Surgical experience with retroperitoneal heterotopic heart transplantation in the large white domestic swine.

Accelerated coronary atherosclerosis following heart transplantation is the main limiting factor for long-term survival, aside from graft failure and complications due to immunosuppression. Graft coronary vasculopathy is due to chronic rejection of the vascular wall leading to intimal hyperplasia in coronary arteries. Numerous heterotopic heart transplantation models have been used in different species to study the immunology and pathophysiology following graft implantation. This study reports our experience with the retroperitoneal heterotopic heart transplantation in Large White domestic swine using immunological typing. This approach mimics the kinetics of slow low-grade rejection in clinical human heart transplantation. One hundred and fifty-four retroperitoneal (n = 154) heterotopic heart transplantations were performed using Large White swine sampled for the major histocompatibility class (MHC) class I antigen and blood type using the microlymphotoxicity technique. Acute rejection studies were performed by intentional mismatch of the swine lymphocyte alloantigen (SLA) and chronic rejection studies were done in allografts implanted in donor-recipients matched for blood type and class I antigen to assess the effects of rejection per se, hypercholesterolemia, intracoronary L-NAME infusion, and endothelial denudation on the development of graft coronary vasculopathy. Assessment of in vitro coronary arterial vascular reactivity in standard organ chamber experiments comprised the core of vascular biology studies in this large animal model. Eighty (52%) transplanted recipients survived until the elective date of sacrifice at 60 days, 14 (9.1%) died during the surgery, 21 (13.6%) died <24 h after the transplant, and 8 (5.2%) died of late deaths. The retroperitoneal heterotopic heart transplantation model with blood typing and determination of the SLA class I antigen is a useful model for the study of immunological and vascular events due to graft rejection after heart transplantation.     

Abdominal organ cluster transplantation in pigs and FK

Using a swine abdominal organ cluster transplantation model, we investigated the postoperative function and immunological reactions of a cluster graft and evaluated the immunosuppressive activity of FK506. The animals were divided into two groups. Group I (n = 6) served as controls, while in group II (n = 6) a daily dose of 0.1 mg/kg FK506 was given intramuscularly. Postoperative pancreatitis was the most important factor influencing the early outcome in both groups. In group I, the cause of late death was cachexia due to diabetes mellitus induced by pancreatic rejection. In group II, emaciation despite a well-functioning graft was the principal cause of late death. Histologically, in group I the grade of rejection in the pancreas was more severe than in the liver, and no sign of rejection was observed in group II. In conclusion, the pancreas suffered more severe rejection than the liver, and FK506 could significantly prevent cluster allograft rejection in this model.     

Early biological and immune response to semi-identical liver or kidney allograft in miniature swine

In inbred miniature swine, semi-identical liver allograft recipients survive up to 3 months without immunosuppression, whereas similarly mismatched kidney allografts are uniformly rejected within 2 weeks. The early biological and immunological events were assessed in this unique model. SLA(d/d) pigs (MGH, Harvard Medical School, Boston, MA, USA) received liver or kidney allograft from heterozygous SLA(c/d) miniature swine. Survival, graft function, histology, intragraft cytokines, peripheral lymphocyte and platelet count, plasma cortisol level and cellular/humoral anti-donor immune response were assessed. Kidney allografts were uniformly rejected within 2 weeks, whereas liver allografts survived for up to 87 days. After both liver and kidney transplantation, the peripheral lymphocyte count decreased during the first week concomitantly to a significant elevation of plasma cortisol level. Early decrease of peripheral platelet count was observed after liver but not renal transplantation. Up-regulation of transforming growth factor beta1 (TGF-beta1) and interferon-gamma (IFN-gamma) was observed during the first postoperative week in semi-identical liver allografts and IFN-gamma as well as IL-10 in kidney allografts. In liver recipients, labelled autologous lymphocytes accumulated in the liver graft and native spleen, whereas after renal allograft, lymphocytes accumulated in the native spleen and liver but never in the kidney allograft. Specific cellular anti-donor unresponsiveness was observed from the first post-transplant day in both liver and kidney recipients, while the humoral anti-donor response remained intact. In semi-identical liver allograft, recipient rejection is milder and slower than in similarly matched kidney allograft. The intragraft up-regulation of TGF-beta1 in semi-identical liver allograft might be one mediator to explain the modulation of rejection after liver transplant. The rapid, nonspecific accumulation of recipient lymphocytes in the liver allograft but not in kidney allograft might also play a role in the different survival time in this model.     

