Abstract
Cardiac xenotransplantation (CXTx) might be a promising approach to bridge the gap between the supply and demand of a donor heart. The survival of cardiac xenograft has been significantly extended in pig-to-nonhuman primate (NHP) CXTx, with records of 195 days and 945 days for orthotropic and heterotopic CXTx, respectively. To present the history of CXTx, we list the reported clinical CXTx, compare pigs and NHPs as sources of hearts, and compare three different kinds of preclinical CXTx models. The application of genetically modified pigs and novel immunosuppressive drugs accelerates the development of CXTx, and we summarize the reported pig-to-NHP CXTx with detailed information. Besides, we discuss the underlining mechanisms and potential preventive strategies of immunological barriers, including hyperacute rejection, acute humoral xenograft rejection, acute cellular xenograft rejection, chronic rejection, coagulation dysfunction, and systemic inflammation. Though intense cellular infiltration in cardiac xenograft has only been documented in a small number of studies, we especially stress the importance of cellular rejection in CXTx, because we believe it is often masked by the rapid and strong humoral response and it may eventually become a more important and common type of xenograft rejection. In addition, we conclude other obstacles as well as possible solutions in CXTx, such as perioperative cardiac xenograft dysfunction, detrimental xenograft overgrowth, and porcine endogenous retroviruses. Finally, we briefly introduce several other approaches that have been proposed to deal with the organ heart shortage crisis, and we firmly believe that CXTx provides the best near-term solution.
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Change history
15 June 2021
A Correction to this paper has been published: https://doi.org/10.1007/s10741-021-10127-4
Abbreviations
- aCD154mAb:
-
Anti-CD154 monoclonal antibody
- aCD20mAb:
-
Anti-CD20 monoclonal antibody
- aCD40mAb:
-
Anti-CD40 monoclonal antibody
- apC:
-
Activated protein C
- ACXR:
-
Acute cellular xenograft rejection
- ADCC:
-
Antibody-dependent cytotoxicity
- AHXR:
-
Acute humoral xenograft rejection
- APC:
-
Antigen-presenting cell
- AT:
-
Antithrombin
- β4GALNT2:
-
β-1,4-N-Acetyl-galactosa-minyl transferase 2
- CC:
-
Consumptive coagulation
- CCS:
-
Cyclophosphamide, cyclosporine A, and steroids/corticosteroids
- CMAH:
-
Cytidine monophosphate-N-acetylneuraminic acid hydroxylase
- CR1:
-
Complement receptor type 1
- C-RP:
-
C-reactive protein
- CVF:
-
Cobra venom factor
- CXTx:
-
Cardiac xenotransplantation
- DXR:
-
Delayed xenograft rejection
- FcR:
-
Fc receptor
- FDA:
-
Food and Drug Administration
- GP1b:
-
Glycoprotein 1b
- GT:
-
Galactosyltransferase
- hCRP:
-
Human complement regulatory proteins
- hEPCR:
-
Human endothelial protein C-receptor
- hTBM:
-
Human thrombomodulin
- hTFPI:
-
Human tissue factor pathway inhibitor
- HAR:
-
Hyperacute rejection
- HLA-I:
-
Human leukocyte antigen class I
- Ig:
-
Immune globulin
- IL:
-
Interleukin
- I/R:
-
Ischemic/reperfusion
- ISHLT:
-
International Society for Heart and Lung Transplantation
- MAC:
-
Membrane attack complex
- MHC-I:
-
Major histocompatibility antigens class I
- MMF:
-
Mycophenolate mofetil
- NHP:
-
Nonhuman primate
- NK:
-
Natural killer
- pC:
-
Protein C
- PCXD:
-
Perioperative cardiac xenograft dysfunction
- PD-1:
-
Programmed cell death 1
- PD-L1:
-
Programmed cell death ligand 1
- pEC:
-
Porcine endothelial cell
- PERVs:
-
Porcine endogenous retrovirus
- SIRP-α:
-
Signal regulatory protein α
- SLA-I:
-
Swine leukocyte antigen class I
- SIXR:
-
Systemic inflammation in xenograft recipients
- TCRs:
-
T cell receptors
- TF:
-
Tissue factor
- TGF-β:
-
Transforming growth factor β
- TMA:
-
Thrombotic microangiopathy
- TNF-α:
-
Tumor necrosis factor-α
- vWF:
-
von Willebrand Factor
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This research was supported by Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2019-I2M-1-002).
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Shu, S., Ren, J. & Song, J. Cardiac xenotransplantation: a promising way to treat advanced heart failure. Heart Fail Rev 27, 71–91 (2022). https://doi.org/10.1007/s10741-020-09989-x
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DOI: https://doi.org/10.1007/s10741-020-09989-x