Prolongation of lung xenograft survival in rats with a short course of deoxyspergualin and cyclosporin A

The efficacy of 15-deoxyspergualin (DSG), cyclosporin A (CyA), and splenectomy-alone or in combination-in prologing the survival of concordant lung xenotransplants was studied in the hamster-to-rat model. In the untreated group, rejection occurred within 3 days, with an elevation of lymphocytotoxic antibody titers. The rejected lung revealed that ED1+cells were more prevalent than MRC OX8+cells in the perivascular infiltrates. In the DSG group, the antibody response was suppressed and median survival increased to 7.5 days. The rejected lungs demonstrated a highly significant depression in ED1+cellular infiltration and a moderate MRC OX8+cellular infiltration. When maintenance CyA was combined with a short course of DSG, survival dramatically increased to beyond 100 days. There were no deposits of IgM, IgG, or C3 or of any cell infiltrate in the grafts of two animals sacrificed 107 and 119 days post-transplantation. We conclude that initial treatment with DSG combined with continuous CyA can suppress acute rejection in the hamster-to-rat lung xenograft model, resulting in longterm graft survival.     

Transimission of donor lymphocytes in clinical lung transplantation

Passenger mononuclear cells in organ grafts are known to influence the alloimmune response to the graft. To assess their relevance in clinical lung transplantation, we studied the amount, distribution, cell types, and surface marker expression of mononuclear cells in human donor lungs. Two major compartments of mononuclear cells could be differentiated: lymph nodes containing resting T and B lymphocytes, and the lung tissue itself, containing mainly activated lymphocytes as well as monocytes/macrophages. Tissue-associated mononuclear cells make up 20–40x10⁹ cells per lung, about 30–50 % of which are lymphocytes. Tissue-associated lymphocytes are predominantly T and NK cells; most of the T cells are CD8⁺ CD45R0⁺ and express HLA-DR. Strong expression of the adhesion molecules LFA-1 and ICAM-1 is present on infiltrating cells as well as on resident cells of the organ. Moreover, the lymphocytes inside the lung tissue are functionally highly active, with a strong stimulatory as well as alloreactive potency. Thus, large numbers of allogeneic mononuclear cells and particularly large numbers of functionally active lymphocytes are obviously transmitted by human lung allografts. The immunological in vivo relevance of these cells after lung transplantation may include allostimulation and graft-versus-host activity, but also beneficial immunomodulatory effects.     

Comparison of Three Tacrolimus-Based Immunosuppressive Regimens in Lung Transplantation

Immunosuppressive therapy for solid organ transplantation has significantly evolved over the past decade. While these therapies have been found to be beneficial in abdominal organ transplantation, the efficacy of these therapies remains unclear in lung transplantation. We retrospectively compared three potent immunosuppressive regimens in our lung transplant population: Group 1 (tacrolimus/azathioprine/prednisone), Group 2 (tacrolimus/azathioprine/prednisone/daclizumab) and Group 3 (tacrolimus/mycophenolate mofetil/prednisone/daclizumab). We compared these three groups with respect to 3-year rates of acute rejection, chronic rejection, infection and survival. A total of 109 patients was followed during the course of this study. There were 32 patients in Group 1, 49 patients in Group 2 and 28 patients in Group 3. Freedom from acute rejection at 1 and 3 years were higher in Group 3 compared with Group 1 (p < 0.05). The overall incidence of infection up to 3 years after transplantation was comparable among all three groups. Freedom from chronic rejection and survival at 1 and 3 years did not differ among the three groups. In conclusion, we determined the safety and efficacy of three potent immunosuppressive regimens in lung transplantation. Addition of daclizumab and MMF to a tacrolimus-based immunosuppressive regimen decreased the incidence of acute rejection episodes without increasing any adverse events in our lung transplantation population.     