Immunomodulation after combined spleen and kidney transplantation in swine

AIM: Organ transplantation is the most effective treatment for several degenerative end-stage diseases. While the mainstream immunosuppression can achieve satisfactory results, the therapy has either side effects and flaws. The golden target to reach should be a stable tolerance with the transplanted organ accepted without a long term drug administration. Recent studies demonstrated a tolerogenic effect of spleen cells. Aim of this study is to evaluate a model of combined spleen and whole organ transplantation in a significant preclinical setting in swine. METHODS: Twenty-five outbred Landrace/Large-White swine underwent combined spleen/kidney transplantation (SKTx). The experiments were stratified into 3 groups per randomization. Group 1 (N=7) received kidney transplantation (KTx) alone with no immunosuppressive treatment. Group 2 (N=9) had a combined KTx and whole graft spleen Tx. Group 3 (N=9) had KTx and spleen cells (DST), injected through the portal vein. Renal lab tests were collected to evaluate the onset of rejection. Survivals were evaluated as well. The end-point of the study was at onset of kidney failure or at the limit of 60 postoperative day (POD) in non-rejecting animals. Tissue samples were collected to evaluate grade and severity of rejection. RESULTS: Controls died from kidney failure within 10(th) POD. Group 2 and 3, had a delayed renal graft rejection and an overall prolonged graft survival. Whole graft and spleen cells injection share this effect, while spleen administration through the portal route proved a superior effect, which is significant compared to controls (Kaplan Meier survival analysis P<0.05). CONCLUSIONS: These results, from a non immunosuppressed setting, suggest that spleen plays a key role as an immunomodulatory organ.     

Kombinierte Nieren-Pankreas-Transplantation

BACKGROUND: Differences in graft survival due to gender have been reported after transplantation of the kidney, liver, and heart. However, little is known about the role of donor and recipient gender in simultaneous pancreas-kidney transplantation. METHODS: Single-centre analysis was performed of first simultaneous pancreas-kidney transplantations performed between 1994 and 2005 at the Bochum Transplant Center in Germany (n=218). RESULTS: Recipients of female donor organs exhibited acute organ rejections earlier and more frequently (P<0.05). Male recipients of organs from male donors had a lower risk of acute rejection than recipients of female donor organs (P<0.05). In addition to female donor gender, higher donor age and early kidney dysfunction were risk factors for perioperative rejection (P<0.05). Long-term kidney and pancreas function was best in male-donor-to-female-recipient transplants over the time periods of 7 and 3 years, respectively (P<0.05). Risk factors of long-term organ failure were: the need of revision laparotomy, organ rejection, and early postoperative organ dysfunction (P<0.05). CONCLUSION: This is the first report of graft function after simultaneous pancreas-kidney transplantation looking specifically at gender differences with respect to donor and recipient. There was an increased risk of organ rejection of female donor organs.     

Changes in Total Serum Glycosaminoglycan Levels in Patients Undergoing Renal Transplantation: Preliminary Data

Purpose To study the involvement of glycosaminoglycans (GAGs) in the immunological process of renal disease. They are related to cytokines, which are known to play an important role in acute graft rejection after renal transplantation.Methods We studied 40 patients on maintenance hemodialysis for chronic renal failure, who underwent renal transplantation from a live donor. We measured serum GAGs preoperatively, intraoperatively, and on postoperative days (PODs) 2 and 10. The clinical outcome and other biochemical markers, such as blood urea nitrogen and serum creatinine, were also recorded.Results The total serum GAG levels decreased after renal transplantation in patients with normal graft function (group N). However, in patients with acute graft rejection post-transplantation (group R), the GAG levels remained significantly elevated.Conclusions Total serum GAGs fluctuate in renal transplantation and their association with graft rejection should be investigated further.     

