Induction of Tolerance Towards Solid Organ Allografts Using Hematopoietic Cell Transplantation in Large Animal Models.
Tolerance
hematopoietic cell transplantation
large animal model
organ transplantation
preclinical
Journal
OBM transplantation
ISSN: 2577-5820
Titre abrégé: OBM Transplant
Pays: United States
ID NLM: 101751093
Informations de publication
Date de publication:
2019
2019
Historique:
entrez:
18
9
2020
pubmed:
1
1
2019
medline:
1
1
2019
Statut:
ppublish
Résumé
The application of hematopoietic cell transplantation for induction of immune tolerance has been limited by toxicities associated with conditioning regimens and to graft-versus-host disease (GVHD). Decades of animal studies have culminated into sufficient control of these two problems, making immune tolerance a viable alternative to life-long application of immunosuppressive drugs to prevent allograft rejection. 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 extensively evaluated in appreciation of the ultimate need to obtain organs from MHC-mismatched unrelated donors. Nonmyeloablative conditioning regimens have been shown to be successful in inducing immune tolerance across all three animal models. Postgrafting immunosuppression is also important in assuring sustained donor hematopoiesis for tolerance. Donor chimerism need not be permanent to establish stable engraftment of donor organs, thereby essentially eliminating the risk of GVHD. Using nonmyeloablative HCT with monoclonal antibody immunosuppression, the kidney has been successfully transplanted in MHC-mismatched nonhuman primates. Nonmyeloablative HCT for the establishment of temporary mixed chimerism has led to the establishment of stable tolerance against solid organ allografts in large animal models. The kidney, considered a tolerogenic organ, has been successfully transplanted in the clinic. Other organs such as heart, lung, and vascularized composite allografts (face and hands), remain distant possibilities. Further study in large animal models will be required to improve tolerance against these organs before success can be attained in the clinic.
Sections du résumé
BACKGROUND
BACKGROUND
The application of hematopoietic cell transplantation for induction of immune tolerance has been limited by toxicities associated with conditioning regimens and to graft-versus-host disease (GVHD). Decades of animal studies have culminated into sufficient control of these two problems, making immune tolerance a viable alternative to life-long application of immunosuppressive drugs to prevent allograft rejection.
METHODS
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 extensively evaluated in appreciation of the ultimate need to obtain organs from MHC-mismatched unrelated donors.
RESULTS
RESULTS
Nonmyeloablative conditioning regimens have been shown to be successful in inducing immune tolerance across all three animal models. Postgrafting immunosuppression is also important in assuring sustained donor hematopoiesis for tolerance. Donor chimerism need not be permanent to establish stable engraftment of donor organs, thereby essentially eliminating the risk of GVHD. Using nonmyeloablative HCT with monoclonal antibody immunosuppression, the kidney has been successfully transplanted in MHC-mismatched nonhuman primates.
CONCLUSIONS
CONCLUSIONS
Nonmyeloablative HCT for the establishment of temporary mixed chimerism has led to the establishment of stable tolerance against solid organ allografts in large animal models. The kidney, considered a tolerogenic organ, has been successfully transplanted in the clinic. Other organs such as heart, lung, and vascularized composite allografts (face and hands), remain distant possibilities. Further study in large animal models will be required to improve tolerance against these organs before success can be attained in the clinic.
Identifiants
pubmed: 32944710
doi: 10.21926/obm.transplant.1903080
pmc: PMC7494220
mid: NIHMS1566020
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : NCI NIH HHS
ID : P01 CA078902
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA015704
Pays : United States
Déclaration de conflit d'intérêts
Competing Interests The authors have declared that no competing interests exist.
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