Bone marrow stem cells modified with human interleukin 10 attenuate acute rejection in rat lung allotransplantation

Jaroslaw Pieróg; Luca Tamo; Richard Fakin; Gregor Kocher; Mathias Gugger; Tomasz Grodzki; Thomas Geiser; Amiq Gazdhar; Ralph A Schmid

doi:10.1093/ejcts/ezx257

Bone marrow stem cells modified with human interleukin 10 attenuate acute rejection in rat lung allotransplantation

Eur J Cardiothorac Surg. 2018 Jan 1;53(1):194-200. doi: 10.1093/ejcts/ezx257.

Authors

Jaroslaw Pieróg^{1

2

3}, Luca Tamo^{1

3

4}, Richard Fakin¹, Gregor Kocher^{1

3}, Mathias Gugger⁵, Tomasz Grodzki², Thomas Geiser^{3

6}, Amiq Gazdhar^{3

6}, Ralph A Schmid^{1

3}

Affiliations

¹ Department of General Thoracic Surgery, University Hospital Bern, Bern, Switzerland.
² Department of General Thoracic Surgery and Lung Transplantation, Pomeranian Medical University, Szczecin, Poland.
³ Department of Clinical Research, University of Bern, Bern, Switzerland.
⁴ Graduate School, University of Bern, Bern, Switzerland.
⁵ Promed AG, Freiburg, Switzerland.
⁶ Department of Pulmonary Medicine, University Hospital Bern, Bern, Switzerland.

PMID: 28950337
DOI: 10.1093/ejcts/ezx257

Abstract

Objectives: The aim of this study was to investigate new therapeutic options to attenuate acute rejection in a rat lung allograft model. Cell-based gene therapies have recently been reported as a novel curative option in acute and chronic diseases for which conventional treatments are not available. We studied the effect of human interleukin 10 (hIL-10) on expressing bone marrow-derived mesenchymal stem cells (BMSCs) in combination with cyclosporine A (CsA) on acute rejection of lung allografts in the rat.

Methods: Lung allotransplantation was performed from male Brown Norway donor to male Fisher (F344) rats. Rat BMSCs were transfected with hIL-10 in vitro and introduced in the graft prior to implantation. Group A (n = 5) received CsA intraperitoneally (2.5 mg/kg body weight) for 5 days post-transplant; Group B (n = 5) received BMSC and CsA and Group C (n = 5) received hIL-10-BMSC before implantation and CsA. Graft function was assessed by blood gas levels only from the graft on day 5; tissue was sampled for histological grading of rejection and measurement of the wet-to-dry ratio.

Results: All Group A control animals showed severe signs of rejection. On Day 5, all grafts in Group C showed improved gas exchange (mean arterial partial pressure of oxygen 222.2 ± 40.38 mmHg vs 92.36 ± 20.92 mmHg in Group B and 42.72 ± 18.07 mmHg in Group A). Histological examination revealed moderate-to-severe rejection in all animals in Group A [International Society for Heart and Lung Transplantation Level III B (ISHLT)] in contrast to low-to-moderate rejection in Group B (II-IIIA) and much improved histological grade in Group C (I-IIA). Moreover, the wet-to-dry ratio was also reduced in Group C (4.8 ± 1.19 compared with 4.78 ± 0.62 in Group B and 9.36 ± 0.90 in Group A).

Conclusions: The hIL-10 BMSC represent a promising novel method for localized cell-based gene therapy for acute rejection in a rat lung allograft model.

Keywords: Acute rejection; IL-10; Lung transplantation; Stem cells.

MeSH terms

Acute Disease
Animals
Bone Marrow Cells / immunology
Combined Modality Therapy
Cyclosporine / therapeutic use*
Enzyme-Linked Immunosorbent Assay
Graft Rejection / prevention & control*
Humans
Immunosuppressive Agents / therapeutic use*
Interleukin-10 / therapeutic use*
Lung Transplantation*
Male
Mesenchymal Stem Cell Transplantation / methods*
Random Allocation
Rats
Rats, Inbred F344
Transplantation, Homologous
Treatment Outcome

Substances

Immunosuppressive Agents
Interleukin-10
Cyclosporine