Nakajima, Takako Eguchi

AbstractBackgroundHepatectomy is standard treatment for colorectal liver metastases; however, it is unclear whether liver metastases from other primary cancers should be resected or not. The Japanese Society of Hepato‐Biliary‐Pancreatic Surgery therefore created clinical practice guidelines for the management of metastatic liver tumors.MethodsEight primary diseases were selected based on the number of hepatectomies performed for each malignancy per year. Clinical questions were structured in the population, intervention, comparison, and outcomes (PICO) format. Systematic reviews were performed, and the strength of recommendations and the level of quality of evidence for each clinical question were discussed and determined. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations.ResultsThe eight primary sites were grouped into five categories based on suggested indications for hepatectomy and consensus of the guidelines committee. Fourteen clinical questions were devised, covering five topics: (1) diagnosis, (2) operative treatment, (3) ablation therapy, (4) the eight primary diseases, and (5) systemic therapies. The grade of recommendation was strong for one clinical question and weak for the other 13 clinical questions. The quality of the evidence was moderate for two questions, low for 10, and very low for two.A flowchart was made to summarize the outcomes of the guidelines for the indications of hepatectomy and systemic therapy.ConclusionsThese guidelines were developed to provide useful information based on evidence in the published literature for the clinical management of liver metastases, and they could be helpful for conducting future clinical trials to provide higher‐quality evidence.

Abstract Stimulatory killer Ig-like receptors (KIRs) are expressed by various lymphocytes, including NK cells and subsets of T cells. In NK cells, KIRs associate with the adapter molecule KARAP/DAP12, which confers the ability to function as an independent activation unit. The function of KIRs and killer cell activating receptor-associated protein (KARAP)/DAP12 in T cells is unclear. By flow cytometry, we demonstrated that CD4+CD28null T cells heterogeneously express KIRs and/or KARAP/DAP12. In clones that lacked expression of KARAP/DAP12, the stimulatory KIR KIR2DS2 signaled through the JNK pathway, but did not activate the ERK pathway. However, in the presence of KARAP/DAP12, stimulation through KIR2DS2 led to phosphorylation of both JNK and ERK. Transfection experiments confirmed that KIR2DS2-mediated ERK phosphorylation was dependent on KARAP/DAP12. The differential signaling of KIR2DS2 through association with alternative adapter molecules resulted in differential regulation of cellular activity. In clones that lacked expression of KARAP/DAP12, stimulation of KIR2DS2 did not induce cytotoxicity. However, KIR2DS2 did augment suboptimal TCR stimulation, leading to enhanced IFN-γ production. In clones that expressed KARAP/DAP12, KIR2DS2 directly activated both cytotoxicity and IFN-γ production without the need for TCR-derived signals. The function of stimulatory KIRs in T cells is determined by the expression of the appropriate adapter molecule. Expression of KARAP/DAP12 is sufficient to convert a costimulatory KIR into a stimulatory molecule. These differing functions mediated by alternative signaling pathways have implications for the pathogenesis of diseases such as rheumatoid arthritis and acute coronary syndromes, in which aberrant expression of KIRs on T cells is frequently observed.

CD4 T cells, through the release of cytokines as well as direct effector functions, have been implicated in promoting inflammation of the atherosclerotic plaque. Plaque-infiltrating CD4 T cells include a specialized subset of CD4 + CD28 − T cells that express a unique profile of regulatory receptors and are responsive to novel microenvironmental cues. Here we report that CD4 + CD28 − T cells, either isolated from the plaque tissue or from the blood of patients with acute coronary syndrome (ACS), spontaneously express interleukin (IL)-12 receptors, even in the absence of antigenic stimulation. CD4 + CD28 − IL-12R + cells responded to IL-12 stimulation with the upregulation of the chemokine receptor CCR5 and the C-type lectin receptor CD161, both implicated in regulating tissue homing of effector T cells. IL-12 treatment of CD4 + CD28 − T cells enhanced their chemotaxis and transendothelial migration toward the chemokine CCL5. In vivo relevance for the role of IL-12 in regulating the recruitment of CD4 + CD28 − T cells into the atheroma was examined in human atheroma-SCID mouse chimeras. Exposure of nonstimulated CD4 + CD28 − T cells to IL-12 was sufficient to amplify T-cell accumulation within the inflamed plaque, and coadministration of anti-CCR5 antibodies blocked T-cell recruitment into the plaque. Thus, CD4 + CD28 − T cells functionally resemble NK cells, which have proinflammatory activity even in the unprimed state and respond to any IL-12–inducing host infection with a shift in tissue trafficking and accrual in inflammatory lesions.

