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Clopidogrel Preserves Microvascular Integrity in Orthotopic Tracheal Transplants affected by Obliterative Bronchiolitis
Abstracts S255 6( 90)
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The Duration of Donor CD4 T Cell Chimerism Following Human Lung Transplantation Is Not Affected By Human Leukocyte Antigen and Natural Killer Cell Alloreactivity O. Gjorgjimajkoska ,1 D. Mallon,1 J. Jayaraman,2 J. Traherne,2 J. Trowsdale,2 A. Mulder,3 F.H. Claas,3 C.J. Taylor,4 E.M. Bolton,1 A. Bradley,1 C. Lewis,5 J. Parmar,5 G.J. Pettigrew.1 1Department of Surgery, University of Cambridge, Cambridge, United Kingdom; 2Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom; 3Dept Immunohaematology and Bloodtransfusion, Leiden University Medical Center, Leiden, Netherlands; 4Tissue Typing Laboratory, Addenbrooke’s Hospital, Cambridge, United Kingdom; 5Papworth Hospital, Papworth, United Kingdom.
Clopidogrel Preserves Microvascular Integrity in Orthotopic Tracheal Transplants affected by Obliterative Bronchiolitis C. Heim ,1 M.A. Khan,2 B. Motsch,1 S. Müller,1 M. Ramsperger-Gleixner,1 T. Stamminger,3 M.R. Nicolls,2 M. Weyand,1 S. Ensminger.4 1Department of Cardiac Surgery, Erlangen, Germany; 2Veterans Affairs Palo Alto Health Care System, Stanford University School of Medicine, CA; 3Department of Virology, Erlangen, Germany; 4Department of Cardiac Surgery, Bad Oeynhausen, Germany.
Purpose: Graft passenger lymphocytes are known to influence auto- and allo-immune responses following transplantation. The fate of the donor passenger CD4 T cells is unclear and maybe influenced by the degree of Human Leukocyte Antigen (HLA) disparities and the natural killer (NK) cell alloreactivity. Thus, we investigated the relationship between the duration of donor CD4 T cell chimerism; the degree of HLA mismatches and NK cell alloreactivity in lung transplant recipients. Methods: The presence and persistence of donor CD4 T cell chimerism following primary lung transplantation was determined by flow cytometric analysis of recipients’ peripheral blood at set time-points after transplantation, with donor CD4 T cells identified on the basis of expression of mismatched donor HLA (n= 21). Results: Donor CD4+T cell chimerism was observed in all patients. The level of chimerism detected varied from 0.06% to 6% of the recipient CD4 T cell population. Donor CD4 T cells disappeared from the recipients’ peripheral blood with three distinct patterns: early, intermediate and late loss of chimerism that occurred within 6 weeks, 3 - 6 months, and more than 11 months post-transplant, respectively (Figure 1). All patients received poorly matched grafts, with 12 of 21 patients mismatched at more than > 5 HLA antigens. Similarly, recipient NK cell alloreactivity against donor cells was expected in 10 of 21 recipient/donor pairs. Nevertheless, there was no correlation between the duration of donor CD4 T cell chimerism and either the degree of HLA mismatch or NK cell alloreactivity. Conclusion: Donor CD4 T cell chimerism following lung transplantation is common, but the duration of chimerism varies considerably between patients. Although the clinical significance of CD4 T cell chimerism is yet to be determined, our data demonstrates that neither the degree of HLA mismatching nor NK cell alloreactivity influence its duration.
Purpose: Survival after lung transplantation is mainly limited by the development of chronic lung allograft dysfunction (CLAD). The aim of this study was to investigate if platelet inhibition by clopidogrel has an influence on the microvascular integrity of orthotopic tracheal allografts and the formation of obliterative bronchiolitis, present in the majority of patients suffering from CLAD. Methods: C57Bl/6 (H2b) donor tracheas were orthotopically transplanted into CBA.J (H2k) recipients. Mice received clopidogrel alone or in combination with everolimus. Grafts were analyzed by serial tissue PO2 monitoring by a fluorescence quenching technique. Blood flow monitoring was performed by laser Doppler flowmetry and a Lectin-binding assay to analyze the function of the microvasculature on postoperative days 4, 10 and 30. Results: Isografts showed a stable tissue PO2 and blood flow during the initial timepoints after transplantations. In contrast, allografts showed a steady decline in tissue PO2 and blood flow in rejecting airway allografts until the PO2 nadirs 10-12 days after transplantation. Continous administration of clopidogrel (Clopi) or Everolimus (Evero) alone and in combination (EC) significantly improved tissue oxygenation, limited microvascular leakiness, and prevented airway ischemia. (Fig.1). Conclusion: These data demonstrate that clopidogrel alone and in combination with everolimus ameliorates microvascular injury during acute airway rejection and subsequently reduces post-transplant obliterative bronchiolitis.
6( 92) Correlation of Physiological Data at Ex Vivo Lung Perfusion and Reperfusion in a Rat Ischemia-Reperfusion Model Using Plasmin H. Motoyama , F. Chen, K. Hijiya, M. Takahashi, K. Ohata, T. Yamada, M. Sato, A. Aoyama, T. Bando, H. Date. Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan. Purpose: Donor lung thrombi are considered a significant etiology for primary graft dysfunction. We hypothesized that thrombolysis in an ex vivo lung perfusion (EVLP) before lung transplantation could alleviate IRI, resulting in the reduction of primary graft dysfunction. The aim of this study was to confirm this hypothesis and to assess correlations of several physiological data at the end of EVLP and reperfusion.