Effect of cyclosporin on lung diffusing capacity in renal transplant patients

A prospective lung function study pre- and postrenal transplantation was performed on 21 patients in order to evaluate whether cyclosporin decreased the lung diffusing capacity due to lung toxicity. Initial inclusion criteria were absence of respiratory symptoms and normal findings in both chest X-ray and pulmonary function tests. Participants had to be nonsmokers. We determined spirometry including lung volumes, arterial blood gases, carbon monoxide diffusing capacity by the single breath method (D_LCO_SB), and rate of CO uptake per unit of lung volume (KCO) before and 3, 6, and 12 months after transplantation. Immunosuppression consisted of prednisone and cyclosporin, maintaining total blood levels between 100 and 250 ng/ml. Spirometric and blood gases data remained within reference levels during the follow-up. Hemoglobin (Hb) pretransplant concentrations remained low, returning to their normal levels posttransplantation. Pretransplant D_LCO_SB levels were slightly decreased but fell within the therapeutic range after correction for Hb concentration, unlike the mean KCO levels which remained slightly diminished despite their correction. In post-transplant controls, the values obtained for both D_LCO_SB and KCO were significantly higher at the different post-transplant intervals (P<0.005) than pretransplantation but only when compared without Hb correction. No significant differences for D_LCO_SB were found when corrected values were compared, and an improvement in the KCO appeared to be significant at 12 months posttransplantation. Based on these findings, we feel that when serum levels are within the therapeutic range, cyclosporin fails to alter the respiratory function or the pulmonary diffusing capacity of the lung.     

Does high MHC class II gene expression in normal lungs account for the strong immunogenicity of lung allografts?

Clinical experience has demonstrated that lung allografts are considerably more immunogenic than liver allografts although both organs contain equivalent amounts of lymphoreticular tissue. Northern blot analysis of MHC class II gene expression in various murine organs with I-AB and I-EB gene-specific oligonucleotide probes revealed that MHC class II expression in lungs is semiquantitatively higher than in the liver and other organs with the exception of the spleen. We conclude that this high MHC class II expression strongly suggests that the lymphoreticular tissue in the lungs is in a state of activation. This may be an important reason for the strong immunogenicity of lung allografts.     

Liver transplantation for massive hepatic haemangiomatosis causing restrictive lung disease

A 34-yr-old man with hepatic haemangiomatosis presented fororthotopic liver transplantation. His massively distended abdomencaused thoracic compression and severe restrictive lung disease.Respiratory failure was the principal indication for transplantation.Increased airway pressures, pulmonary hypertension, systemichypotension caused by aorto-caval compression, and blood loss,complicated the intra-operative anaesthetic management. Weaningfrom mechanical ventilation was impaired by acute and chronicmetabolic alkalosis, and diaphragmatic laxity. Br J Anaesth 2000; 86: 431–4     

HLA-DRB1 compatibility in cadaver kidney transplantation: correlation with graft survival and function

The introduction of genomic HLA-DR typing has stimulated a re-evaluation of the role of HLA-DR compatibility on cadaver kidney transplantation. We retrospectively studied the influence of HLA-DRB1 matching on the survival of 416 patients using univariate and Cox regression analysis as well as its influence on the occurrence of rejection episodes and on creatinine level at the 3rd month in the 198 recipients for whom these data were available. The following parameters were also considered: HLA-A,B compatibility, donor and recipient age, graft number, pretransplant blood transfusions and panel reactive antibodies (PRA). Twenty-four month graft survival was 100% for transplants with zero mismatches (n=47), 87.9% for those with one mismatch (n-191) and 81.3% for those with two mismatches (n=178). In the Cox model, HLA-DRB1 matching was the most significant variable influencing graft survival (47% of ² P=0.001), followed by HLA-A,B matching (23%, P=0.02) and donor age (19%, P=0.04). Ninety-two percent of the patients with zero mismatches experienced no rejection episodes in the first 3 posttransplant months compared with 62% and 41% of patients with one and two mismatches, respectively. Mean creatinine level (mg/dl) was 1.2, 1.4, and 1.5 in patients with zero, one, and two mismatches, respectively. Should these results be confirmed by prospective studies, HLA-DRB1 compatibility will have to be considered as an organ allocation criterion.     

