Induction of Tolerance towards Solid Organ Allografts Using Hematopoietic Cell Transplantation in Large Animal Models

Abstract

Background: The application of hematopoietic cell transplantation for induction of immune tolerance has been limited by toxicities associated with conditioning regimens and to graftversus-host disease (GVHD). Decades of animal studies have culminated into sufficient control of these two problems, making immune tolerance a viable alternative to lifelong application of immunosuppressive drugs to prevent allograft rejection. Methods: Studies in mice have paved the way for the application of HCT with limited toxicity in large animal models. Resultant studies in the pig, dog, and ultimately the nonhuman primate have led to appropriate methods for achieving nonmyeloablative irradiation protocols, dose, and timing of post-grafting immunosuppressive drugs, monoclonal antibody therapy, and biologicals for costimulatory molecule blockade. The genetics field has been

Immunogenicity and tolerance induction in vascularized composite allotransplantation

“…A well-recognized challenge is the significant difference between small and large VCA models where translation from small animals to pre-clinical-relevant models or clinical scale has been unsuccessful. Protocols for applying calcineurin inhibitors and donor stem cell transplantation, for example, showed promising outcomes in mice but failed in applying tolerance induction for larger models ( 135 ). Some considerations for future studies include recognizing that allo-specific memory B and T cells can form in both large animal and humans due to prior antigen exposure, whereas this feature is not observed in mice.…”

Evolution of haematopoietic cell transplantation for canine blood disorders and a platform for solid organ transplantation

“…In general, kidney transplantation in dogs without tolerance induction was associated with high morbidity and mortality and thromboembolic complications, which were major causes of death (Hopper et al, 2012). A solution to this problem was the inclusion of DLA-identical HCT for induction of immune tolerance to replace life-long immunosuppression for allograft survival (for review, see Graves, Mathes, et al, 2019).…”

“…In general, kidney transplantation in dogs without tolerance induction was associated with high morbidity and mortality and thromboembolic complications, which were major causes of death (Hopper et al., 2012 ). A solution to this problem was the inclusion of DLA‐identical HCT for induction of immune tolerance to replace life‐long immunosuppression for allograft survival (for review, see Graves, Mathes, et al., 2019 ). Decades of canine studies successfully reduced conditioning toxicity, improved HCT engraftment and prevented GVHD, making immune tolerance through HCT a viable alternative to life‐long immunosuppressive drug therapy for the prevention of solid organ graft rejection.…”

Developments and translational relevance for the canine haematopoietic cell transplantation preclinical model

“…152 have been successfully transplanted into canines following induced tolerance using HCT. [156][157][158][159][160][161][162] In nephrectomized marrow transplanted recipients, allografted kidneys from respective marrow donors were accepted in five of five dogs for periods greater than 1 year without additional immunosuppression. 163 In control dogs receiving an identical protocol without HSC infusion, all showed signs of acute rejection after transplant at a mean of 24 days.…”

“…Haematopoietic cell chimerism following HCT has shown to be an effective method for inducing immune tolerance and preventing rejection of solid organ transplantation (SOT). Several solid organs, including skin, gut, heart and lung, have been successfully transplanted into canines following induced tolerance using HCT 156‐162 . In nephrectomized marrow transplanted recipients, allografted kidneys from respective marrow donors were accepted in five of five dogs for periods greater than 1 year without additional immunosuppression 163 .…”