Injury to hepatocytes and non-parenchymal cells during the preservation of human livers with UW or HTK solution: a determination of hepatocellular enzymes in the effluent perfusate for preoperative evaluation of the transplant quality

Abstract  In 50 livers harvested for transplantation, injury was assessed by determination of the enzymes in the effluent perfusate after cold ischemia. The results were compared to the histology and the clinical course after transplantation. Whereas the release of the markers of endothelial cell injury did neither correlate with the history of the graft nor with the postoperative course, the release of hepatocellular enzymes in the perfusate did indicate preexisting damage of the liver even when the biopsy showed normal liver tissue. Of 12 livers with high activity of hepatocellular enzymes in the effluent (activity of more than twice the median), 7 showed delayed onset of function or a primary non-function. In the other 38 livers with an enzyme activity below this borderline no delayed function or primary non-function was observed. Because of additional influences a prognosis of the function after transplantation was not possible, but the determination of the enzymes in the effluent of marginal livers probably allows the preoperative recognition of organs which will do well.     

Immunoglobulin G profile in hyperacute rejection after multivisceral xenotransplantation

Galvao FHF, Soler W, Pompeu E, Waisberg DR, Mello ES, Costa ACL, Teodoro W, Velosa AP, Capelozzi VL, Antonangelo L, Catanozi S, Martins A, Malbouisson LMS, Cruz RJ, Figueira ER, Filho JAR, Chaib E, D′Albuquerque LAC. Immunoglobulin G profile in hyperacute rejection after multivisceral xenotransplantation. Xenotransplantation 2012; 19: 298–304. © 2012 John Wiley & Sons A/S. Abstract: Introduction: Xenotransplantation is a potential solution for the high mortality of patients on the waiting list for multivisceral transplantation; nevertheless, hyperacute rejection (HAR) hampers this practice and motivates innovative research. In this report, we describe a model of multivisceral xenotransplantation in which we observed immunoglobulin G (IgG) involvement in HAR. Methods: We recovered en bloc multivisceral grafts (distal esophagus, stomach, small intestine, colon, liver, pancreas, and kidneys) from rabbits (n = 20) and implanted them in the swine (n = 15) or rabbits (n = 5, control). Three hours after graft reperfusion, we collected samples from all graft organs for histological study and to assess IgG fixation by immunofluorescence. Histopathologic findings were graded according to previously described methods. Results: No histopathological features of rejection were seen in the rabbit allografts. In the swine‐to‐rabbit grafts, features of HAR were moderate in the liver and severe in esophagus, stomach, intestines, spleen, pancreas, and kidney. Xenograft vessels were the central target of HAR. The main lesions included edema, hemorrhage, thrombosis, myosites, fibrinoid degeneration, and necrosis. IgG deposition was intense on cell membranes, mainly in the vascular endothelium. Conclusions: Rabbit‐to‐swine multivisceral xenotransplants undergo moderate HAR in the liver and severe HAR in the other organs. Moderate HAR in the liver suggests a degree of resistance to the humoral immune response in this organ. Strong IgG fixation in cell membranes, including vascular endothelium, confirms HAR characterized by a primary humoral immune response. This model allows appraisal of HAR in multiple organs and investigation of the liver’s relative resistance to this immune response.     

Detrimental effects of controlled reperfusion on renal function after porcine autotransplantation are fully compensated by the use of Carolina rinse solution

Despite extensive efforts in the fields of donor selection and management, standardisation of organ retrieval procedures, storage solutions, and novel immunosuppressive protocols, the rates of delayed graft function (DGF) after renal transplantation have been stagnating between 30% and 50%. As DGF exerts negative influences on acute rejection episodes and long-term organ function, the early phase of transplantation immediately following reperfusion deserves special interest. Several studies on machine-controlled reperfusion showed promising results in various organs, in experimental and clinical settings. Moreover, the flushing of organs with Carolina rinse solution (CR) immediately prior to reperfusion has been proven beneficial and is being clinically applied in human liver transplantation in recognised departments. In our study, we set up an autogenic porcine kidney transplantation model and assessed the normal values (control group) for creatinine clearance (ClCr) and urine output per hour (U/h) after "standard" reperfusion similar to clinical transplantation. Subsequently, kidneys of the experimental group 1 were reperfused at a blood pressure (RR) under the systemic level by means of a roller pump. Group 2 kidneys were rinsed with CR before controlled reperfusion, analogous to group 1. Both groups were compared with each other and with the assessed normal values. Our findings for Group 1 are that pressure-reduced reperfusion negatively affected immediate graft function. ClCr was reduced from 9.9 (control group) to 3.4 ml/min, U/h from 233 to 132 ml ( P<0.05). Group 2 showed that rinsing the kidneys with CR before reperfusion improved functional parameters highly significantly, compared with group 1 (ClCr: 13.5 vs 3.4 ml/min, U/h: 384 vs 132 ml; P<0.05) and even showed a positive trend compared with the control group (ClCr: 13.5 vs 9.9 ml/min, U/h: 384 vs 233 ml; P=0.0546). We can conclude that in a model of porcine renal autotransplantation, pressure-reduced reperfusion via a roller pump is detrimental to early kidney graft function. The flushing of organs with CR prior to controlled reperfusion significantly improves ClCr as well as urine output.     

