TABLE 2.

Mechanisms of liver transplantation ACR and tolerance uncovered by rat OLT models

Cell type	Mechanisms	Effect	Outcome	References
Cytotoxic T cells	Recognize alloantigen presented by APCs through direct or indirect recognition	Initiate downstream cell death pathways, inflammatory cytokine production, and immune cell recruitment to the liver graft	ACR	36,49,73
Th cells	Th1 and Th17 cells secrete IFN-γ, TNF, IL-2, IL-17, IL-22	Promote proinflammatory microenvironment	ACR	39,46,48,50,60,63,64,75
	Th2 cells produce IL-10, TGF-β, IL-4, IL-13	Promote anti-inflammatory microenvironment	Tolerance	39,46,48,60
Treg	Produce IL-10 and TGF-β	Modulate and maintain immature DC phenotype	Tolerance	58
	Secrete exosomes	Inhibit CD8+ T-cell levels and function		51
DCs	Express FasL	Induce immunosuppressive T-cell (Treg, Th2) differentiation, reduce T-cell proliferation, induce antigen-specific T-cell apoptosis/anergy, reduce MHC and costimulatory molecule expression	Tolerance	45,58,60,62,90
	Secrete IL-10 and TGF-β
Macrophages, KCs	Express costimulatory molecules	Activate lymphocytes and inflammatory cytokine secretion	ACR	55
	Produce IL-10 and TGF-β	Downregulate MHC and costimulatory molecule, upregulate MGAT5, which decreases T-cell activation and induces Treg differentiation	Tolerance	41
	Express PD-L1	Inhibit T-cell proliferation, induce apoptosis, and suppress inflammatory cytokines	Tolerance	37
MSCs	Express TGF-β	Induce Treg expansion and reduce Th17 frequency	Tolerance	43,63,72
	Boost IL-10 produced by Treg	Promote anti-inflammatory microenvironment		63
	Express PD-L1	Bind PD-1 to induce immunoregulatory signals		42,76
	Express HO-1	Expand Treg population, maintain ACR attenuation past POD7		48
Molecule/pathway	Role in ACR	ACR/tolerance	ACR rat model	References
Gal-1/NF-κB/RelB	Gal-1 transfusion maintains tolerant DC phenotype and alleviates ACR	Tolerance	DA→LEW	60,65
	Limits DC-mediated CD4+ proliferation and increased Treg/Th17 ratio through NF-κB/RelB-IL-27 pathway	Tolerance
	Reduces NF-κB/RelB to maintain tolerant DC	Tolerance
Gal-9	Perfusion with recombinant Ad-Gal-9 suppressed Th1 and Th17 differentiation	Tolerance	LEW→BN	39
Inflammasome activation pathway	Blocking ASC-mediated caspase-1 activation of IL-1β reduces ACR inflammation	Tolerance	DA→LEW	68
Ceruloplasmin/Nrf-2/ROS	Knock-down of ceruloplasmin diminished hepatocyte survival and lost protection from oxidative damage	Tolerance	DA→LEW	67
IL-22/STAT3	Neutralization of IL-22 early in IRI stage worsened graft function	ACR	LEW→BN	50
	Neutralization of IL-22 late in ACR stage improved function	Tolerance
NFAT-BATF/JUN/IRF4-IL-21	Inhibition of BATF/JUN/IRF4 complex attenuated rejection injury and decreased Bcl-6 and IL-21 in Tfh	ACR	DA→LEW	66
Fas/FasL	Mediates T-cell apoptosis to promote spontaneous acceptance of graft	Tolerance	DA→LEW	62,90
ERS-related IRE-1α/TRAF2/NF-κB	Suppression by gastrodin resulted in ACR attenuation and promotion of tolerogenic macrophage phenotype	ACR	LEW→BN	40
OX40/OX40L	Blocking OX40/OX40L resulted in less hepatic damage and longer survival	ACR	LEW→BN	44
HO-1	Overexpression of HO-1 expanded Treg to maintain tolerance	Tolerance	LEW→BN	48
CTLA-4/B7	Blocking CD28-B7 results in improved liver function and increased levels of immunomodulatory cytokines	Tolerance	LEW→BN	45,55
IDO	Overexpression of IDO led to fewer ACR symptoms and better survival	Tolerance	LEW→BN	55
Autophagy pathway	Blocking autophagy decreased CD8+ T function, prolonging graft survival	ACR	LEW→BN	36
FGL/STAT1/NF-κB	Overexpression of sFGL2 ameliorates ACR through anti-inflammatory cytokines and inhibit STAT1, NF-κB signaling, and induces immunoregulatory macrophage polarization	Tolerance	LEW→BN	52
IL-34/PI3K/Akt	Overexpression of IL-34 polarized immunoregulatory macrophages and inhibited ACR	Tolerance	LEW→BN	53
β-actin	Stabilizing β-actin increases CD8+ T-cell apoptosis and predicts ACR episodes	ACR	LEW→BN	49
PD-L1	MSCs upregulate PD-L1 expression to attenuate ACR	Tolerance	LEW→BN	42
	PD-L1 expression on KCs downregulated in ACR	Tolerance		37
	Silencing PD-L1 increases inflammatory cytokines and decreases tolerogenic cytokines			37
	MSCs modified to express PD-L1Ig inhibited lymphocyte activity and attenuated ACR	Tolerance	Wistar→SD	76

ACR, acute cellular rejection; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; BN, Brown Norway; CTLA-4, cytotoxic T-lymphocyte–associated protein 4; DA, Dark Agouti; DC, dendritic cell; ERS, endoplasmic reticulum stress; FasL, Fas ligand; Gal, galectin; HO-1, heme oxygenase-1; IDO, indoleamine 2,3-dioxygenase; IL, interleukin; IRI, ischemia-reperfusion injury; KC, Kupffer cell; LEW, Lewis; MGAT5, anti-N-acetylglucosaminyltransferase V; MSC, mesenchymal stem cell; NFAT, nuclear factor of activated T cell; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; OLT, orthotopic liver transplantation; PD-1, programmed cell death protein 1; PD-L1, programmed death ligand 1; ROS, reactive oxygen species; SD, Sprague Dawley.