CCR5 in T Cell-Mediated Liver Diseases: What’s Going On?¹

The liver contains a large population of resident lymphocytes, including CD8⁺ and CD4⁺ T cells; T cells that are crucial elements in the adaptive immune response. Furthermore, NK and NKT cells, which are key components of the innate immune system, are highly enriched in the liver (Refs. 1 and 2 ; Fig. 1). Thus, the liver plays a critical role in the first-line host defense against incoming foreign Ags absorbed from gut, where it maintains a balance between tolerance and generation of an immune response. Disruption of this balance through multiple mechanisms, including T cell activation, could potentially lead to the development of liver diseases. T cell-mediated liver diseases, including viral liver diseases (such as hepatitis B virus (HBV)³ and hepatitis C virus (HCV)), autoimmune hepatitis (AIH), and graft-vs-host disease (GVHD)), affect >300 million people worldwide (3, 4) Whatever the stimulus for development of T cell-mediated liver diseases, the final common pathway is an influx and activation of T cells (CD4⁺, CD8⁺, NKT cells, and regulatory T (Treg) cells) in the liver.

Over the past 10 years, chemokines have been the focus of a great deal of research pertaining to their role in promoting leukocyte trafficking and recruitment during inflammatory responses. It is perhaps not surprising that chemokines are often regarded as “the commander-in-chief” of leukocyte migration.

Chemokines are a large family of specialized heparin-binding proteins, the primary and traditional function of which is to regulate the trafficking of leukocytes (5, 6). These proteins can promote T cell differentiation to either Th1- or Th2-type responses by augmenting or directionally differentiating T cells toward polarized type 1 or type 2 responses (5). Chemokines are subdivided into four subfamilies (C-X-C, C-C, C, and C-X₃-C) based on their amino-terminal cysteine residues (6, 7, 8). To date, 43 human chemokines have been described previously (7, 8).

The biological actions of chemokines are mediated through a family of seven transmembrane G protein-coupled receptors (GPCRs) present on the surface of target cells (6, 7, 8, 9). Chemokine receptors belong to a large superfamily of GPCRs, a diverse class of cell surface receptors that include receptors for neurotransmitters and proteinases. Presently, 19 different human chemokine receptors have been characterized (6, 7, 8, 9). Specifically, 6 C-X-C chemokine receptors, designated CXCR1 to CXCR7, and 11 C-C chemokine receptors, denoted CCR1 to CCR11, are known (6, 7, 8, 9). Receptors for lymphotactin (XCR1) and fractalkine (CX₃CR1) have also been characterized (7, 8).

The CCR5 chemokine receptor is a CC chemokine receptor that is expressed on many cell types, including NKT cells, CD4⁺ T cells, CD8⁺ T cells, and macrophages (7, 8, 10, 11). CCR5 mediates its biological effects by interacting with any of these three ligands: CCL3, CCL4, and CCL5 (6, 8, 11). CCR5 is preferentially expressed on Th1 cells (11, 12), suggesting that this receptor may be important in the recruitment of IFN-γ-producing CD4⁺ T cells to inflammatory sites; however, this remains controversial (13).

The CCR5 receptor came to worldwide attention about a decade ago after being identified as one of the major coreceptors for HIV infectivity, and CCR5 ligands were noted to possess anti-HIV activity (14). The observation that Caucasian individuals who have a natural CCR5 mutation, CCR5Δ32 (i.e., a 32-bp deletion in this gene results in a nonfunctioning receptor that is trapped in the endoplasmic reticulum and therefore not expressed at the cell surface), resist HIV infection (14, 15) further highlighted the fundamental role of CCR5 in HIV pathogenesis. In the last decade, significant progress has also been made in the development of CCR5 antagonist as potential therapies for HIV infectivity. Regrettably, recent early clinical trials of some CCR5 antagonists were abruptly halted due to profound hepatotoxicity (16, 17, 18), implicating CCR5 as potentially modulating the hepatic inflammatory response. In agreement with CCR5 deficiency modulating the hepatic inflammatory response, the CCR5Δ32 mutation was recently reported to exacerbate the severity of hepatic inflammation and injury in some T cell-mediated liver diseases (discussed below). In addition, CCR5 has also been implicated in the pathology of numerous autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and type 1 diabetes (19).

