Mechanisms of Tolerance Induction in Liver Transplantation: Lessons Learned from Fetomaternal Tolerance, Autoimmunity and Tumor Immunity
Abstract
:1. History of Organ Transplantation
2. The Liver as an Immune-Privileged Organ
3. Impact of Liver Resident Cells on Liver Transplant Immunology
3.1. Impact of Hepatic Innate-like Lymphocytes on Liver Transplant Immunology
3.2. Impact of Hepatic DCs on Liver Transplant Immunology
3.3. Impact of Kupffer Cells, Hepatic Stellate Cellsand LSECs on Liver Transplant Immunology
Inflammation/Rejection | Immune Regulation/Tolerance Induction |
---|---|
Liver allograft Peripheral NKG2D+ CD56dim CD16+ NK cells shift to the liver graft in the patients with EAD [30] | Liver allograft Donor liver-resident NKG2A+ CD56bright CD16+/− NK cells for the inhibition of CD8+ T cell-mediated rejection [32] |
Inflamed liver Activation of iNKT cells during acute liver injury [39]; Proinflammatory cytokine production by sulfatide-reactive dNKT cells in patients with AIH [40] | Inflamed liver Prevention of liver inflammation by dNKT cells through the induction of anergy in iNKT cells [39] Liver allograft Tolerance induction by α-GalCer-activated iNKT cells [37] |
Peripheral blood Lower value of the Vδ1+/Vδ2+ ratio as a predictive biomarker for rejection [45] | Liver allograft Elevation of Vδ1+γδ T cells in patients with stable liver allograft function [44] |
Inflamed liver cDC1 for the stimulation of naïve CD4+ T cells and the induction of cytotoxic CD8+ T cells [49]; cDC2 for regulating type II immune responses to parasites, helminths and fungi [50,51] | Normal liver Immature state of cDCs (lower expression of MHC II and TLR4) with higher IL-10 production [53,54,55] Liver allograft PD-L1+pDCs-mediated reduction in infiltrating PD-1+ TIM-3+ CD8+ T cells and the induction of Treg [60,61] |
Inflamed liver/Liver allograft Involvement of Kupffer cell activation in liver injury and liver transplant rejection [63,64,65,66] | Liver allograft Induction of FasL and IDO in Kupffer cells for the inhibition of alloreactive T cell response [71,72,73,74,75] |
Liver allograft Involvement of hepatic stellate cell activation in long-term liver allograft fibrosis and chronic rejection [78,79] | Liver allograft Involvement of hepatic stellate cell activation in the induction of immune tolerance via Fas/FasL- or PD-L1-mediated apoptosis induction and MDSC induction [80,81,82,84] |
Inflamed liver/Liver allograft Accumulation of neutrophils and macrophages and proinflammatory cytokine production in the liver by aging-associated LSEC dysfunction [91]; Rejection-induced severe damage of LSECs [92] | Normal liver LSEC-mediated induction of oral tolerance [87] Inflamed liver/Liver allograft LSEC-mediated clearance of scavenger cells, antibody-coated immune complexes and PAMPs/DAMPs [86]; Induction of allogeneic T cell tolerance [88,89,90] |
4. Mechanical Similarities and Differences between Liver Transplant Immunology and Fetomaternal Tolerance, Autoimmunity or Tumor Immunity
4.1. Liver Transplantation vs. Pregnancy
4.2. Liver Transplantation vs. Autoimmunity
4.3. Liver Transplantation vs. Tumor Immunity
5. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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Donor (MHC) | Recipient (MHC) | Model | Reference |
---|---|---|---|
DA (RT1a) | PVG (RT1c) | Tolerance | [17] |
PVG (RT1c) | DA (RT1a) | Tolerance | [18] |
DA (RT1a) | LEW (RT1l) | Acute rejection | [18] |
LEW (RT1l) | DA (RT1a) | Tolerance | [18] |
BN (RT1n) | LEW (RT1l) | Tolerance (delayed rejection) | [18] |
LEW (RT1l) | BN (RT1n) | Acute rejection | [18] |
Rejection Marker | Expression | Functions in HCC | Reference |
---|---|---|---|
miR-146a (rat) [139] | Plasma, Liver tissue | Lower expression of miR-146a in HCC tissues (human) | [140] |
Tumor suppressor microRNA, VEGF inhibition (human, cell line) | [133] | ||
miR-301a (rat) [126] | Liver tissue | Upregulation of miR-301a in HCC tissues (human) | [141] |
Onco-microRNA, IRF-1 inhibition (human, cell line) | [137] | ||
miR-199a-3p (rat) [142] | Plasma, Liver tissue | Lower expression of miR-199a-3p in HCC tissues (human) | [143] |
Tumor suppressor microRNA, mTOR, PAK4 inhibition (animal model) | [134] | ||
miR-181a-5p (human) [144] | Plasma | Lower expression of miR-181a-5p in HCC tissues (human) | [145] |
Tumor suppressor microRNA, Egr1 inhibition (human, cell line) | [135] | ||
miR-155-5p (human) [144] | Plasma | Upregulation of miR-155-5p in HCC tissues (human) | [146] |
Onco-microRNA, M2 macrophage polarization (human) | [138] | ||
miR-122-5p (human) [147] | Plasma | Lower expression of miR-122-5p in HCC tissues (human) | [148] |
Tumor suppressor microRNA, MDR1 inhibition (cell line, animal model) | [136] |
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Nakano, T.; Goto, S.; Chen, C.-L. Mechanisms of Tolerance Induction in Liver Transplantation: Lessons Learned from Fetomaternal Tolerance, Autoimmunity and Tumor Immunity. Int. J. Mol. Sci. 2024, 25, 9331. https://doi.org/10.3390/ijms25179331
Nakano T, Goto S, Chen C-L. Mechanisms of Tolerance Induction in Liver Transplantation: Lessons Learned from Fetomaternal Tolerance, Autoimmunity and Tumor Immunity. International Journal of Molecular Sciences. 2024; 25(17):9331. https://doi.org/10.3390/ijms25179331
Chicago/Turabian StyleNakano, Toshiaki, Shigeru Goto, and Chao-Long Chen. 2024. "Mechanisms of Tolerance Induction in Liver Transplantation: Lessons Learned from Fetomaternal Tolerance, Autoimmunity and Tumor Immunity" International Journal of Molecular Sciences 25, no. 17: 9331. https://doi.org/10.3390/ijms25179331