HLA matching and outcome of heart transplantation.
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Graft Rejection↗
Biomedical subjects
T Wekerle
Publications and source records attributed to T Wekerle.
Induction of alloantigen-specific hyporesponsiveness in vitro by n-butyrate: antagonistic effect of cyclosporin A.
The short-chain fatty acid n-butyrate has recently been shown in vitro to specifically downregulate T cell reactivity to nominal antigen or to alloantigen, which possibly results from inhibition of cell cycle progression in early G1 phase during antigen contact. In the present study, we investigated the effect of cyclosporin A (CyA) on the modulation of alloreactivity in human mixed lymphocyte culture (MLC) by n-butyrate. Whereas in primary culture, CyA additively enhanced inhibition of DNA synthesis by n-butyrate, the effect of this agent on secondary T cell reactivity was clearly antagonized by CyA. Thus, specific downregulation of proliferative responsiveness to restimulation with antigen from the original donor, observed in cultures pretreated with n-butyrate alone, was at least partially prevented by the addition of CyA to the primary culture. Our in vitro finding indicates that specific downregulation of T cell alloreactivity by n-butyrate might depend on a calcium-dependent T cell receptor (TCR)-mediated signal sensitive to the immunosuppressive action of CyA.
Butyrates↗
Lung retransplantation: institutional report on a series of twenty patients.
BACKGROUND AND METHODS: Between 1986 and 1995, 124 isolated lung and 29 combined heart-lung transplantations were performed at our institution. Twenty of these procedures were retransplantations. Four different types of reoperations were performed: ipsilateral single lung retransplantation (n = 3), single lung retransplantation after bilateral or heart-lung transplantation (n = 7), bilateral retransplantation after bilateral lung transplantation (n = 5), and bilateral retransplantation after single lung transplantation (n = 5). Nine patients underwent retransplantation while still in the intensive care unit after the primary transplantation. Indications for retransplantation in these patients were primary graft failure in seven and bronchial complications in two patients. In 11 patients a late retransplantation (3 to 30 months after the first transplantation) was performed. The indication was obliterative bronchiolitis in nine and late bronchial complications in two patients. Overall, 13 patients were ventilator-dependent before retransplantations. RESULTS: Overall survival was 52.8% and 36.2% at 1 and 12 months, respectively. For early retransplantation the survival rate at 1 month was only 22.2% with 2 patients alive 5 and 22 months after the retransplantation. For late retransplantation survival at 1 and 12 months was 70.7% and 50.5%, respectively (p = 0.07), and the longest surviving patient was at 47 months after retransplantation at the time this article was written. Patients who were ventilator-dependent before retransplantation had a significantly worse outcome (survival at 1 and 12 months: 33.8% and 25.4% versus 85.7% and 57.1% for all others, p = 0.055). Of those surviving to date, all were in New York Heart Association class I or II. CONCLUSIONS: We conclude that late and elective lung retransplantation achieves acceptable results when offered to patients with chronic pulmonary dysfunction but with otherwise stable conditions. In view of the poor results, early acute retransplantation should be performed much more restrictively.
Adolescent↗
Tailoring of the lung to overcome size disparities in lung transplantation.
BACKGROUND: Between October 1989 and December 1994 in 13 (four single and nine bilateral lung transplantations) of 124 lung transplantations, pulmonary allografts were considered to be too large to fit into the recipient thoracic cavity. METHODS: In all these patients (emphysema n = 6, fibrosis n = 4, pulmonary hypertension n = 3), the transplanted lungs were trimmed by extra anatomic wedge resections with the use of mechanical stapling devices to reach an acceptable size. RESULTS: No postoperative complication attributable to the tailoring procedure was observed. CONCLUSIONS: Tailoring of the lung is a safe and efficient method to overcome moderate size disparities between donor and recipient lungs.
Humans↗
Influence of human leukocyte antigen matching on long-term outcome after lung transplantation.
BACKGROUND AND METHODS: The importance of human leukocyte antigen matching for long-term outcome after lung transplantation is uncertain. We therefore analyzed retrospectively 78 consecutive primary, isolated lung transplantations (37 female, 41 male; 40 single, 38 bilateral) performed between October 1989 and October 1995 for which human leukocyte antigen typing of both donor and recipient was available. The follow-up ranged from 1 day to 60.3 months. Graft failure, defined as retransplantation or patient death, served as end point. RESULTS: Graft survival was significantly better with one mismatch at the B locus than with two mismatches (p = 0.046): 67% versus 51% and 61% versus 25% graft survival at 12 and 36 months, respectively. For the B and DR loci combined, a marked matching effect was also observed (p = 0.21 for zero to two mismatches versus three to four mismatches: 81% versus 62% and 51% versus 29% graft survival at 12 and 36 months, respectively. The sum of mismatches at the A, B, C, and DR loci combined showed a similar effect (p = 0.17 for zero to four mismatches versus five to eight mismatches: 83% versus 62% and 58% versus 29% graft survival at 12 and 36 months, respectively. Although no clear effect could be shown for the isolated DR locus, the outcome for the three patients with zero mismatches was notably good: one patient is alive at 27 months, two died 37 and 48 months after transplantation. The number of acute rejection episodes showed a clear but insignificant correlation to the number of mismatches. A similar trend was observed for the incidence of bronchiolitis obliterans syndrome. CONCLUSIONS: In summary, a strong influence of human leukocyte antigen matching on the long-term outcome after lung transplantation is suggested by our results. A clear trend toward improved graft survival with better human leukocyte antigen matching was observed, with the most significant effect occurring at the B locus.
