Immune tolerance in liver disease

Abstract

Liver Tolerance is manifest as a bias towards immune unresponsiveness, both in the context of a Major Histocompatibility Complex-mismatched liver transplant and in the context of liver infection. Two broad classes of mechanisms account for liver tolerance. The presentation of antigens by different liver cell types results in incomplete activation of CD8+ T cells, usually leading to initial proliferation followed by either clonal exhaustion or premature death of the T cell. Many liver infections result in relatively poor CD4+ T cell activation, which may be because liver antigen-presenting cells express a variety of inhibitory cytokines and co-inhibitors ligands. Poor CD4+ T cell activation by liver antigens likely contributes to the abortive activation, exhaustion and early death of the CD8+ T cells. In addition, a network of active immunosuppressive pathways in the liver is mediated mostly by myeloid cells. Kupffer cells, myeloid-derived suppressor cells and liver dendritic cells both promote the activation of regulatory T cells, and suppress CD8+ and CD4+ effector T cells. This suppressive network responds to diverse inputs, including signals from hepatocytes, sinusoidal endothelial cells, and hepatic stellate cells. While liver tolerance may be exploited by pathogens, it serves a valuable purpose. Hepatitis A and B infections occasionally elicit a powerful immune response sufficient to cause fatal massive liver necrosis. More commonly, the mechanisms of liver tolerance limit the magnitude of intra-hepatic immune responses, allowing the liver to recover. The cost of this adaptive mechanism may be incomplete pathogen eradication, leading to chronic infection.

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

“…9 Tumors are also known to employ several immunosuppressive mechanisms to prevent antitumor immune responses. 4 Under this stringent immune tolerant environment, we were interested to know whether tumor-infiltrating immune cells of orthotopic liver tumors could be appropriately activated to gain the ability to eliminate tumors.…”

“…8 In addition to tumor-associated immunosuppression, the liver per se is considered as an immunotolerant organ that can promote immunological tolerance to foreign antigens (Ag) and elicit Ag-induced apoptosis of activated CD8 T cells. 9 Therefore, the efficacy of an immunotherapeutic agent is likely to be reduced on encountering these immunosuppressive processes within HCC microenvironment.…”

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

“…In addition, MMR-proficient LM-CRC are immunologically distinct from primary CRC in terms of immune infiltration. 35 Moreover, the unique immune environment in the liver 36 favors immunological tolerance, 36 and one of the mechanisms used by the liver to resist immune responses is the induction of expression of inhibitory receptors on hepatic T cells 37 , 38 and their ligands on hepatocytes and other liver tissue cells. 39 Previously we have observed that intra-tumoral CD8 + cytotoxic T cells (CTL) and CD4 + T helper cells (Th) are functionally compromised in LM-CRC, 40 and we also demonstrated that the suppression mediated by intra-tumoral regulatory T cells (Treg) in LM-CRC can be alleviated by blocking the inhibitory receptor CTLA4 and activating the stimulatory receptor GITR.…”

Review on immunosuppression in liver transplantation

“…This privilege is called "liver tolerance" which is mostly attributed to the role of the regulatory Tcell [2,3] . LT does not require human leukocyte antigen (HLA) matching between donor and recipient [4] , though there is increased interest in understanding HLA and humoral rejection and graft survival.…”