Immunological advantage on small bowel graft induced by simultaneously transplanted liver in porcine auxiliary liver/small bowel transplantation

BACKGROUND: We developed a new porcine model for auxiliary liver/small bowel transplantation (LSBT). The possible immunological advantage on small bowel graft induced by simultaneously transplanted liver in the large animal was assessed. METHODS: Thirty outbreed long-white pigs were randomized into two groups. Group A animals received LSBT without immunosuppressive treatment (n = 10). Group B animals had segmental small bowel allotransplantation without immunosuppressive treatment (n = 10). The postoperative survival time, initial acute rejection time, and pathological rejection scores were analyzed. RESULTS: There was no remarkable difference in survival time between groups A and B (10.33 days vs 12.89 days, P > .05), but the initial time of acute rejection in intestinal grafts in group A was obviously delayed when compared to group B (8.22 days vs 4.33 days, P < .05), and the rejection scores in group A were remarkably lower than those of group B (0 vs 0.44 on postoperative day (POD) 3, P < .05; 0.22 vs 1.78 on POD 5, P < .05; 1.11 vs 2.56 on POD 7, P < .05). CONCLUSIONS: An immunological advantage on intestinal graft can be induced by simultaneously transplanted liver in auxiliary LSBT. Compared to isolated segmental small bowel allotransplantation, the intestinal graft in LSBT has a delayed initial time of acute rejection and lower acute rejection scores. The liver graft may reduce the risk of intestinal rejection and thus protect the bowel graft.     

Safe inclusion of the entire pancreas as a component of the multivisceral graft

BACKGROUND: Multivisceral transplantation (MVtx) involves simultaneous transplantation of the intestine with other organs, often including the pancreas. The pancreas portion of the graft has always been approached with caution because allograft pancreatitis, rejection or technical complications may be devastating in this setting. We reviewed our experience with multivisceral grafts that included the entire pancreas. METHODS: Twenty-five patients received 27 MVtx that included the entire pancreas between July 2003 and November 2006. In five, a modified MVtx with preservation of the native liver was performed. Two patients required retransplantation for severe rejection. Insulin requirements, graft and patient survival were determined at 6-months posttransplant. Serum amylase and lipase levels were analyzed on postoperative days 3, 7, 30, and 180. RESULTS: Twenty of 25 patients with a transplant pancreas graft were alive at 6-months posttransplant. Median serum amylase and lipase levels posttransplant were normal at all time points. One patient exhibited elevation of amylase and lipase at the time of severe acute cellular rejection of the intestinal graft, likely representing simultaneous pancreas allograft rejection, although this was not confirmed by biopsy. There were no episodes of allograft pancreatitis or technical complications. Once weaned from hyperalimentation, all patients remained normoglycemic and insulin-independent 6-months posttransplant. CONCLUSION: In this series, there were no postoperative pancreatic complications, no episode of isolated pancreas allograft rejection, and no loss of pancreatic graft function. None of the five deaths were related to pancreatic graft complications.     

Relationship between postoperative erythromycin breath test and early morbidity in liver transplant recipients

BACKGROUND: Interindividual variability in dosage requirements of the calcineurin inhibitor immunosuppressive agents cyclosporine and tacrolimus after liver transplantation may result from differences in the CYP3A activity of the liver graft. Early postoperative erythromycin breath test (ERMBT) is an in vivo measure of graft CYP3A activity. This study evaluates the usefulness of an early postoperative ERMBT in predicting early morbidity in liver transplant recipients. METHODS: In 26 liver transplant recipients, ERMBT was performed within 2 hr after transplantation. Main end points were the occurrence of cyclosporine and tacrolimus nephrotoxicity, episodes of early graft rejection, early graft function, and graft survival. RESULTS: Cyclosporine and tacrolimus nephrotoxicity were associated with low postoperative ERMBT values (mean 0.63%+/-0.25% 14C/hr vs. 1.35%+/-0.84% 14C/hr, P=0.02). No significant association between early graft rejection and ERMBT values was demonstrated. There was a significant inverse correlation between postoperative ERMBT values and the time to normalization of international normalized ratio as a measure of early graft function (r=-0.78, P<0.001). Graft loss was associated with low postoperative ERMBT values (0.21%+/-0.15% 14C/hr vs. 1.09%+/-0.72% 14C/hr, P=0.002). CONCLUSION: An early postoperative ERMBT may be useful in predicting the development of cyclosporine and tacrolimus nephrotoxicity, severe graft dysfunction, or even graft loss in liver transplant recipients when calcineurin inhibitors are administered according to protocols. Whether ERMBT results may be used to individualize dosage of calcineurin inhibitors needs to be explored.     

