Liver transplant is associated with the induction of peripheral immune tolerance. Liver allografts are accepted spontaneously in most combinations of mismatch in major histocompatibility complex, without any requirements for immunosuppression. Liver nonparenchymal cells (especially dendritic cells and Kupffer cells), costimulatory pathways, and activated T-cell apoptosis may contribute to the induction of liver tolerance. Therefore, liver tolerance is an active process that includes T-cell activation, proliferation, infiltration of the allograft, and T-cell apoptosis. Liver dendritic cells may modulate the amount of alloreactive T cells in liver graft recipients by expressing the coinhibitory molecule programmed death-ligand 1 and the immunosuppressive enzyme indoleamine 2,3-dioxygenase. Liver dendritic cells also may induce activated T-cell apoptosis and Foxp3+ regulatory T cells. Future studies may clarify the precise function of liver nonparenchymal cells, the interactions between programmed death-ligand 1 and other costimulatory signals, and the contribution of the liver microenvironment to the induction and expansion of Foxp 3 regulatory T cells.

Key words : Dendritic cells, Immunosuppression, Indoleamine 2, 3-dioxygenase, Kupffer cells, Programmed death- ligand 1, T cells

Introduction

Inducing organ specific transplant tolerance is an elusive goal and major challenge in clinical transplants. A better understanding of the mechanisms of transplant tolerance is important and timely and may improve therapy. Liver transplants favor the induction of peripheral tolerance. Liver allografts in mice that have varied major histocompatibility complex (MHC) features are spontaneously accepted in most strain combinations without immunosuppressive treatment.^1,2 Therefore, transplants in mice provide an informative model and valuable tool to study the mechanisms of tolerance induction and maintenance. The purpose of this article is to review the mechanisms underlying tolerance in mouse orthotopic liver transplant models to help better understand mechanisms of inherent tolerance. This information may help guide the development of treatment for immune tolerance in heart transplant, kidney transplant, or skin grafts.

The development of mouse liver transplant models
Since the first portacaval shunt and organ transplant model was developed in rats in the 1960s, microsurgical techniques and various mouse models have been developed. The first orthotopic liver transplant model in mice was developed in 1991.¹ The techniques were modified from the rat liver transplant model using a combination of suture and cuff techniques without reconstruction of the hepatic artery (Figure 1). Studies conducted using this model have shown that liver grafts are accepted spontaneously in all strain combinations across MHC barriers without any requirement for immuno-suppression. The tolerance induced by the liver graft includes tolerance to a second graft from the liver donor including heart and skin grafts.^1,2 The mechanism of transfer of tolerance from the liver to the second graft is unknown. Nevertheless, this model is a good tool to study mechanisms of liver tolerance and has been used extensively. Many factors are involved in the mechanisms underlying spontaneous transplant tolerance, including the role of liver dendritic cells, costimulatory molecules, and CD4+ CD25+ Foxp3+ regulatory T cells (Treg cells).^3,4

Although excellent survival has been reported in a nonarterialized rat liver transplant model,⁵ there is controversy about the value of hepatic artery reconstruction.⁶ In the late 1990s, an arterialized orthotopic liver transplant model was established.^7,8 The absence of arterialization can lead to a higher incidence of biliary complications, and hepatic artery reconstruction is mandatory for long-term survival and diminished hepatocellular injury after 24 hours of cold preservation.^7-9 However, this arterialized orthotopic liver transplant model is technically challenging and associated with a high incidence of arterial thrombosis and lower frequency of survival in mice.

Another liver transplant model in mice was developed using part of a liver graft (small-for-size liver transplant model).^10,11 This model mimics the living-donor liver transplant in humans and transplants only 30% of the donor liver. The small-for-size liver transplant model maybe useful to study the mechanisms of liver injury and regeneration.