There are a number of ways CCR5 could potentially modulate the hepatic inflammatory response in T cell-mediated liver diseases. First, since T cell-mediated immune responses play a critical role in hepatocyte damage induced by autoimmunity and viral infection and CCR5 is preferentially expressed on Th1 cells (5, 11, 12), it was inferred that CCR5 could modulate hepatocyte damage during T cell-mediated liver diseases by promoting the recruitment of Th1-expressing cells to the liver. Second, CCR5 deficiency in humans, as well as in experimental animal models of inflammation and infection, is associated with significant increases in tissue levels of the CCR5 ligand CCL5 (14, 20, 21). Therefore, these elevated tissue levels of CCL5 could in turn promote enhanced influx of leukocytes (including T cells) into tissues by binding to its alternate receptor, CCR1, expressed on these cells (20, 21, 22).

In this brief review, we discuss the evidence implicating CCR5 in the pathophysiology of T cell-mediated liver diseases with particular emphasis on viral liver disease (HCV), AIH, and GVHD. Specifically, we provide information from the clinical and experimental setting demonstrating the beneficial (good) or detrimental (bad) role of CCR5 during T cell-mediated hepatic inflammatory response.

AIH is a progressive inflammatory liver disease that predominantly affects women. Although the factors that initiate and regulate AIH remain poorly defined, there is evidence AIH is primarily initiated by CD4⁺ T cells and to a lesser extent by CD8⁺ T cells that recognize self-Ag (4). It is well established that CD4⁺ T cells primarily function as regulators of other immune cells, either through secreted cytokines (e.g., Th1 or Th2) or by direct cell-cell contact (23). However, splitting complex diseases such as AIH, in terms of Th1 and Th2 patterns, is likely an oversimplification. Importantly, IL-4 (a cytokine classically grouped as Th2) exerts proinflammatory effects in the liver. For example, direct expression of IL-4 in the liver of mice using recombinant adenoviruses coding for mouse IL-4 causes a lethal and dose-dependent hepatitis (24), and rIL-4 treatment of mouse primary hepatocytes is known to cause apoptosis of these cells in vitro (24). Furthermore, T cell subtypes other than CD4⁺ T cells can also produce both IFN-γ and IL-4.

NKT cells are a unique T cell lineage that are defined as cells that coexpress the NK cell marker (usually NK1.1) and a highly restricted TCR specific for glycolipid Ag (25). NKT cells have the unusual property of recognizing glycolipid Ags in conjunction with the MHC class I-like molecule, CD1d, and are abundant in the liver (Fig. 1; Refs. 1 , 2 , 25). NKT cells are regarded as a bridge between the innate and adaptive immune systems (26). In recent years, a growing body of evidence has demonstrated that NKT cells are prime targets for immunomodulation due to their ability to secrete high levels of cytokines, including IFN-γ and IL-4, within minutes of activation (25, 26). Interestingly, clinical and experimental studies have associated IL-4 produced by activated hepatic NKT cells with a more aggressive hepatic injury in children with AIH and in experimental AIH (27, 28).

The expression pattern of CCR5 in liver samples or blood specimens of patients with AIH remains unknown; however, levels of CCL3, a CCR5 ligand, are increased in liver biopsies of patients with AIH (29). Given that CCL3 plays an important role in promoting IFN-γ production (5), this chemokine could potentially promote the development of AIH in humans by enhancing IFN-γ secretion from activated CD4⁺ T cells similar to what has been observed in experimental T cell-mediated hepatitis (30). Currently, an ideal animal model of AIH does not exist. However, many of the important insights regarding the potential functional role of CCR5 in the pathology of AIH have been derived primarily from a murine model of T cell-mediated hepatitis (the Con A model of hepatitis) in which genetic deletion of the CCR5 gene was examined for its effect on disease development and severity. Although the Con A hepatitis model is not truly a model of autoimmunity because there is no Ag specificity, Con A-induced hepatitis is a well-characterized murine model of experimental T cell-mediated hepatitis and is felt to mimic many aspects of human AIH (10, 28, 30, 31), including the increased recruitment of activated CD4⁺T cells to the liver and the development of a hepatic Th1 cytokine response, which plays a central role in the development of hepatitis. Con A hepatitis is mediated by activated resident hepatic NKT cells, which produce mainly IL-4 (28), and also by activated CD4⁺ T cells recruited to the liver, which produce IFN-γ (30). Cytokines, including IL-4 and IFN-γ, exert proinflammatory effects during Con A-induced hepatitis (28). It is noteworthy that previous studies have demonstrated that CD1d knockout (KO) and Vα14 KO mice (which have very few NKT cells) and CD4⁺ T cell KO mice all resist Con A-induced hepatitis (28).