Adolescent↗
[Differential diagnosis of round opacities after lung transplantation].
Incidence, aetiology, diagnosis and treatment of round lesions in the lungs were analysed in 64 patients after lung transplantation (33 men, 31 women; mean age 45 [21-68] years; postoperative survival > 2 weeks). These lesions were found in 8 patients 1-10 months (median of 5.8 months) after the transplantation, singly in two, multiple in six. In six patients it was an incidental finding, further elucidated by computed tomography or fine-needle biopsy. The aetiology varied from B-cell "lymphoma" (posttransplant lymphoproliferative disorder-PTLD) in three patients, aspergilloma in two, and bacterial abscess in one. Two patients died of septicaemia (Aspergillus; Pseudomonas aeruginosa/Staphylococcus aureus), while four had a full remission. The solitary lesions disappeared without specific treatment in 2-3 weeks. If round lesions are noted after lung transplantation, rapid histological and microbiological diagnosis and aggressive treatment are necessary to combat an otherwise high death-rate. PTLD and infection (bacterial or mycotic) are the most frequent causes.
Adult↗
Closed circuit perfusion of an isolated rabbit lung. A new model for the evaluation of preservation quality of stored lungs.
The comparison of different preservation methods in lung transplantation demands a well standardized and reproducible animal model. The aim of this study was to establish as in vitro model in which the oxygenation capacity of the lung can be investigated over an extended period of time. Heart-lung blocks from 6 New Zealand white rabbits were harvested, the pulmonary artery and the left ventricle cannulated and the lungs perfused with whole rabbit blood by means of a roller pump and ventilated with room air. A dialyser was installed into the closed circuit perfusion for continuous deoxygenation of the oxygen-saturated blood gained from the left ventricle. Throughout the stable perfusion period the average arterial and venous partial oxygen pressure (pO2) levels were 105.8 +/- 15.5 mmHg and 55.2 +/- 6.2, respectively (P < 0.05). The average peak airway pressure steadily increased from 10.7 +/- 1.2 mmHg at the start of reperfusion to 21 +/- 14.4 mmHg after 180 minutes (P = NS). With this experimental setting it is possible to maintain stable conditions (i.e. constant venous and arterial blood gases) for at least 180 minutes. It is therefore feasible to compare the influences of different preservation methods on the quality of lung function.
Animals↗
Management of severe bronchial ischemia after bilateral sequential lung transplantation.
A case of severe diffuse bronchial ischemia after bilateral sequential lung transplantation is presented. A combination of initial conservative treatment with silicone stenting and late bilateral retransplantation under stable conditions resulted in good clinical outcome. Factors in decision making and technical aspects of the stenting procedure are discussed.
Adult↗
Phylogenetic disparity influences the predominance of direct over indirect pathway of antigen presentation in islet xenotransplantation.
BACKGROUND: Cellular immunity plays a major role in rejection of xenografted islets. Depending on the phylogenetical disparity, direct or indirect antigen presentation is predominant. The aim of this study was to analyze in vitro the predominance of direct or indirect presentation, and in vivo the effect of macrophage depletion on concordant and discordant islet xenograft survival. MATERIALS AND METHODS: In vitro, we performed mouse antirat and mouse antihuman mixed lymphocyte reactions (MLR) after depletion of responder or stimulator antigen-presenting cells. In vivo, streptozotocin-induced diabetic C57BL/6 mice were treated by gadolinium chloride to deplete macrophages and rat or human islets were transplanted under the kidney capsule. Islet function was followed by glycemia and xenografts were analyzed at regular intervals for histology. RESULTS: Mouse antirat MLR showed a predominant direct antigen presentation pathway, whereas in mouse antihuman MLR, direct and indirect pathways were similarly involved. Survival of rat islets was not modified by GdCl therapy. In contrast, survival of human islets was significantly prolonged in GdCl-treated mice. Macrophage infiltration was decreased in concordant and discordant GdCl-treated xenografts at day 4, compared to controls. At day 15, macrophage infiltration was similar in all groups. DISCUSSION: Our results indicate that direct antigen presentation is dominant in rejection of concordant islet xenografts and cannot be influenced by host macrophage depletion. Both direct and indirect antigen presentation are involved in rejection of discordant xenogeneic islets. Macrophage depletion or inhibition should be considered as therapeutic tool for discordant islet xenotransplantation.
