Cardiac xenotransplantation: a promising way to treat advanced heart failure

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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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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Shu, S., Ren, J. & Song, J. Cardiac xenotransplantation: a promising way to treat advanced heart failure. Heart Fail Rev (2020). https://doi.org/10.1007/s10741-020-09989-x

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Keywords

  • Cardiac xenotransplantation
  • Immunological barriers
  • Genetically engineered
  • Porcine endogenous retroviruses
  • Organ crisis