In support of a role for CCR5 in AIH, we (10) and others (22) have recently demonstrated that CCR5 KO mice, when treated with Con A, are highly susceptible to the development of severe hepatitis and subsequent liver failure, relative to wild-type mice. Two unique mechanisms were proposed for these observations (10, 22). In the first study, we demonstrated that activated hepatic CCR5-deficient CD1d tetramer-positive NKT cells resist apoptosis after Con A administration and produce more IL-4 than wild-type controls (10). In addition, in vivo depletion of IL-4 or NKT cells ameliorated liver damage in CCR5 KO mice post-Con A treatment (10). Interestingly, the augmented IL-4 production by CD1d tetramer-positive hepatic NKT cells in Con A-treated CCR5 KO mice was not associated with a corresponding deficiency in IFN-γ production by activated NKT cells (10); therefore, it is likely that the increased survival of CCR5-deficient CD1d tetramer-positive NKT cells together with enhanced IL-4 production is important in the development of liver failure in these mice (10). In support of this hypothesis, stimulation of isolated CCR5-deficient CD1d tetramer-positive NKT cells with Con A or anti-CD3 mAb in vitro caused enhanced IL-4 production by these cells relative to similarly stimulated wild-type NKT cells (10). Of note, IL-4 is known to promote hepatocyte damage in Con A hepatitis through increased Fas ligand (FasL) expression on NKT cells (28). Interestingly, we observed that CCR5 deficiency augments FasL expression on isolated NKT cells after rIL-4 treatment in vitro (10).

In the second study, Moreno et al. (22) demonstrated that enhanced recruitment of CCR1-expressing CD4⁺ T cells, NKT cells (identified as simply NK1.1⁺ cells), and macrophages to the liver of Con A-treated CCR5 KO mice, mediated by the CCR1/CCR5 ligand CCL5, plays a central role in the development of severe hepatitis in these mice after Con A administration. Given that we have recently demonstrated that CCR1-expressing CD4⁺ T cells recruited to the liver produce IFN-γ during Con A-induced hepatitis in normal mice (30), it is likely that an augmented Th1 response via IFN-γ production by CCR1-expressing CD4⁺ T cells directly contributes to the severe hepatitis observed in CCR5 KO mice during Con A-induced hepatitis (22). In wild-type mice, NK cells do not appear play a role in the development of Con A hepatitis (28). However, in follow-up to our initial study, we have recently observed that CCR5 deficiency unmasks a potent proinflammatory role for NK cells during Con A-induced hepatitis (32). Specifically, IL-4 produced by activated CCR5-deficient hepatic NKT cells drives NK cell transactivation, resulting in augmented IFN-γ production by NK cells, and specific depletion of IFN-γ or NK cells leads to a marked reduction in hepatitis in Con A-treated CCR5 KO mice (32). Taken together, these studies (summarized in Fig. 2) suggest that: first, CCR5 signaling negatively regulates activated hepatic NKT cell IL-4 production during Con A-induced hepatitis in wild-type mice because enhanced hepatitis in CCR5 KO mice after Con A administration was associated with exaggerated NKT cell IL-4 production; a finding that was confirmed by in vitro studies (10). Second, IL-4 produced by activated NKT cells subsequently transactivates NK cells to exert proinflammatory effects via augmented IFN-γ production in Con A-treated CCR5 KO mice. Third, in the absence of CCR5, increased hepatic levels of the CCR1/CCR5 ligand CCL5 recruits mononuclear cells, including NK cells (22, 33), to the liver by interacting with its alternate receptor CCR1 and induces a Th1 response via augmented IFN-γ production by NK cells and CD4⁺ T cells (32) within the liver. Finally, an alternative possible explanation of the enhanced susceptibility of CCR5 KO mice to Con A-induced hepatitis is the potential failure of endogenous hepatic anti-inflammatory mechanisms (such as IL-10, an anti-inflammatory cytokine in Con A-induced hepatitis (34)) to curb the inflammatory response in these mice. However, we have observed similar hepatic levels of IL-10 in CCR5 KO mice relative to wild type during Con A-induced hepatitis (M. N. Ajuebor and M. G. Swain, unpublished observation).