Establishment of liver tolerance
The liver may have unique immunologic features, evidenced by impaired immunologic rejection of transplanted allogeneic liver and ineffective immunity to several chronic viral infections. The liver may be capable of producing immunologic tolerance (tolerogenicity). In an oral tolerance model, liver tolerance may induce a state of tolerance systemically,¹² including tolerance to the second graft from the same donor. The CD4+ CD25+ Foxp3+ Treg cells are expanded after allogeneic liver transplant and maintained at a higher level in the liver grafts and recipient spleens. This subset of induced Treg cells may contribute to subsequent maintenance of tolerance.⁴

Liver allografts may be accepted without immunosuppressive therapy in outbred pigs, rats, and all mouse strains.^1,13,14 In dogs, baboons, and humans, immunosuppression is required to prevent rejection of a liver allograft, but the rejection response usually is more easily treated than the rejection response to their organs. Liver graft tolerance is associated with donor leukocyte chimerism in recipient secondary lymphoid organs.¹⁵ In addition, depletion of leukocytes by irradiation in liver donors may disrupt spontaneous graft tolerance and cause acute rejection.¹⁶ Therefore, resident leukocytes in the donor liver may be important in inducing tolerance.

The liver may contribute to the induction of tolerance to systemic and oral antigens. The liver may transfer tolerance to ovalbumin from oval bumin-fed mice to nonfed mice.¹² Peripheral tolerance maybe induced by direct delivery of antigens via the portal vein, but not via the intravenous route.¹⁷ Furthermore, the liver is the site of persistent viral infections such as hepatitis B and hepatitis C, possibly because of an ongoing immune response that fails to clear the virus.^18,19 Therefore, the liver has the unique immunologic property of inducing tolerance to alloantigens.

The underlying mechanisms of spontaneous liver transplant tolerance are unknown, but several factors may be involved. These include liver dendritic cells and their costimulatory signals and cytokines^3,20-22; the continually occurring alloreactive T-cell apoptosis in the liver graft^4,23,24; the balance of cytokines from T-helper cells (Th1 and Th2 cells) in the microenvironment; and the integrated signals delivered by costimulatory molecules on antigen presenting cells.^4,24 The immunotolerance is transferable to previously unexposed syngeneic mice by spleen or liver graft infiltrating cells obtained from long-term liver allograft recipients,² suggesting that a regulatory mechanism is involved. The CD4+ CD25+ Foxp3+ Treg cells are expanded in the liver grafts and recipients spleens after transplant, and Treg cells may help maintain liver graft acceptance. Depletion of CD4+ CD25+ Foxp3+ Treg cells by anti-CD25 monoclonal antibodies prevents liver allograft tolerance and induces liver allograft acute rejection. Liver graft rejection is associated with reduced Treg to effector T-cell ratio, diminished activated-cell apoptosis, decreased cytotoxic T lymphocyte antigen 4, decreased indoleamine 2,3-dioxygenase, and increased interleukin 2 (IL-2) gene expression in liver grafts and host spleens.^4,24 In addition, overexpression of indoleamine 2,3-dioxygenase within the liver allograft or antigen presenting cells causes suppression of activated CD4 or CD8 T-cells and promotes T cell apoptosis.²⁵ Expression of indoleamine 2,3-dioxygenase is higher in spontaneously tolerated murine liver grafts, and 1-methyltryptophan, which blocks indoleamine 2,3-dioxygenase activity, can abolish liver tolerance.26 Therefore, liver nonparenchymal cells, cytotoxic T lymphocyte antigen 4, indoleamine 2,3-dioxygenase, activated T-cell apoptosis, and CD4+ CD25+ Foxp3+ Treg cells all affect the induction and maintenance of liver tolerance (Figure 2).

Liver nonparenchymal cells and tolerance induction
The liver is an important hematopoietic organ. In the liver, varied cell types develop that differ from cells in the blood, including bone marrow-derived dendritic cells and Kupffer cells and non bone marrow-derived liver sinusoidal endothelial cells, hepatic stellate cells, and sessile Kupffer cells. These cells are the liver resident leukocytes, also known as liver nonparenchymal cells. The contribution so liver nonparenchymal cells to hepatic tolerance are poorly defined. Liver dendritic cells and antigen presenting cells, derived from bone marrow, are highly efficient initiators and regulators to immune responses. Dendritic cells regulate immune responses, depending on their maturation status, signals from antigens and the microenvironment.^27,28 The liver produces all 3 major dendritic cell subsets,²⁹ including myeloid, lymphoid, and plasmacytoid to dendritic cells, but limited information is available about the effects of each dendritic cell subset intolerance induction.

