Search

Background: The mixed chimerism approach for intentional induction of donor-specific tolerance was shown to be successful in various models from mice to humans. For transplant patients, the approach would obviate the need for long-term immunosuppression and associated side effects; moreover, it would preclude the risk of late graft loss due to chronic rejection. Widespread clinical application is hindered by toxicities related to recipient pre-conditioning. Herein we aimed to investigate a clinically relevant protocol for tolerance induction to cardiac allografts, sparing CD40 blockade or T-cell depletion., Methods: B6 mice were conditioned with non-myeloablative total body irradiation, fully mismatched BALB/c bone marrow cells, and short-term therapy, based on either anti- lymphocyte function-associated antigen-1 (anti-LFA-1) or anti-CD40L. Multilineage chimerism was followed by flow-cytometric analysis, tolerance was assessed with skin and heart allografts from fully or major histocompatibility complex-mismatched donors. Mechanisms of tolerance were investigated by analysis of donor-specific antibodies (DSAs), mixed lymphocyte reaction (MLR) assays, and deletion of donor-reactive T cells., Results: We found that the combination of cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA4Ig) and rapamycin with LFA-1 blockade enhanced bone marrow engraftment and led to more efficient T-cell engraftment and subsequent tolerization. Although fully mismatched skin grafts were chronically rejected, primarily vascularized heart allografts survived indefinitely and without signs of chronic rejection, independent of minor antigen mismatches., Conclusions: We have demonstarted a robust protocol for the induction of tolerance for cardiac allografts in the absence of CD40 blockade. Our findings demonstrate the potential of a clinically relevant minimal conditioning protocol designed to induce lifelong immunologic tolerance toward cardiac allografts., (Copyright © 2018 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: The mixed chimerism approach induces donor-specific tolerance in both pre-clinical models and clinical pilot trials. However, chronic rejection of heart allografts and acute rejection of skin allografts were observed in some chimeric animals despite persistent hematopoietic chimerism and tolerance toward donor antigens in vitro. We tested whether additional cell therapy with regulatory T cells (Tregs) is able to induce full immunologic tolerance and prevent chronic rejection., Methods: We recently developed a murine "Treg bone marrow (BM) transplantation (BMT) protocol" that is devoid of cytoreductive recipient pre-treatment. The protocol consists of a moderate dose of fully mismatched allogeneic donor BM under costimulation blockade, together with polyclonal recipient Tregs and rapamycin. Control groups received BMT under non-myeloablative irradiation and costimulation blockade without Treg therapy. Multilineage chimerism was followed by flow cytometry, and tolerance was assessed by donor-specific skin and heart allografts., Results: Durable multilineage chimerism and long-term donor skin and heart allograft survival were successfully achieved with both protocols. Notably, histologic examination of heart allografts at the end of follow-up revealed that chronic rejection is prevented only in chimeras induced with the Treg protocol., Conclusions: In a mouse model of mixed chimerism, additional Treg treatment at the time of BMT prevents chronic rejection of heart allografts. As the Treg-chimerism protocol also obviates the need for cytoreductive recipient treatment it improves both efficacy and safety over previous non-myeloablative mixed chimerism regimens. These results may significantly impact the development of protocols for tolerance induction in cardiac transplantation., (© 2014 International Society for Heart and Lung Transplantation Published by International Society for the Heart and Lung Transplantation All rights reserved.)

Although short- and long-term results after organ transplantation have improved considerably in recent years, morbidity and mortality rates in graft recipients remain high. The induction of lifelong donor-specific tolerance would dramatically improve outcome after organ transplantation. Although many tolerance protocols have been successful in rodent studies, most of these approaches have failed when attempted in large animals or humans. Robust tolerance, in contrast, has been demonstrated with mixed chimerism regimens not only in rodents but also in large animal models, including non-human primates. Furthermore, mixed chimerism protocols have been developed that would be feasible in cadaveric, and thus in thoracic, transplantation. The induction of mixed hematopoietic chimerism is therefore an attractive experimental approach for development of clinical tolerance protocols. One of the obstacles to widespread clinical application of this concept is the remaining toxicity of the host conditioning. Recent advances, however, have led to substantially milder protocols that could become clinically acceptable in the foreseeable future. This article provides a short overview of the basic mechanisms by which immunologic tolerance may be induced, describes the concept of mixed chimerism as a promising approach for clinical tolerance induction, and reviews recent progress in developing clinically feasible mixed chimerism protocols.

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.

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.

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.

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.