Postoperative intravenous infusion of donor-derived transplant acceptance-inducing cells as an adjunct immunosuppressive therapy in a porcine pulmonary allograft model

Abstract

Summary There is very limited published information testifying to the safety and possible complications of cell‐based therapies. Accurately assessing the potential risks of translating novel, cell‐based immunosuppressive protocols into clinical trials is therefore extremely difficult. This report describes the use of a pulmonary allograft model in outbred miniature pigs as a preliminary step in the development of a safe, clinically feasible, cell‐based immunosuppressive protocol. Single lung transplants were performed in 22 MHC Class I‐mismatched donor–recipient pairs, which were randomized between four treatment groups. For the first 28 days postoperatively, all animals were immunosuppressed with methylprednisilone and tacrolimus, with or without preoperative irradiation; subsequently, pharmacological immunosuppression was stopped in all treatment groups. Animals in two groups also received a central venous infusion of donor‐derived ‘transplant acceptance‐inducing cells’ (TAICs) on the seventh and 14th days postoperatively. Allograft survival was monitored by sequential chest X‐rays, bronchoscopies and transbronchial biopsy histologies. No acute adverse events were associated with the administration of TAICs and there was no evidence of accelerated graft rejection. The observations presented in this report represent an important first step towards the development of a clinically applicable protocol for the use of TAIC therapy in lung transplantation.

The divergent roles of macrophages in solid organ transplantation

“…M regs have been used in immunodeficient mice [81], and in non-immunosuppressed recipients of a mismatched heterotopic heart allografts, to ameliorate symptoms of rejection and prolong allograft survival [15]. Furthermore, administration of M regs to porcine recipients of single lung allografts improved graft prognosis [82]. …”

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

“…23,24 Furthermore, GvHD is absent when diverse IRR regimes in combination and donor-derived antigen presenting cells are applied in an experimental model of porcine lung transplantation. 25 …”

Local administration of Mitomycin‐C‐Treated peripheral blood mononuclear cells (PBMCs) prolongs allograft survival in vascularized composite allotransplantation

“…Fändrich et al showed in rat allogeneic heart and kidney transplant model that only a slight prolongation of graft survival results when immunosuppressive cell therapy is being administered postoperatively whereas treatment 5 days prior to transplantation indefinitely prolongs graft survival . Similarly, a postoperative cell therapy regime did not significantly prolong pulmonary allograft survival in pigs . This might be explained by the time required for immunosuppressive cells to induce regulatory T‐cells.…”