SummaryThis review discusses the function and localisation of lymphocytes resident within the human liver, under both physiological and pathological conditions. Through description of the mechanisms that mediate lymphocyte recruitment into tissues, this article explains how hepatic endothelial and epithelial cells regulate the recruitment of specific lymphocyte subpopulations. We illustrate that the expression of adhesion molecules and chemokines is crucial to the control of lymphocyte adhesion. Thus, in the normal liver, adhesion molecules such as vascular adhesion protein-1 (VAP-1), intercellular adhesion molecule-1 (ICAM-1) and intercellular adhesion molecule-2 (ICAM-2), and chemokines such as regulated on activation, normal T cell expressed and secreted (RANTES), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), interferon γ inducible protein-10 (IP-10), MIG and interferon inducible T-cell alpha chemoattractant (ITAC) are involved in lymphocyte binding to different endothelial compartments. However, in response to inflammation or injury, additional expression of adhesion molecules such as VCAM-1, P-selectin and E-selectin, as well as higher levels of chemokines, permits the attraction and retention of specific effector populations of lymphocytes. We also discuss the expression and function of a newly defined adhesion protein, (VAP-1), and suggest that the unique functions of this protein may provide therapeutic potential for the treatment of liver disease.

Using HLA class I-viral epitope tetramers to monitor herpes virus-specific CD8+ T cell responses in humans, we have shown that a significant fraction of responding cells revert from a CD45RO+ to a CD45RA+ state after priming. All tetramer-binding CD45RA+ cells, regardless of epitope specificity, expressed a phenotype LFA-1highCCR7low that was stable for at least 10 years in infectious mononucleosis patients and indefinitely in asymptomatic carriers. CD8+CD45RA+LFA-1high cells were not present in cord blood but in adults account for up to 50% of CD8+CD45RA+ cells. These CD45RA+LFA-1high cells have significantly shorter telomeres than CD45RA+LFA-1low cells, suggesting that the latter represent a naive population, while the former are memory cells. CD45RA+ memory cells are a stable population of noncycling cells, but on stimulation they are potent producers of IFN-γ, while naive CD8+ cells produce only IL-2. The chemokine receptor profile and migratory potential of CD45RA+ memory cells is very similar to CD45RO+ cells but different to naive CD8 cells. In accord with this, CD45RA+ memory cells were significantly underrepresented in lymph nodes, but account for virtually all CD8+CD45RA+ T cells in peripheral tissues of the same individuals.

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Poorer outcome in the diabetics undergoing OLT, particularly in those with ALD, suggests the need for a more detailed pre-OLT assessment of these patients, particularly those with insulin and tablet controlled diabetes.

Over 170 million people are infected with the hepatitis C virus worldwide, resulting in a large disease burden and significant mortality. Hepatitis C virus is rarely cleared in the acute phase of the infection and most patients become chronically infected; a proportion of these patients develop progressive liver disease and fibrosis. The outcome of infection depends on the immune responses of both the innate and cognate immune systems, and these in turn are orchestrated by networks of cytokines and chemokines. There is evidence that a vigorous type 1 immune response to viral proteins is required for viral elimination, and the recruitment of such effector cells to the liver is dependent on the local activity of specific inducible chemokines. Multiple factors determine the ability of the hepatitis C virus to survive host immune responses, including an ability to alter the cytokine profile secreted by T cells and to cause resistance to the effects of antiviral cytokines such as interferon. In the present review, we briefly cover the important advances made in this area over the past 12 months.

Summary Background Chronic continuous abdominal pain (CCAP) is characteristic of centrally mediated gastrointestinal pain disorders. It consumes significant healthcare resources yet is poorly understood, with minimal cohort‐specific data in the literature. Aims To examine in a large cohort of CCAP patients, (a) diagnostic features, (b) iatrogenic impact of opioids and surgery, (c) drug treatment effects and tolerance. Methods Consecutive tertiary CCAP referrals to a neurogastroenterology clinic (2009‐2016) were reviewed for Rome IV and neuropathic pain criteria. Medical, surgical and drug histories, interventions and outcomes were correlated with clinical diagnosis and associated opioid use. Results Of 103 CCAP patients (mean age 40 ± 14, 85% female), 50% had physiological exacerbations precluding full Rome IV Centrally Mediated Abdominal Pain Syndrome criteria. However, there were no significant differences between patients who satisfied Rome IV criteria and those who did not. Overall, 81% had allodynia (a nonpainful stimulus evoking pain sensation). Opioid use was associated with allodynia (P = 0.003). Prior surgery was associated with further operations post CCAP onset (P < 0.001). Although 68% had undergone surgical interventions, surgery did not resolve pain in any patient and worsened pain in 35%. Whilst duloxetine was the most effective neuromodulator (P = 0.003), combination therapy was superior to monotherapy (P = 0.007). Conclusions This is currently the largest cohort CCAP dataset that supports eliciting neuropathic features, including allodynia, for a positive clinical diagnosis, to guide treatment. Physiological exacerbation of CCAP may represent visceral allodynia, and need not preclude central origin. Use of centrally acting neuromodulators, and avoidance of detrimental opioids and surgical interventions appear to predict favourable outcomes.

(Gut 1999;45:306-309)

In hepatitis C virus (HCV) infection the immune response is ineffective, leading to chronic hepatitis and liver damage. Primed CD8 T cells are critical for antiviral immunity and subsets of circulating CD8 T cells have been defined in blood but these do not necessarily reflect the clonality or differentiation of cells within tissue. Current models divide primed CD8 T cells into effector and memory cells, further subdivided into central memory (CCR7+, L-selectin+), recirculating through lymphoid tissues and effector memory (CCR7−, L-selectin−) mediating immune response in peripheral organs. We characterized CD8 T cells derived from organ donors and patients with end-stage HCV infection to show that: 1) all liver-infiltrating CD8 T cells express high levels of CD11a, indicating the effective absence of naive CD8 T cells in the liver. 2) The liver contains distinct subsets of primed CD8+ T cells including a population of CCR7+ L-selectin− cells, which does not reflect current paradigms. The expression of CCR7 by these cells may be induced by the hepatic microenvironment to facilitate recirculation. 3) The CCR7 ligands CCL19 and CCL21 are present on lymphatic, vascular, and sinusoidal endothelium in normal liver and in patients with HCV infection. We suggest that the recirculation of CCR7+/L-selectin− intrahepatic CD8 T cells to regional lymphoid tissue will be facilitated by CCL19 and CCL21 on hepatic sinusoids and lymphatics. This centripetal pathway of migration would allow restimulation in lymph nodes, thereby promoting immune surveillance in normal liver and renewal of effector responses in chronic viral infection.