Extracorporeal membrane oxygenation for lung transplant recipients with primary severe donor lung dysfunction

Primary severe donor lung dysfunction (DLD) is a significant complication after lung transplantation (LTx), and a high mortality is reported with conventional therapy. The purpose of this report is to review the experience of the University of Pittsburgh with extracorporeal membrane oxygenation (ECMO) for primary severe DLD after LTx. From September 1991 to May 1995, 220 LTx were performed at our center. Eight patients (8/220=3.6%) with severe DLD after LTx required ECMO support. The age of LTx recipients was 44±5 years (mean±SD); seven patients were female and one was male. Indications for LTx were: chronic obstructive pulmonary disease in four patients, bronchiectasis in two, and pulmonary hypertension in two. There were three single LTx and five bilateral LTx. The interval from LTx to institution of ECMO was 5.6±3.2 h (range 0–10 h). Three patients were supported with veno-venous (v-v) ECMO and five had veno-arterial (v-a) ECMO. The duration of ECMO support was 7.3±4.8 days (range 3–15 days). activated glotting time (ACT) was maintained between 110 and 180 s with intermittent use of heparin. Seven patients (7/8=87%) were successfully weaned from ECMO and six patients (6/8=75%) were discharged home; they are currently alive after a follow-up of 17±10.1 months. One patient died on ECMO support for refractory DLD and another died 2 months after ECMO wean from multisystem organ failure. At 6 months follow-up, forced expiratory volume in 1 s (FEV1) is 2.35±0.91 (75%±17.4% predicted) and mean forced vital capacity (FVC) is 2.53±0.81 (64%±14% predicted). We conclude that ECMO can be lifesaving when instituted early after primary severe DLD. The v-v ECMO support is preferred when the patient is hemodynamically stable and adequate long-term function of the allograft is anticipated.     

Combined donor specific transfusion and anti-CD154 therapy achieves airway allograft tolerance

BACKGROUND: The state of tolerance allows long term graft survival without immunosuppressants. Lung transplantation tolerance has not been consistently achieved in either small or large animal models. METHODS: The mechanisms and effectiveness of a tolerance induction protocol consisting of donor specific transfusion (DST; day 0) and a short course of co-stimulatory blockade (anti-CD154 antibody; days -7, -4, 0 and +4) were studied in the mouse heterotopic tracheal transplant model of chronic lung rejection. C57BL/6 mice received BALB/c tracheal grafts (day 0) and were treated with DST alone, anti-CD154 alone, the combination (DST/anti-CD154), or no treatment. No non-specific immunosuppressants were used. RESULTS: DST/anti-CD154 in combination, but neither treatment alone, markedly prolonged the lumen patency and survival (>100 days) of fully histo-incompatible allografts (p<0.05 versus control allografts at every time point studied up to 16 weeks) without immunosuppression. This protocol was donor antigen specific as third party grafts (C3H) were promptly rejected. In addition, DST/anti-CD154 did not result in mixed chimerism but induced transplantation tolerance via a peripheral mechanism(s), which included significantly reduced cytotoxic T cell activity (p<0.001) and a significantly increased percentage of CD4+CD25+ cells (p = 0.03). CONCLUSIONS: The DST/anti-CD154 protocol successfully induced and maintained long term, donor specific tolerance in the mouse heterotopic airway graft model of chronic lung rejection. This finding may lead us closer to successful tolerance induction in lung transplantation.     

Lung and heart-lung transplantation

This report is a brief summary on current events related to lung and heart-lung transplantation. Eleven patients have undergone transplantation of the heart and both lungs at Stanford University. The ages ranged from 22–45, the average age being about 36 years, and included were four females and seven males. The diagnosis was primary pulmonary hypertension in three and Eisenmenger syndrome-congenital heart disease with pulmonary hypertension-in eight. Eight patients are living and well, two to more than 24 months after transplantation of the heart and both lungs. All these patients were discharged and are fully rehabilitated, which is an important consideration. There have been three operative deaths, one was secondary to two previous operations that made our operation much too long, another was secondary to the use of intravenous cyclosporine, and the third was related to the poor maintenance of the donor lung. Three of the eleven patients were catheterized following the transplant from six months to a year after transplantation, and the pulmonary artery pressure and pulmonary vascular resistance were absolutely normal in all three of these individuals. Of course the plan is to go ahead with further catheter studies at yearly intervals in all of the patients. The last patient underwent transplantation in January, 1983. I think no matter how effective or how ingenious the medical staff is with artificial organs, it will be a long time before these early results of transplantation of the heart and both lungs can be matched by any types of artificial organ implants. Supported in part by a grant (HL 13108) from the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, and from the Dr. Ralph and Marian Falk Foundation for Medical Research Gist of a Lecture given at the Japan Surgical Society, April 7, 1983.     