As mentioned previously, a substantial body of evidence has previously suggested a proinflammatory role for CCR5 in promoting the development of autoimmune diseases such as type 1 diabetes and rheumatoid arthritis by augmenting Th1 responses. However, recent studies suggesting that CCR5 signaling also exerts an anti-inflammatory role in autoimmunity (as shown in Con A-induced hepatitis) conforms with a previous observation in the viral influenza A virus (20) infectious model.

GVHD is an immunologically mediated complication of bone marrow transplantation that often affects the liver and other organ system (35). The liver disease associated with GVHD is often described as a T cell-mediated liver disease based on the fact that T cells have been implicated as key mediators in the pathophysiology of GVHD. Specifically, GVHD is caused by infiltrating donor T cells (primarily CD8⁺ T cells) attacking Ags expressed on recipient cells (35). In support of this is the observation that inflammatory infiltrates composed of donor T cells (mainly CD8⁺ T cells) are found in lesions of patients with GVHD (35), and the depletion of CD8⁺ T cells from donor T cells before transfer into the recipient reduces the incidence of GVHD in the clinical setting (36). Many factors can potentially promote the generation of a Th1 response, but T cells are widely regarded as a central figure in promoting Th1 responses via IFN-γ production (37). Since increased expression of IFN-γ has been controversially associated with the progression of GVHD in both humans and experimental animal models (35), it has been proposed that the recruitment of donor CD8⁺ T cells from the blood to the site of liver injury during GVHD could be potentially explained by increased expression of CCR5, a chemokine receptor that is preferentially expressed on Th1 cells. Moreover, increased CCR5 expression has been observed in peripheral blood buffy coats of patients with GVHD (38).

Evidence for a role of CCR5 in the pathology of GVHD has come from a number of studies using experimental murine models of GVHD. Specifically, increased expression of CCR5 on recruited donor T cells (mainly CD8⁺ T cells) in the liver of nonirradiated (i.e., unconditioned) recipient mice was observed during GVHD (39). Furthermore, treatment of the nonirradiated recipient mice with an anti-CCR5 blocking Ab markedly reduced liver damage in association with the reduced recruitment of both CCR5-expressing CD8⁺ T cells and FasL expression on CD8⁺ T cells in the liver during GVHD (39). Although the CCR5 ligands (CCL3, CCL4, and CCL5) are differentially increased in the liver during GVHD (39, 40), CCL3 has emerged as a central figure for inducing the recruitment of CCR5-expressing CD8⁺ T cells into liver during GVHD. Specifically, anti-CCL3-neutralizing Ab treatment inhibited the hepatic infiltration of CCR5-expressing CD8⁺ T cells and improved liver damage in nonirradiated recipient mice (39). Surprisingly, IFN-γ production by liver-infiltrating T cells was not reduced by blocking CCR5, suggesting that IFN-γ may not necessarily be critical for the induction of liver injury during GVHD in nonirradiated mice (39). It is noteworthy that while a Th1 response via IFN-γ production was previously associated with the development of GVHD in both nonirradiated and irradiated (i.e., conditioned) recipient mice, in recent years, the role of IFN-γ in GVHD pathogenesis has become less clear and more complicated than previously thought (35, 39, 41). Despite this, STAT4, a signaling molecule that promotes Th1 responses, was shown to contribute to the development and severity of GVHD in irradiated recipient mice (41). The reason underlying this discrepancy in the development of a Th1 response remains undefined and needs further detailed investigation. Further support of a proinflammatory role for CCL3 in GVHD derives from the observation that the transfer of CCL3-deficient donor T cells caused a significant reduction in the influx of CD8⁺ T cells into the liver coupled with reduced liver pathology in recipient mice (42). Of note, CCL3 has been shown to be produced by liver-infiltrating CD8⁺ T cells during experimental GVHD (43). For this reason, it seems likely that CCL3 produced by CD8⁺ T cells recruited to the liver recruits additional CD8⁺ CTLs to the liver via CCR5 and consequently promotes liver damage during GVHD.

Although the proinflammatory effects of CCR5 in the pathogenesis of GVHD have been well documented, it is becoming increasingly clear that CCR5 can also suppress inflammatory responses during GVHD. In particular, the transfer of CCR5-deficient donor T cells into irradiated (i.e., conditioned) recipient mice was reported to exacerbate GVHD, in association with an increase of donor CD8⁺ T cell infiltrates in the liver (44). Therefore, the functional role of CCR5 during GVHD appears to be model dependent since in nonirradiated recipient mice CCR5 blockade inhibits the hepatic inflammatory response, whereas in irradiated recipient mice, CCR5 blockade enhances the hepatic inflammatory response. These findings suggest that the CCR5Δ32 mutation could possibly predispose conditioned (i.e., irradiated) patients to the occurrence of GVHD after stem cell transplantation.

