Dendritic Cell-Mediated Regulation of Liver Ischemia-Reperfusion Injury and Liver Transplant Rejection

Abstract

Liver allograft recipients are more likely to develop transplantation tolerance than those that receive other types of organ graft. Experimental studies suggest that immune cells and other non-parenchymal cells in the unique liver microenvironment play critical roles in promoting liver tolerogenicity. Of these, liver interstitial dendritic cells (DCs) are heterogeneous, innate immune cells that appear to play pivotal roles in the instigation, integration and regulation of inflammatory responses after liver transplantation. Interstitial liver DCs (recruited in situ or derived from circulating precursors) have been implicated in regulation of both ischemia/reperfusion injury (IRI) and anti-donor immunity. Thus, livers transplanted from mice constitutively lacking DCs into syngeneic, wild-type recipients, display increased tissue injury, indicating a protective role of liver-resident donor DCs against transplant IRI. Also, donor DC depletion before transplant prevents mouse spontaneous liver allograft tolerance across major histocompatibility complex (MHC) barriers. On the other hand, mouse liver graft-infiltrating host DCs that acquire donor MHC antigen via “cross-dressing”, regulate anti-donor T cell reactivity in association with exhaustion of graft-infiltrating T cells and promote allograft tolerance. In an early phase clinical trial, infusion of donor-derived regulatory DCs (DCreg) before living donor liver transplantation can induce alterations in host T cell populations that may be conducive to attenuation of anti-donor immune reactivity. We discuss the role of DCs in regulation of warm and liver transplant IRI and the induction of liver allograft tolerance. We also address design of cell therapies using DCreg to reduce the immunosuppressive drug burden and promote clinical liver allograft tolerance.

Repair of Limb Ischemia Is Dependent on Hematopoietic Stem Cell Specific-SHP-1 Regulation of TGF-β1

“…76 Our data indicate that HSPCs play an important role in revascularization and function recovery likely by appropriately secreting TGF-β1, which is regulated by SHP-1. Although several other hematopoietic lineage cells including MKs/platelets, 77 dendritic cells, 38,78 and natural killer cells 79 produce high amounts of TGF-β1 in response to ischemic stress, we posit that HSPCsderived TGF-β1 in PB is responsible for the fluctuation of TGF-β1 levels in our Shp-1 −/− FAL model due to several lines of evidence we gathered about the response of HSPCs to TGF-β1. Furthermore, SHP-1 deficiency in HSC did not result in differences in the mobilization of cytokines such as, CXCL12, G-CSF, and GM-CSF (Figure S3B and SBC), as they all increased in response to ischemia and stayed high regardless of SHP-1 status.…”

Myeloid Trem2 Dynamically Regulates the Induction and Resolution of Hepatic Ischemia-Reperfusion Injury Inflammation

“…In acute liver injury induced by APAP, Trem2 was shown to be responsible for the emergence of restorative macrophages during the resolution phase of inflammation, but global knockout obscured the characteristic role of myeloid Trem2 in this process [ 15 ] because Trem2 also plays an important role in Kupffer cells and dendritic cells during sterile inflammation [ 20 , 21 ]. Based on this, we aimed to elucidate the unique role of myeloid Trem2 in regulating the phenotypic reprogramming of macrophages in response to hepatic ischemia-reperfusion injury.…”

Role of the immune system in liver transplantation and its implications for therapeutic interventions

“… 58 Conversely, IFN‐α produced by pDCs can stimulate hepatocytes to express CX3CL1, potentially leading to the recurrence of hepatocellular carcinoma. 59 In addition to these three major subtypes, there are monocyte‐derived DCs (moDCs) obtained in vitro and regulatory DCs (DCregs), which are recognized as key players in immune tolerance regulation in LT. 60 …”