肺移植供肺保护进展

肺移植成为终末期肺病的惟一治疗手段。然而其死亡率仍高于其他实质器官移植,供肺保存过程中损伤机制的探讨与保存方法的改进将有利于提高生存率。     

Effect of prostaglandin E1 on preservation injury of canine liver grafts preserved in UW solution

This study investigated whether prostaglandin E₁ (PGE₁) could reduce hepatic injury to the liver graft caused by harvesting and 24-h preservation in University of Wisconsin (UW) solution in a canine model. The PGE₁-treated group was intravenously administered 0.5 g/kg per minute of PGE₁ for 30 min before harvesting, as well as a concentration of 1 mg/l PGE₁ in the washout and UW solutions. In both the PGE₁-treated and the control group, all recipients survived for 1 week or more after transplantation. Arterial ketone body ratio (AKBR) remained over 1.0 in the early postoperative period. The PGE₁ group showed significant reductions in guanase, GOT, and LDH during the early postoperative period compared to the untreated control group. Histological examination disclosed partial mitochondrial swelling, hepatocyte vacuolation, and necrosis in the control group, while such abnormalities were rarely seen in the PGE₁ group. These results suggest that PGE₁ can effectively reduce hepatic injury to liver grafts preserved in UW solution prior to transplantation.     

Non-tuberculous mycobacteria in end stage cystic fibrosis: implications for lung transplantation

BACKGROUND: WC and NS contributed equally. Non-tuberculous mycobacteria (NTM) frequently colonise patients with end stage cystic fibrosis (CF), but its impact on the course of the disease following lung transplantation is unknown. METHODS: Lung transplant recipients with CF who underwent lung transplantation at our institution between January 1990 and May 2003 (n=146) and CF patients awaiting lung transplantation in May 2003 (n=31) were studied retrospectively. RESULTS: The prevalence rate of NTM isolated from respiratory cultures in patients with end stage CF referred for lung transplantation was 19.7%, compared with a prevalence rate of 13.7% for NTM isolates in CF lung transplant recipients. The overall prevalence of invasive NTM disease after lung transplantation was low (3.4%) and was predicted most strongly by pre-transplant NTM isolation (p=0.001, Fisher's exact test, odds ratio (OR) 6.13, 95% CI 3.2 to 11.4). This association was restricted to Mycobacterium abscessus (p = 0.005, Fisher's exact test, OR 7.45, 95% CI 2.9 to 16.9). While NTM disease caused significant morbidity in a small number of patients after transplantation, it was successfully treated and did not influence the post-transplant course of the disease. CONCLUSION: The isolation of NTM before transplantation in CF patients should not be an exclusion criterion for lung transplantation, but it may alert the clinician to patients at risk of recurrence following transplantation.     

Role of Endogenous Endothelin-1 in Transplant Obliterative Airway Disease in the Rat

Endothelin-1 (ET-1) expression is increased after lung transplantation in association with ischemia reperfusion injury and acute rejection. However, little is known of the role of ET-1 during the development of obliterative bronchiolitis. In this study, we investigated the biological significance of ET-1 in obliterative airway disease development using a rat tracheal allograft model. Immunoreactivity of ET-1 and its receptors ET-RA and ET-RB was increased four-fold in allografts compared with syngrafts and localized to mononuclear cells and smooth muscle cells of the myofibroproliferative lesion and airway wall, indicating that ET-1 may mediate its effects in both a paracrine and autocrine manner in smooth muscle cells. Inhibition of ET-1 action by a nonselective ET-1 receptor antagonist, bosentan, significantly decreased tracheal occlusion, which was linked to delayed epithelial necrosis, suppressed smooth muscle cell proliferation, and a marked reduction in the number of interleukin-1beta and interleukin-2 immunoreactive cells. Our findings show that endogenous ET-1 activation is associated with obliteration of the airway wall, and blocking signaling downstream of ET-1 receptors leads to attenuation of obliterative airway disease. The results suggest that ET-1 has a proproliferative and proinflammatory role in the development of obliterative bronchiolitis.