A potential mechanism that could account for CCR5 blockade enhancing the hepatic inflammatory response in irradiated mice during GVHD may include a reduced CCR5-mediated accumulation of Treg cells (CD4⁺CD25⁺ T cells) within the liver (45). In agreement with this hypothesis, CCR5-deficient Treg cells are unable to suppress GVHD-induced lethality, and this observation correlates with the reduced hepatic accumulation of CCR5-deficient Treg cells, as compared with wild-type Treg cells, in GVHD (45). Naturally occurring Treg cells are CD4⁺ T cells that mature in the thymus, represent 5–10% of the peripheral CD4⁺ T cell population, and are characterized by the constitutive expression of the transcription factor Foxp3 (46). Interestingly, both mice and humans deficient in a functional Foxp3 protein suffer from severe autoimmune disease (46). An alternative mechanism underlying the enhancement of the hepatic inflammatory response after CCR5 blockade in irradiated mice during GVHD could potentially include a reduced CCR5-mediated accumulation of NKT cells within the liver. Specifically, a recent study reported a correlation between the reduced hepatic accumulation of NKT cells with the progression of GVHD (47). Therefore, the role of CCR5 in NKT cell accumulation in the liver during GVHD in irradiated mice warrants further investigation.

HBV and HCV are hepatotropic viruses that replicate mainly in the liver. In both infections, liver damage occurs as a consequence of the immune response to virus present within the liver. Over 300 million people worldwide are persistently infected with HBV and HCV and risk developing chronic liver disease, cirrhosis, and hepatocellular carcinoma. Despite many common features in their pathogenesis, HBV and HCV differ markedly in their virological properties, as well as in their immune escape and survival strategies (reviewed by Ref. 3). Although HBV is a DNA virus whereas HCV is an RNA virus, similar cell types (including NKT cell and CD8⁺ and CD4⁺ T cells) have been implicated in the pathogenesis of both liver diseases (3). Although, animal models of HBV infection are well characterized (reviewed by Ref. 3), the role of CCR5 in the pathogenesis of clinical and experimental animal models of HBV infection remains undetermined (and represents a potential fertile ground for investigation). Therefore, in this review, we will specifically discuss the role of CCR5 in the pathophysiology of viral hepatitis induced by HCV.

The cellular immune response is thought to play a key role in the pathogenesis of HCV infection. Specifically, cells of innate (NK and NKT cells), as well as adaptive (CD4⁺ and CD8⁺ T cells) immunity, have been implicated in the pathogenesis of acute and chronic HCV infection (48). It is broadly accepted that these different cell types are key figures in promoting Th1 responses since they can promptly induce the secretion of IFN-γ once activated (23, 25, 26). Based on this, it was proposed that these cells could potentially curtail viral replication and hepatic injury during acute and chronic HCV infection by promoting Th1 responses via IFN-γ production. In agreement with this hypothesis, an increased CD8⁺ T cell response via IFN-γ production was associated with viral clearance and recovery from acute HCV infection in patients (49) and in chimpanzees (50). Furthermore, a genetic predisposition to enhanced NK cell function (through IFN-γ production) was reported to contribute to the spontaneous clearance of HCV in infected individuals (51). In contrast to acute HCV infection, the development of persistent chronic HCV infection has been correlated with an impaired Th1 response (i.e., reduced IFN-γ production) due to defective CD8⁺ T and NK cell responses during HCV infection (49, 52). Impaired NKT cell function has also been reported to promote HCV chronicity (53). Specifically, human CD1d-restricted NKT cells have been reported to favor a Th1 bias (by producing IFN-y but not IL-4) during HCV infection; however, the numbers of these cells were observed to be lower in the liver of HCV-infected individuals relative to healthy individuals (53).