In the periphery, cross-presentation of endogenous antigens by dendritic cells, especially CD8+ dendritic cells, may induce CD8+ T-cell tolerance against self. However, nonhematopoietic antigen presenting cells in the liver, skin, parenchymal tissues, and lymph nodes may present endogenous and exogenous antigens to CD8+ T cells during steady-state conditions. These antigen-presenting cells contribute to the induction, maintenance, and regulation of peripheral CD8+ T-cell tolerance by several mechanisms.³⁰ Spontaneous liver tolerance in mice is associated with the persistence of donor dendritic cells in lymphoid tissue and high levels of apoptosis of alloreactive T cells.²³ Increasing liver dendritic cell numbers and maturation by treatment with FMS-related tyrosine kinase 3 ligand (Flt 3 ligand) may induce acute liver allograft rejection and prevent apoptosis of activated T cells.^21,22,31,32 Promotion of indefinite heart graft survival by donor dendritic cells and costimulation blockades associated with marked apoptosis of host T cells.³³ Therefore, apoptosis may be important in blocking host alloactivity and inducing tolerance. In rats, donor liver-derived dendritic cells may cause apoptotic depletion of alloreactive T cells, and this may cause donor-specific tolerance.³⁴ Dendritic cells may induce various types of Treg cells, including type 1 regulatory T cells (Tr1 cells) that produce interleukin 10 (IL-10), T helper 3 (Th3) cells that produce TGF-β, and CD4+ CD25+ Foxp3+ Treg cells; dendritic cells also may modulate allogeneic T-cell responses.^28,35

Liver Kupffer cells derived from bone marrow comprise the largest population of liver macrophages and may contribute to liver tolerance to soluble antigens and allografts. Depletion of Kupffer cells may impair systemic tolerance to antigens in the portal valve in and may eliminate or reverse portal and liver graft tolerance.^16,36,37 Little information is available about the effect of Kupffer cells in liver tolerance. Kupffer cells in the liver are constantly exposed to harmless food antigens and bacterial products of commensal gut bacteria and to bacterial and viral pathogens. In addition, Kupffer cells constitutively express many proinflammatory cytokines including IL-10,TGF-β, IL-1, IL-6, IL-12, IL-18, tumor necrosis factor α, and indoleamine 2,3-dioxygenase, and may modulate differentiation and proliferation of other immune cells in the liver.^18,38,39 This suggests that Kupffer cells maybe important in regulating immunoreactions in the liver and contributing to liver-mediated systemic immune tolerance.⁴⁰

The liver hosts several other important cell types including hepatic stellate cells, liver sinusoidal endothelial cells, and radiation-resistant sessile Kupffer cells.^18,41,42 These cells are known as liver resident antigen presenting cells because they are resident in the liver, are not derived from bone marrow, and have antigen presenting function. Indirect antigen presentation by liver sinusoidal endothelial cells contributes to alloreactive T-cell tolerance induced by portal venous injections of donor splenocytes.⁴³ Hepatic stellate cells contribute to liver fibrosis, regeneration, and immuno-regulation. Hepatic stellate cells induce activate T-cell apoptosis, protect mouse islet allografts from rejection, and expand CD4+ CD25+ Foxp3+ Treg cells in an IL-2–dependent manner in vitro and in vivo.^44,45 In addition, hepatic stellate cells may reduce T-cell proliferation in response to alloantigens, suppress acute graft-versus-host disease, and prolong recipient survival.⁴⁶

The liver induces tolerance by antigen presentation or elimination of effector T cells. Hepatic dendritic cells are scarcely immunogenic for CD8T cells. Liver sinusoidal endothelial cells not only can induce tolerance by, suppress neighboring antigen presenting cells, and may also be able to induce T-cell immunity.⁴⁷ When soluble antigen MHC class 1 molecules are cross-presented by liver sinusoidal endothelial cells to previously unexposed CD8+ T cells, T-cell tolerance is induced; this requires interaction between coinhibitory B7-H1 molecule on liver sinusoidal endothelial cells and programmed cell death 1 on CD8 T cells. T-cell tolerance mediated by liver sinusoidal endothelial cells may be abolished when T-cell receptor encounter similar MHC class I peptide molecules that are presented by liver sinusoidal endothelial cells during viral infection of the liver.

