Splenocyte Infusion and Whole-Body Irradiation for Induction of Peripheral Tolerance in Porcine Lung Transplantation: Modifications of the Preconditioning Regime for Improved Clinical Feasibility

Katharina Jansson, DVM; Karla Dreckmann, DVM; Wiebke Sommer, MD; Murat Avsar, MD; Jawad Salman, MD; Thierry Siemeni, MD; Ann-Kathrin Knöfel, PhD; Linda Pauksch, MD; Jens Gottlieb, MD; Jörg Frühauf, MD; Martin Werner, MD; Danny Jonigk, MD; Martin Strüber, MD; Axel Haverich, MD; Gregor Warnecke, MD

doi:10.1097/TXD.0000000000000689

Transplantation Direct (Jul 2017)

Splenocyte Infusion and Whole-Body Irradiation for Induction of Peripheral Tolerance in Porcine Lung Transplantation: Modifications of the Preconditioning Regime for Improved Clinical Feasibility

Katharina Jansson, DVM,
Karla Dreckmann, DVM,
Wiebke Sommer, MD,
Murat Avsar, MD,
Jawad Salman, MD,
Thierry Siemeni, MD,
Ann-Kathrin Knöfel, PhD,
Linda Pauksch, MD,
Jens Gottlieb, MD,
Jörg Frühauf, MD,
Martin Werner, MD,
Danny Jonigk, MD,
Martin Strüber, MD,
Axel Haverich, MD,
Gregor Warnecke, MD

Affiliations

Katharina Jansson, DVM: 1 Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.
Karla Dreckmann, DVM: 2 The German Centre for Lung Research, Hannover Medical School, Hannover, Germany.
Wiebke Sommer, MD: 1 Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.
Murat Avsar, MD: 1 Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.
Jawad Salman, MD: 1 Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.
Thierry Siemeni, MD: 1 Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.
Ann-Kathrin Knöfel, PhD: 1 Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.
Linda Pauksch, MD: 1 Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.
Jens Gottlieb, MD: 2 The German Centre for Lung Research, Hannover Medical School, Hannover, Germany.
Jörg Frühauf, MD: 4 The Department of Radiation Therapy and Oncology, Hannover Medical School, Hannover, Germany.
Martin Werner, MD: 4 The Department of Radiation Therapy and Oncology, Hannover Medical School, Hannover, Germany.
Danny Jonigk, MD: 5 The Institute for Pathology, Hannover Medical School, Hannover, Germany.
Martin Strüber, MD: 6 The Richard DeVos Heart & Lung Transplant Program, Frederik Meijer Heart & Vascular Institute, Grand Rapids, MI.
Axel Haverich, MD: 1 Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.
Gregor Warnecke, MD: 2 The German Centre for Lung Research, Hannover Medical School, Hannover, Germany.

DOI: https://doi.org/10.1097/TXD.0000000000000689
Journal volume & issue: Vol. 3, no. 7
p. e170

Abstract

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Background. Preoperative low-dose whole-body irradiation (IRR) with 1.5 and 7 Gy thymic IRR of the recipient, combined with a perioperative donor splenocyte infusion lead to reliable donor specific peripheral tolerance in our allogeneic porcine lung transplantation model. To reduce the toxicity of this preconditioning regime, modifications of the IRR protocol and their impact on allograft survival were assessed. Methods. Left-sided single lung transplantation from major histocompatibility complex and sex mismatched donors was performed in 14 adult female minipigs. Recipient animals were exposed to 3 different protocols of nonmyeloablative IRR within 12 hours before transplantation. All animals were administered a donor splenocyte infusion on the day of lung transplantation. Intravenous pharmacologic immunosuppression was withdrawn after 28 postoperative days. Allograft survival was monitored by chest radiographs and bronchoscopy. Results. IRR prolonged transplant survival in a dose- and field-dependent manner. Shielding of the bone marrow from IRR (total lymphoid IRR at 1.5 and 7 Gy thymic IRR) significantly reduced protocol toxicity defined as thrombocytopenia and consecutive increased bleeding propensity, but had a less effective impact on graft survival. Whole-body IRR at 0.5 and 7 Gy thymic IRR proved to be ineffective for reliable tolerance induction. Eventually, high levels of circulating CD4+CD25high regulatory T cells were present in long-term survivors. Conclusions. These data show that the infusion of donor-specific alloantigen in combination with IRR is efficient once a threshold dose is exceeded.

Published in Transplantation Direct

ISSN: 2373-8731 (Online)
Publisher: Wolters Kluwer
Country of publisher: United States
LCC subjects: Medicine: Surgery
Website: http://journals.lww.com/transplantationdirect/Pages/default.aspx

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