The Immunological Basis of Liver Allograft Rejection

Abstract

Liver allograft rejection remains a significant cause of morbidity and graft failure in liver transplant recipients. Rejection is caused by the recognition of non-self donor alloantigens by recipient T-cells. Antigen recognition results in proliferation and activation of T-cells in lymphoid tissue before migration to the allograft. Activated T-cells have a variety of effector mechanisms including direct T-cell mediated damage to bile ducts, endothelium and hepatocytes and indirect effects through cytokine production and recruitment of tissue-destructive inflammatory cells. These effects explain the histological appearances of typical acute T-cell mediated rejection. In addition, donor specific antibodies, most typically against HLA antigens, may give rise to antibody-mediated rejection causing damage to the allograft primarily through endothelial injury. However, as an immune-privileged site there are several mechanisms in the liver capable of overcoming rejection and promoting tolerance to the graft, particularly in the context of recruitment of regulatory T-cells and promotors of an immunosuppressive environment. Indeed, around 20% of transplant recipients can be successfully weaned from immunosuppression. Hence, the host immunological response to the liver allograft is best regarded as a balance between rejection-promoting and tolerance-promoting factors. Understanding this balance provides insight into potential mechanisms for novel anti-rejection therapies.

Capecitabine Can Induce T Cell Apoptosis: A Potential Immunosuppressive Agent With Anti-Cancer Effect

“…Therefore, we chose metronomic chemotherapy (a new type of chemotherapy featuring low-dose, uninterrupted, and continuous administration) dose or maximum tolerated dose of CAP to treat normal mice by oral gavage to explore the feasibility of CAP as a potential immunosuppressive agent (23). First, considering myelosuppression, the common side effect of 5-FU (the active ingredient transformed by CAP in vivo) (11, 2 4) , w e m u s t e v a l u a t e w h e t h e r C A P a l s o c a u s e s (25,26). Immunosuppressants commonly used in clinical practice mainly target T cells to prevent rejection (27,28).…”

High Mobility Group Box 1 Contributes to the Acute Rejection of Liver Allografts by Activating Dendritic Cells

“…The indirect pathway refers to the biological process whereby recipient DCs take up, process, and present alloantigens on recipient MHC molecules to host T cells ( 9 , 10 ). In the semi-indirect pathway, recipient DCs interact with intact donor MHC molecules on their surface via direct cell–cell interactions or the fusion of exosomes derived from donor DCs, which subsequently trigger T cell activation ( 11 , 12 ). Successfully activated recipient naïve T cells can mobilize into the graft liver and differentiate into Th1 or Th17 subsets characterized by the secretion of IL-2 or IFN-γ, and IL-17, respectively ( 12 ).…”

“…In the semi-indirect pathway, recipient DCs interact with intact donor MHC molecules on their surface via direct cell–cell interactions or the fusion of exosomes derived from donor DCs, which subsequently trigger T cell activation ( 11 , 12 ). Successfully activated recipient naïve T cells can mobilize into the graft liver and differentiate into Th1 or Th17 subsets characterized by the secretion of IL-2 or IFN-γ, and IL-17, respectively ( 12 ). Th1 cytokines including IL-2 and IFN-γ enhance immune injury by recruiting more inflammatory cells into the liver grafts, whilst IL-17 impairs tolerance and recruits neutrophils ( 12 , 13 ).…”

“…Successfully activated recipient naïve T cells can mobilize into the graft liver and differentiate into Th1 or Th17 subsets characterized by the secretion of IL-2 or IFN-γ, and IL-17, respectively ( 12 ). Th1 cytokines including IL-2 and IFN-γ enhance immune injury by recruiting more inflammatory cells into the liver grafts, whilst IL-17 impairs tolerance and recruits neutrophils ( 12 , 13 ). Furthermore, alloreactive T cells generate CD8 + T cell responses and mediate graft tissue injury, causing damage to the biliary epithelium, hepatocytes, and endothelium cells ( 12 ).…”

“…Th1 cytokines including IL-2 and IFN-γ enhance immune injury by recruiting more inflammatory cells into the liver grafts, whilst IL-17 impairs tolerance and recruits neutrophils ( 12 , 13 ). Furthermore, alloreactive T cells generate CD8 + T cell responses and mediate graft tissue injury, causing damage to the biliary epithelium, hepatocytes, and endothelium cells ( 12 ). Many damage-associated molecular pattern molecules (DAMPs) released from damaged hepatocytes and liver sinusoidal endothelial cells promote cross-talk between DCs and alloreactive T cells, which induce inflammation after liver transplantation ( 14 , 15 ).…”