In summary, resident liver leukocytes that may or may not be derived from bone marrow are important in regulating liver tolerance. Further studies may clarify the specific molecular pathways in these cells that regulate liver transplant tolerance, induce and expand Treg cells, and activate T-cell apoptosis.

Costimulatory molecules in tolerance induction
Kupffer cells and liver dendritic cells express a significantly lower level of MHC class 2 and costimulatory molecules B7-1, B7-2, CD40, and programmed death-ligand 1; acrasin competent antigen presenting cells; and may inhibit T-cell activation induced by dendritic cells.^48,49 Kupffer cells and dendritic cells expand CD4+ CD25+ Treg cells in vitro, induce indoleamine 2,3-dioxygenase expression in the liver, and prolong the survival of allogeneic hepatocytes.^50,51 In addition, the down-stream mechanism of Kupffer cells may include stimulation of indoleamine 2,3-dioxygenase production and induction of activated T-cell apoptosis.^18,39 Contributions of the resident live antigen presenting cells to liver tolerance induction are poorly understood. Liver sinusoidal endothelial cells in the liver may respond to lipopolysaccharide from the gut by inhibiting costimulatory molecules, synthesizing anti-inflammatory cytokines (eg, IL-10 and TGF-β), expressing the negative costimulatory molecules programmed death ligand 1 and indoleamine 2,3-dioxygenase, and inducing activated T-cell apoptosis.^18,39,52 These reactions may cause T-cell tolerance that may be exploited by a well-adapted pathogen. Dendritic cells, especially plasmacytoid dendritic cells, express high quantities of the coinhibitory molecule programmed death ligand 1, which correlates with Foxp3+ Treg cells and liver graft tolerance in humans and regulates Foxp3+ T-reg cell induction in mice.^53,54 The induction of Foxp3+ T-reg cells by dendritic cells depends on the indoleamine 2,3-dioxygenase pathway.⁵⁵ Therefore, liver dendritic cells may modulate the amount of alloreactive T cells in liver graft recipients by expressing the coinhibitory molecule programmed death ligand 1 and the immunosuppressive enzyme indoleamine 2,3-dioxygenase and inducing activated T-cell apoptosis and Foxp3+Treg cells.

Regulatory T cells
The CD4+ CD25+ Treg cells are a naturally occurring subset of CD4+ T cells and comprise 5% to 10% of peripheral CD4 T cells. The CD4+ CD25+ Treg cells are important in self-immune homeostasis and may be the principal regulator of self-tolerance and transplant tolerance.⁵⁶ The Foxp3 gene, a member of the forkhead winged helix protein family of transcription factors, is a specific molecular marker for CD4+ CD25+ Treg cells that controls Treg cell development and function.⁵⁷ Donor-specific Treg cells that had no previous exposure had immuno-suppressive properties that were stimulated in the peripheral blood of tolerant patients, and the frequency of these cells was decreased in intolerant patients. Therefore, Treg cells may promote transplant tolerance.⁵⁸ Hepatic stellate cells protect cotransplanted islet allografts by exerting comprehensive inhibitory effects on T cells, including apoptotic death in graft-infiltrating antigen-specific effector T cells and marked expansion of CD4+ Foxp3+ Treg cells.⁵⁹ The expression of B7-H1, a product molecule of the signaling of interferon γ, on hepatic stellate cells are responsible for inducing T-cell apoptosis but has no effect on the expansion of Treg cells; therefore, undetermined effector molecules produced by interferon γ signaling are involved in this immune suppressive process.⁵⁹

Adoptive transfer of CD25+ CD4+ Treg cells to mice that had no previous exposure prevents autoimmune disease and promotes allograft survival⁶⁰; depletion of CD25+, CD4+, and Treg cells induces auto immune disease and antitumor immunity,⁶¹ prevents acceptance of liver and skin grafts, and accelerates heart graft rejection in mice.⁶² The CD4+ CD25+ Treg cells are generated in the thymus and the periphery.^63,64 In addition, these Treg cells can be induced from CD4+ CD25-effector T cells in the periphery by many types of antigen presenting cells such as immature dendritic cells, Kupffer cells, and hepatic stellate cells.^18,45,50 The mechanism of Treg induction is unclear. However, B7 costimulatory signals, the immunosuppressive cytokine sIL-10 and TGF-β and IL-2 are necessary for Treg induction.^45,64 Therefore, CD4+ CD25+ Treg cells contribute to peripheral tolerance and may be useful in regulating transplant immunity.

