carina; the esophageal arteries vascularizing the posterior tracheal wall and esophagus; and the contralateral anterolateral surface of the tracheal allograft, finally flushing through the descending cervical veins into the AVC. As a result of perfusion with EC through this tracheal circulation, all group 1 grafts appeared histologically normal for their entire length during the period of investigation, except for scattered areas of ischemia. These ischemic areas were located exclusively at the level of the tracheocutaneous anastomosis and probably were related to formation of fibrotic tissue. This demonstrates that allograft perfusion with a preservative solution before extraction minimizes the ischemia-reperfusion injury at the level of the airway epithelium observable in unperfused tracheal allografts. 2 Another piece of indirect evidence supporting this conjecture is that the incidence of histologically documented rejection in this group was rather high (45%); this could be related to excellent preservation of the graft mucosae and submucosae, where experimental 25 and clinical 26,27 studies have demonstrated that major histocompatibility complex class II antigens, the trigger cells of alloimmune response, are regularly distributed. This hypothesis is also offered as a clarification for the extremely low incidence (0.3%) of graft rejection observed in our previous work, 2 in which more frequent and severe ischemic lesions of the mucosae and submucosae may have suppressed the expression of class II major histocompatibility complex molecules.
Simultaneous thyrotracheoesophageal transplantation resulted in an amelioration of the tracheal vascularization compared with thyrotracheal transplantation alone, but the small sample size may have precluded statistical significance. Nevertheless, the fact that tracheal grafts belonging to group 2 had, despite their significantly longer length, almost twofold lower incidence and severity of ischemic lesions and significantly earlier exocrine function than did group 1 grafts suggests that the esophagus increases the vascular network of the trachea by supplying important nutrients to the posterior tracheal wall (Fig. 4), intratracheal airway epithelium, and walls of the "tracheal" arteries and veins. It is noteworthy that this increased tracheal vascularization was obtained without major immunologic repercussions related to the combined thyrotracheal and esophageal transplantation. It is well known that two organs may be more immunogenic than a single one because of the increased lymphatic mass transplanted, and previous clinical 28,29 and experimental 30 studies have provided evidence for this assumption. Our results showed no significant differences, however, at similar cyclosporine levels, in the incidence and severity of tracheal graft rejection between either form of transplantation. This suggests that the engrafted esophagus does not increase the immunologic response of the recipient. Interestingly, there were three dyssynchronous rejections; we speculate that factors other than major histocompatibility complex alloantigen expression predispose the alloimmune response to a greater degree in one organ than the other of a pair.
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2 allograft revascularization was made by interposing the donor's subclavian artery to the recipient's subclavian artery. This was a technically demanding procedure that included an upper sternotomy, dissection of the anterosuperior mediastinum and thoracic inlet, manipulation of the phrenic and vagus nerves and parietal pleurae, and ligation of almost all branches of the recipient's subclavian artery. Clinical experience with tracheal surgery has clearly demonstrated that the cervical trachea and upper two thirds of the mediastinal trachea can be managed through a simple collar incision into the neck. 9 Consequently, we have developed this implantation technique in which the donor's subclavian artery, incorporating the inferior thyroid artery, is interposed between the right common artery after a simple cervical incision and dissection. This not only reduces the ischemic time but greatly facilitates the performance of the vascular anastomoses and avoids sacrifice of important subclavian arterial branches, including the vertebral artery. Moreover, the venous return is made by a simple anastomosis between the donor's AVC and the external jugular vein, which in pigs has a greater size than the internal jugular vein; this avoids crossclamping of the brachiocephalic confluence and thus eliminates potential risks inherent in the reduction of venous return. On the basis of our experience with the heterotopic groups, we performed orthotopic transplantation of long-segment tracheal allografts, either alone or in combination with the esophagus. The first two pigs in both groups had early expiratory dyspnea and so were killed immediately. Their tracheal grafts appeared normal at pathologic examination. The only plausible explanation for this observation was that the long-segment tracheal grafts were less rigid than usual and tended to collapse, producing airway obstruction during expiration. Consequently, a temporary stenting of the airway was inserted, and none of the pigs had airway obstruction thereafter. All grafts were histologically viable when the animals were killed, none had airway bacterial colonization, and tracheal smooth muscle function was well preserved. This and the fact that only one had stenosis or granulation formation at the anastomotic sites further support the belief that grafts were adequately perfused during the period of investigation. One could argue that the operative hazards of adding two esophageal anastomoses to the tracheal transplantation could be obviated by simply transplanting along with the trachea the entire or to a lesser degree only the anterior muscular wall of the esophagus, denuded of its mucosa. Although we have no evidence to confirm this hypothesis, its clinical relevance is evident, and we believe that this method would probably be equally effective in preserving the blood supply to the posterior wall of the trachea.
In conclusion, our presented results clearly demonstrate that one of the major concerns of tracheal transplantation, the surgical mechanisms leading to revascularization, has been resolved. By applying our harvesting and implantation techniques, long segments of tracheal allografts can be successfully engrafted with their own vascular pedicles. Although the underlying pathophysiologic mechanisms are different, this experience suggests that donor pretreatment with EC and combined thyrotracheoesophageal (without increasing recipient alloimmune response) transplantation are equally effective in reducing airway ischemia after transplantation. Orthotopic transplantation of long tracheal segments necessitates temporary stabilization of the tracheal wall to prevent airway collapse. However, two other major areas of concern must still be addressed before human tracheal transplantation can be considered feasible in clinical practice. These are (1) prevention of host rejection 31 and (2) justification.
Acknowledgments
We thank Dr. B. Charley (INRA, Jouy-en-Josas, France) for providing the unlabeled monoclonal antibodies, Dr. P. Dervanian for artistic illustration, and Laboratoire Sandoz, Inc., for providing cyclosporin. We also acknowledge the excellent technical assistance of Chantal Verriest, Michèle Gaillard, Burel Rémi, Gusmini Pascal, Hegésippe Langouste, and Baudet Bruno.
Footnotes
From the Department of Thoracic and Vascular Surgery and Heart-Lung Transplantation a and Experimental Surgical b and Immunological c Laboratories, Hopital Marie-Lannelongue, Paris-Sud University, Le Plessis-Robinson, France. 
References
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