The conventional view of chemokines is that they contribute to the pathology of infectious and autoimmune diseases by promoting the recruitment of leukocytes to sites of tissue injury. Small animal models of HCV infection are not widely available (48). However, data from HCV-infected chimpanzees demonstrating increased chemokine (including CCL2, CCL4, CCL5, and CXCL10) expression in the HCV-infected liver suggest a potential role for these chemokines in the pathophysiology of HCV infection (50). In agreement with this, increased expression of CCR5 ligands (CCL3, CCL4, and CCL5) and their receptor, CCR5, has been observed in the livers of patients infected with HCV (11, 54). Accordingly, it was hypothesized that CCR5 interacts with its ligands expressed in the liver to promote the recruitment of Th1-expressing cells into the liver to mediate the clearance of HCV-infected hepatocytes (11, 54). Concurrent with this finding was the observation that reduced CCR5 expression on CD8⁺ T cells (due to receptor internalization) by the HCV structural protein E2 after interaction with CD81 (a cell surface receptor that is widely expressed on hepatocytes where it is a coreceptor for HCV binding (55)) diminished Th1 responses and sustained chronic HCV infection (56, 57). However, this finding remains controversial because an increase in the number of CCR5-expressing CD8⁺ T cells has also been associated with increased inflammatory activity during chronic HCV infection (58). Regardless, the accepted dogma is that a strong antiviral Th1 driven immune response is associated with viral clearance during acute HCV infection. Moreover, antiviral therapy with IFN-α containing regimens effectively treats some individuals with chronic HCV infection. Interestingly, the efficacy of IFN-α has been attributed to its ability to partially up-regulate CCR5 expression on T cells during HCV infection (59). In addition, ribavirin (a nucleoside analog used with IFN to treat HCV infection) is believed to be effective in HCV treatment in part by biasing the hepatic cytokine profile to a Th1 response (60).

The observation that down-regulation of CCR5 expression on T cells impedes the clearance of HCV-infected hepatocytes during HCV infection led to the proposal that CCR5-deficient individuals may be prone to an increased susceptibility to HCV infection. Indeed, the frequency of the CCR5Δ32 mutation was reported to be 3-fold higher in patients with chronic HCV infection relative to healthy controls (61). Specifically, the CCR5Δ32 mutation was associated with increased viral load and CD8⁺ T cell counts in the peripheral blood in a specific group of patients with hemophilia who were coinfected with HCV (but remained HIV free) (61). However, this study remains controversial because a number of studies have emerged with contradictory data. For example, other investigators have reported that the CCR5Δ32 mutation did not correlate with an increased incidence or severity of HCV infection (62, 63). A possible explanation for this discrepancy may be attributed to the fact that increased severity in HCV infection due to CCR5Δ32 mutation was specific to a group of patients with hemophilia in the study by Woitas et al. (61). Interestingly, the CCR5Δ32 mutation has been associated with reduced portal inflammation and more advanced fibrosis in HCV-infected patients (64). These data are supported by the data showing that polymorphism at −403 of the CCL5 gene promoter (which results in increased CCL5 gene transcription) is also associated with reduced portal inflammation in HCV-infected individuals (64). In light of the contradicting results from different studies, the precise role of CCR5 in HCV infection awaits further elucidation.

In summary, the role of CCR5 in antiviral immunity in liver disease remains undefined due to the lack of appropriate animal models. It will be of interest to see ultimately whether observations made in CCR5-deficient mice treated with Con A will be paralleled in animal models of HCV infection in the future.

Since its first description as a HIV coreceptor, CCR5 has come into prominence as a regulator of the inflammatory response through its participation in immune cell movement and its influence over immune cell function. In the context of T cell-mediated liver disease, CCR5 and its respective ligands have been implicated in the recruitment of effector T cell subtypes into the liver, as well as in their modulation of the inflammatory response through the regulation of the production of their specific cytokines (e.g., IFN-γ) and their surface molecule expression (e.g., FasL). As a result of these properties, CCR5 would appear to represent a potential novel target for therapeutic intervention in the treatment of T cell-mediated liver diseases. However, experiments using CCR5-deficient mice, as well as clinical trials using CCR5 antagonist in HIV-infected patients, suggest that blockade or lack of CCR5 can have complex effects with regards to the development of hepatic inflammation through altered expression of chemokines, cellular recruitment, and expression of cellular effector functions. Although CCR5 inhibition represents a potential novel therapeutic area for T cell-mediated hepatitis, it seems clear that inhibition of CCR5-mediated cross-talk through receptor inhibition or deletion may have divergent and unforeseen effects upon the hepatic inflammatory response, which may be dependent upon the hepatic insult rendered.

We are grateful to our colleagues Drs. Cory Hogaboam (University of Michigan Medical School), Mitch Kronenberg (La Jolla Institute For Allergy and Immunology), Amanda Proudfoot (Serono Pharmaceutical Research Institute), and Yang Yang (University of Calgary) for their collaboration and for exciting discussions over the years.