The mechanisms of Treg cell action are unclear. The immunosuppressive function of Treg cells may occur by cell-cell contact, mediated by the costimulatory molecule cytotoxic T lymphocyte antigen 4, and programmed death ligand 1, and by soluble immunosuppressive factors such as IL-10 and TGF-β.^65,66 The Treg cells can directly suppress the effector CD4+ and CD8+ T cells by reducing IL-2 production and inducing activated T-cell apoptosis.⁶⁷ The cytokine IL-2, a growth factor of T cells, is important for Treg cell development and survival.⁶⁸ Mice deficient in IL-2 and CD28 do not have Treg cells, and the number of Treg cells is decreased in B7 deficient mice.⁶⁹ In addition, the tryptophan catabolism enzyme indoleamine 2,3-dioxygenase supports dendritic cell-mediated Treg cell induction and the immunosuppressive function of Treg cells.⁷⁰ The Treg cells modulate tryptophan catabolism by inducing indoleamine 2,3-dioxygenase production; this is done by a mechanism that is dependent on cytotoxic T lymphocyte antigen 4 and that suppresses downstream T-cell activation.²⁵ Therefore, indoleamine 2,3-dioxygenase may be down-stream of Treg cell-mediated immunosuppression.

In a spontaneous liver transplant tolerance model in mice, CD4+ CD25+ Foxp3+ Treg cells are increased in liver grafts and recipients spleens after transplant, and this is associated with increased cytotoxic T lymphocyte antigen 4, TGF-β, and indoleamine 2,3-dioxygenase expression, decreased IL-2 expression, and increased T-cell apoptosis in the liver grafts and host spleens. Depletion of recipient CD4+ CD25+ Foxp3+ Treg cells significantly reduces the survival of live allografts, protects alloreactive T cells from apoptotic death, reduces the number of Foxp3+ Treg cells, and decreases cytotoxic T lymphocyte antigen 4, and indoleamine 2,3-dioxygenase gene expression.^4,24 Liver nonparenchymal cells favor the induction of Foxp3+ Treg cells in vitro and depend on the expression of programmed death–ligand 1. The liver dendritic cells deficient in programmed death–ligand 1 do not induce Foxp3+ Treg cells, and the liver grafts are promptly rejected from the programmed death–ligand 1-/-donors (unpublished data). Therefore, the tolerant state induced in liver transplant maybe caused by the effects of Foxp3+ CD25+ CD4+ Treg cells and activated T-cell apoptosis, which are possibly induced by liver nonparenchymal cells through programmed death ligand 1 signaling. Indoleamine 2,3-dioxygenase expression is correlated with liver graft tolerance and may function down-stream from CD4+ CD25+ Foxp3+ Treg cell.

The information obtained from mouse models may be useful in guiding translational medicine in humans. The Foxp3+ Treg cells may be used as an immunodiagnostic tool in clinical kidney transplant.^71-73 Several protocols for therapy for human transplant patients based on Foxp3+ Treg cells have been developed and have shown promising results.^58,74

Conclusions

In summary, mouse liver transplant models are valuable tools to study the mechanism so inherent liver tolerance. Studies based on these models have shown that CD4+ CD25+ Foxp3+ Treg cells induce functional tolerance and apoptosis of activated alloreactive T cells and promote liver transplant tolerance. Liver nonparenchymal cells, especially dendritic cells, and the costimulatory molecule programmed death-ligand 1 are important in initiating the Foxp3+ Treg cell-mediated immuno-suppressive cascade. Future studies may clarify the precise function of the varied liver nonparenchymal cells, the interactions between programmed death-ligand 1 and other costimulatory signals, and the contribution of the liver microenvironment to the induction and expansion of Foxp3 Treg cells. It is feasible that manipulating Treg cells as an immuno-modulatory strategy may induce graft tolerance.

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