The effect of selective inhibition of inducible nitric oxide synthase on cytochrome P450 after liver transplantation in a rat model

BACKGROUND: Activity levels of cytochrome P450 (CYP) provide markers for liver function and graft rejection episodes after orthotopic liver transplantation (OLT). Some in vitro studies have shown decreased CYP activation of inducible nitric oxide synthase (iNOS) in rejecting liver grafts. The aim of this study was to evaluate CYP isoenzyme activity changes in vivo and to examine histopathologic aspects during inhibition of iNOS after treatment with aminoguanidine (AG) using OLT in the rat. MATERIALS AND METHODS: Thirty DA-(RT1av1) rats that served as donors and LEWIS-(RT(1)) rats as recipients were divided into three groups: group I (controls, syngeneic rats; n = 6), group II (allogeneic rats without immunosupression; n = 11), and group III (allogeneic rats with AG treatment; n = 13). On postoperative days 5, 8, and 10 we performed laboratory investigations and liver biopsies for histopathologic investigations. RESULTS: On postoperative day 5, activities of CYP-1A1 and -3A4 were significantly lower (P = .022) in group III and the activity of CYP-1A2 higher (P < .05) compared with group II. At postoperative days 8 and 10, the activities of all CYP isoenzymes were significant higher in AG-treated rats (group III) in contrast with group II after allogeneic OLT without immunosuppression. Histopathologic findings revealed less distinct rejection signs in group III specimens after AG treatment compared with group II. CONCLUSION: Summarizing our results, we concluded that AG treatment led to increased CYP activity and less distinction of graft rejection after OLT in rats.     

Interleukin-27 in liver xenotransplantation: A rational target to mitigate ischemia reperfusion injury and increase xenograft survival

Transplantation of xenogeneic organs is an attractive solution to the existing organ shortage dilemma, thus, securing a clinically acceptable prolongation of xenograft survival is an important goal. In preclinical transplantation models, recipients of liver, kidney, heart, or lung xenotransplants demonstrate significant graft damages through the release of pro-inflammatory molecules, including the C-reactive protein, cytokines, and histone-DNA complexes that all foster graft rejection. Recent studies have demonstrated that mitigation of ischemia reperfusion injury (IRI) greatly improves xenograft survival. Organ IRI develops primarily on a complex network of cytokines and chemokines responding to molecular cues from the graft milieu. Among these, interleukin 27 (IL-27) plays an immunomodulatory role in IRI onset due to graft environment-dependent pro- and anti- inflammatory activities. This review focuses on the impact of IL-27 on IRI of liver xenotransplants and provides insights on the function of IL-27 that could potentially guide genetic engineering strategies of donor pigs and/or conditioning of organs prior to transplantation.     

Decrease in arterial ketone body ratio indicating graft dysfunction after liver transplantation.

In 3 cases of living related liver transplantation, arterial ketone body ratio (AKBR) showed secondary decrease in the early postoperative period, indicating the graft dysfunction more rapidly and sensitively than other liver function tests. Significance of AKBR for monitoring the graft function in postoperative management after liver transplantation is discussed.     