6( 91)
The Duration of Donor CD4 T Cell Chimerism Following Human Lung Transplantation Is Not Affected By Human Leukocyte Antigen and Natural Killer Cell Alloreactivity O. Gjorgjimajkoska ,1 D. Mallon,1 J. Jayaraman,2 J. Traherne,2 J. Trowsdale,2 A. Mulder,3 F.H. Claas,3 C.J. Taylor,4 E.M. Bolton,1 A. Bradley,1 C. Lewis,5 J. Parmar,5 G.J. Pettigrew.1 1Department of Surgery, University of Cambridge, Cambridge, United Kingdom; 2Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom; 3Dept Immunohaematology and Bloodtransfusion, Leiden University Medical Center, Leiden, Netherlands; 4Tissue Typing Laboratory, Addenbrooke’s Hospital, Cambridge, United Kingdom; 5Papworth Hospital, Papworth, United Kingdom.
Clopidogrel Preserves Microvascular Integrity in Orthotopic Tracheal Transplants affected by Obliterative Bronchiolitis C. Heim ,1 M.A. Khan,2 B. Motsch,1 S. Müller,1 M. Ramsperger-Gleixner,1 T. Stamminger,3 M.R. Nicolls,2 M. Weyand,1 S. Ensminger.4 1Department of Cardiac Surgery, Erlangen, Germany; 2Veterans Affairs Palo Alto Health Care System, Stanford University School of Medicine, CA; 3Department of Virology, Erlangen, Germany; 4Department of Cardiac Surgery, Bad Oeynhausen, Germany.
Purpose: Graft passenger lymphocytes are known to influence auto- and allo-immune responses following transplantation. The fate of the donor passenger CD4 T cells is unclear and maybe influenced by the degree of Human Leukocyte Antigen (HLA) disparities and the natural killer (NK) cell alloreactivity. Thus, we investigated the relationship between the duration of donor CD4 T cell chimerism; the degree of HLA mismatches and NK cell alloreactivity in lung transplant recipients. Methods: The presence and persistence of donor CD4 T cell chimerism following primary lung transplantation was determined by flow cytometric analysis of recipients’ peripheral blood at set time-points after transplantation, with donor CD4 T cells identified on the basis of expression of mismatched donor HLA (n= 21). Results: Donor CD4+T cell chimerism was observed in all patients. The level of chimerism detected varied from 0.06% to 6% of the recipient CD4 T cell population. Donor CD4 T cells disappeared from the recipients’ peripheral blood with three distinct patterns: early, intermediate and late loss of chimerism that occurred within 6 weeks, 3 - 6 months, and more than 11 months post-transplant, respectively (Figure 1). All patients received poorly matched grafts, with 12 of 21 patients mismatched at more than > 5 HLA antigens. Similarly, recipient NK cell alloreactivity against donor cells was expected in 10 of 21 recipient/donor pairs. Nevertheless, there was no correlation between the duration of donor CD4 T cell chimerism and either the degree of HLA mismatch or NK cell alloreactivity. Conclusion: Donor CD4 T cell chimerism following lung transplantation is common, but the duration of chimerism varies considerably between patients. Although the clinical significance of CD4 T cell chimerism is yet to be determined, our data demonstrates that neither the degree of HLA mismatching nor NK cell alloreactivity influence its duration.
Purpose: Survival after lung transplantation is mainly limited by the development of chronic lung allograft dysfunction (CLAD). The aim of this study was to investigate if platelet inhibition by clopidogrel has an influence on the microvascular integrity of orthotopic tracheal allografts and the formation of obliterative bronchiolitis, present in the majority of patients suffering from CLAD. Methods: C57Bl/6 (H2b) donor tracheas were orthotopically transplanted into CBA.J (H2k) recipients. Mice received clopidogrel alone or in combination with everolimus. Grafts were analyzed by serial tissue PO2 monitoring by a fluorescence quenching technique. Blood flow monitoring was performed by laser Doppler flowmetry and a Lectin-binding assay to analyze the function of the microvasculature on postoperative days 4, 10 and 30. Results: Isografts showed a stable tissue PO2 and blood flow during the initial timepoints after transplantations. In contrast, allografts showed a steady decline in tissue PO2 and blood flow in rejecting airway allografts until the PO2 nadirs 10-12 days after transplantation. Continous administration of clopidogrel (Clopi) or Everolimus (Evero) alone and in combination (EC) significantly improved tissue oxygenation, limited microvascular leakiness, and prevented airway ischemia. (Fig.1). Conclusion: These data demonstrate that clopidogrel alone and in combination with everolimus ameliorates microvascular injury during acute airway rejection and subsequently reduces post-transplant obliterative bronchiolitis.
6( 92) Correlation of Physiological Data at Ex Vivo Lung Perfusion and Reperfusion in a Rat Ischemia-Reperfusion Model Using Plasmin H. Motoyama , F. Chen, K. Hijiya, M. Takahashi, K. Ohata, T. Yamada, M. Sato, A. Aoyama, T. Bando, H. Date. Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan. Purpose: Donor lung thrombi are considered a significant etiology for primary graft dysfunction. We hypothesized that thrombolysis in an ex vivo lung perfusion (EVLP) before lung transplantation could alleviate IRI, resulting in the reduction of primary graft dysfunction. The aim of this study was to confirm this hypothesis and to assess correlations of several physiological data at the end of EVLP and reperfusion.