Animals↗
Role of CD40-CD154 pathway in the rejection of concordant and discordant xenogeneic islets.
BACKGROUND: Costimulatory blockade has been shown to allow long-term survival of xenogeneic islets. The aim of the present study was to evaluate the role of recipient CD40 and CD154 in the rejection process of concordant and discordant islet xenotransplantation (Tx). METHODS: Diabetic C57BL/6 mice, CD40- or CD154 knockout (KO) mice were transplanted with either concordant rat or discordant human islets. EXPERIMENTAL DESIGN: group 1, control (ie, C57BL/6 mice received islet Tx without therapy); group 2, C57BL/6 mice received islet Tx with anti-CD154 monoclonal Ab (mAb) therapy; group 3, CD40 KO mice; and group 4, CD154 KO mice were used as recipients without therapy. Mouse anti-rat mixed lymphocyte reactions (MLR) were performed using mouse splenocytes obtained from animals transplanted with rat islets in groups 1 to 4. RESULTS: In group 2, short-term anti-CD154 mAb therapy significantly prolonged rat-to-mouse and human-to-mouse xenograft survival, compared to controls. In CD40-KO and CD154-KO recipients, survival of concordant or discordant islets was not prolonged significantly compared to control groups. Mouse anti-donor rat cellular responses were reduced approximately 50% in group 2 but remained unmodified in groups 3 and 4, when compared to group 1. CONCLUSIONS: Improved graft survival and reduced MLR responses against donor cells in vitro among the anti-CD154 mAb-treated mice could be explained by specific targeting of activated T cells with subsequent inactivation by anergy and/or elimination by apoptosis, or complement- or cellular-mediated mechanisms. Rejection of xenografts and strong MLR responses against donor cells in vitro in CD40 or CD154 KO animals is possible through efficient activation of alternate pathways of costimulation.
Animals↗
Role of peripheral clonal deletion in tolerance induction with bone marrow transplantation and costimulatory blockade.
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Abatacept↗
The advantage of allocating kidneys from old cadaveric donors to old recipients: a single-center experience.
BACKGROUND: In January 1999 a new kidney allocation program was launched by the Eurotransplant Foundation, the 'Eurotransplant Senior Program' (ESP). Cadaveric donors above the age of 65 yr are allocated to kidney transplant recipients of the same age group. METHODS: Using a single-center database, 91 patients who underwent first renal transplantation at the age of 65 yr and older in the years 1999-2002 were identified. Fifty-six patients were transplanted through ESP allocation (study group) and 35 patients (control group) via normal Eurotransplant Kidney Allocation System (ETKAS) procedure. RESULTS: Age, sex and comorbid conditions did not differ by group. The rate of acute rejection episodes, primary non-function, delayed graft function, perioperative mortality did not differ by group. Serum creatinine was significantly lower in the ETKAS group (1.3 vs. 1.9 mg/dL; p=0.015) from six months after the transplantation on. Overall graft survival at six yr was 56% in the ETKAS group and 52% in the ESP group. With 73% in the ETKAS group and 71% in the ESP group, cumulative patient survival according to the Kaplan-Meier estimation was not statistically different at five yr. CONCLUSIONS: We did not find a relevant difference in the outcome between young and old kidney transplants in old recipients after this long observation period.
Aged↗
A new flush solution for extended lung preservation.
BACKGROUND: The aim of this study was to compare the effect of the most frequently used clinical preservation solution (Euro-Collins, group I) with a newly composed low potassium, glucose- and insulin-containing preservation solution (141 mmol/L sodium, 6.4 mmol/L potassium, 119 mmol/L chloride, 5 mmol/L magnesium, 10 gm/L glucose, 10 gm/L dextrane and 20 U/L insulin) (group II) on postischemic lung function. METHODS: We studied 12 isolated New Zealand White rabbit lungs in a closed circuit model during the first 4 hours of reperfusion after 24 hours of ischemic hypothermic storage. RESULTS: Oxygenation capacity, defined by the difference between the arterial and venous oxygen tension was significantly higher in group II compared with group I after 10 (58.7 +/- 5.8 versus 34.9 +/- 7.5 mm Hg), 30 (63.5 +/- 7.8 versus 27.3 +/- 10.4 mm Hg) and 180 minutes (77.7 +/- 7.2 versus 8.8 +/- 5.6 mm Hg). Ventilatory pressure was significantly lower in group II after 1 minute (11.3 +/- 1.3 mm Hg versus 13.7 +/- 0.5 mm Hg, p < 0.05), with no significant difference thereafter. No significant difference was found in pulmonary vascular resistance except after 20 minutes (30.8 +/- 1.2 dyns/cm5 [group I] versus 27.1 +/- 1.1 dyns/cm5 [group II], p < 0.05). CONCLUSION: These data suggest that this new solution provides superior lung function after 24 hours ischemic time compared with Euro-Collins solution.
Animals↗