The role of antibodies in dysfunction of pig-to-baboon pulmonary transplants

OBJECTIVE: Pulmonary transplantation has become the preferred treatment for end-stage lung disease, but application of the procedure is limited because of a paucity of donors. One way to solve donor limitations is to use animal organs as a donor source or xenotransplantation. The current barrier to pulmonary xenotransplantation is the rapid failure of the pulmonary xenograft. Although antibodies are known to play a role in heart and kidney xenograft rejection, their involvement in lung dysfunction is less defined. This project was designed to define the role of antibodies in pulmonary graft rejection in a pig-to-baboon model. METHODS: Orthotopic transgenic swine left lung transplants were performed in baboons depleted of antibodies by one of three techniques before transplantation: (1) ex vivo swine kidney perfusion, (2) total immunoglobulin-depleting column perfusion, and (3) ex vivo swine lung perfusion. Results were compared with those of transgenic swine lung transplants in unmodified baboons. RESULTS: All three techniques of antibody removal resulted in depletion of xenoreactive antibodies. Only pretransplantation lung perfusion improved pulmonary xenograft function compared with lung transplantation in unmodified baboons. CONCLUSIONS: The pathogenesis of pulmonary injury in a swine-to-primate transplant model is different from that in renal and cardiac xenografts. Depletion of antibodies alone does not have a beneficial effect and may actually be detrimental.     

肝肾胰联合移植的围手术期处理

目的总结肝胰肾联合移植围手术期处理的经验。方法报告肝、胰、肾一期联合移植治疗1例乙型肝炎后肝硬化、肝功能不全合并慢性肾功能不全伴慢性胰腺炎导致胰岛素依赖型糖尿病患者的临床特点及治疗体会。对患者围手术期处理及相关资料进行回顾性分析。结果采用胰液空肠内引流及原位背驮式同期尸体肝、胰、肾联合移植。手术顺利，移植肝脏及胰腺功能1周内逐渐恢复，肾功能延迟恢复。术后第16天因移植肾血流下降，切除移植肾脏，于原移植部位行第2次肾移植，肾功能逐渐恢复正常。至2005年11月随访10个月，患者未发生排斥反应及明显感染，移植肝、胰、肾功能均正常，一般情况良好。结论肝胰肾联合移植技术安全，术后因各脏器对功能恢复所需内环境各不相同，矛盾较多，围手术期处理对患者的长期存活至关重要。     

Serum total bile acids monitoring after experimental orthotopic liver transplantation

The aim of this study was to evaluate the usefulness of serum total bile acids estimation in monitoring liver allograft recipients. To this end frequent blood samples and simultaneous needle biopsies of the liver were taken after orthotopic liver transplantation in unimmunosuppressed pigs. Serum bile acids were found to rapidly increase during the anhepatic phase of the transplantation procedure and to decrease after implantation of the liver graft. A normal serum bile acids level in the early postoperative phase was indicative of a technically successful transplantation procedure. A total of 28 successful transplantations was performed. Six recipients accepted the allograft without any histological sign of rejection. In 18 pigs the liver was rejected, the survival time of these animals ranged from 6 to 80 days. Four animals showed a transient rejection episode during the first months after transplantation. In nonrejecting animals serum bile acids remained undisturbed during the entire 4-month study period. In all cases of rejection serum bile acids promptly increased to very high levels of 100 to 700 mumol/liter (reference range 1 to 14 mumol/liter). Serum bile acids were found to be superior to standard liver function tests in detecting the process of liver rejection at an earlier stage. These results indicate that serum total bile acid estimation is a simple and useful test to monitor liver allograft recipients.     

Indirect Recognition of MHC Class I Allopeptides Accelerates Lung Allograft Rejection in Miniature Swine

The role of indirect allorecognition in graft rejection is examined in two experiments using a swine lung transplantation model. First, two swine received class I mismatched grafts without immunosuppression; another two recipients were treated postoperatively with cyclosporine (CsA). These swine exhibited acute and chronic rejection, respectively. All four recipients developed T-cell reactivity to donor-derived class I major histocompatibility complex (MHC) peptides. Second, six swine were immunized with synthetic donor-derived class I allopeptides prior to transplantation. Control groups consisted of nonimmunized recipients (n = 6) and recipients immunized with an irrelevant peptide (n = 3). These recipients all received a 12-day course of post-operative CsA. Swine immunized with allopeptides exhibited accelerated graft rejection, as compared to both control groups (p < 0.01 and p = 0.03, respectively). Within the experimental group, the dominant histologic finding was acute rejection (AR). Obliterative bronchiolitis (OB) was seen in the graft with the longest survival. Both control groups showed a lesser degree of AR, with four out of six nonimmunized swine ultimately developing OB. These studies suggest that indirect allorecognition is operative during lung allograft rejection, and that pre-transplant sensitization to donor-derived MHC allopeptides can accelerate graft rejection.