The inflammatory infiltrate in atherosclerotic plaque is composed of T cells and macrophages. CD4 + T cells with a unique phenotype, CD4 + CD28 null , are preferentially recruited into culprit lesions. These T cells are distinct from classic CD4 + CD28 + T cells in gene expression and function, including their ability to mediate cytolysis. In this study, we have investigated the regulation of CD4 + CD28 null T-cell cytolytic function. In patients with acute coronary syndromes (ACS), CD4 + CD28 null T cells express killer immunoglobulin-like receptors (KIRs). KIRs encompass a polymorphic family of receptors that recognize HLA class I molecules and have been implicated in self-tolerance. CD4 + CD28 null T-cell clones from patients with ACS and age-matched controls were compared for their KIR-expression profile. T-cell clones derived from the patients expressed a broader spectrum of KIRs ( P <0.001) with preference for the stimulatory variant, CD158j. Additionally, CD4 + T-cell clones from patients but not those from controls acquired de novo expression of the DAP12 molecule, an adapter chain that transmits CD158j-derived signals. Cumulative expression of CD158j and DAP12 endowed cytolytic competence on CD4 + CD28 null T cells, allowing them to kill in the absence of T-cell receptor triggering. Our data demonstrate that CD4 + CD28 null T cells in ACS are characterized by a unique gene expression profile. Consequently, these T cells acquire cytolytic capability that can bypass the need for T-cell receptor triggering and, thus, impose a threat to self-tolerance.

Background — CD4 T lymphocytes accumulate in unstable plaque. The direct and indirect involvement of these T cells in tissue injury and plaque instability is not understood. Methods and Results — Gene profiling identified perforin, CD161, and members of the killer-cell immunoglobulin-like receptors as being differentially expressed in CD4 + CD28 null T cells, a T-cell subset that preferentially infiltrates unstable plaque. Frequencies of CD161 + and perforin-expressing CD4 T cells in peripheral blood were significantly increased in patients with unstable angina (UA). CD161 appeared on CD4 + CD28 null T cells after stimulation, suggesting spontaneous activation of circulating CD4 T cells in UA. Perforin-expressing CD4 + T-cell clones from patients with UA exhibited cytotoxic activity against human umbilical vein endothelial cells (HUVECs) in redirected cytotoxicity assays after T-cell receptor triggering and also after stimulation of major histocompatibility complex class I–recognizing killer-cell immunoglobulin-like receptors. HUVEC cytolysis was dependent on granule exocytosis, as demonstrated by the paralyzing effect of pretreating CD4 + CD28 null T cells with strontium. Incubation of HUVECs with C-reactive protein (CRP) increased HUVEC lysis in a dose-dependent fashion. Conclusions — In patients with UA, CD4 T cells undergo a change in functional profile and acquire cytotoxic capability. Cytotoxic CD4 T cells effectively kill endothelial cells; CRP sensitizes endothelial cells to the cytotoxic process. We propose that T-cell–mediated endothelial cell injury is a novel pathway of tissue damage that contributes to plaque destabilization. The sensitizing effect of CRP suggests synergy between dysregulated T-cell function and acute phase proteins in acute coronary syndromes.

Rheumatoid arthritis (RA) is a heterogeneous syndrome of which a subset of patients develops vascular inflammation. The genetic determinants that confer risk for rheumatoid vasculitis are not known, but patients with vascular complications are known to have an expansion of CD4+CD28null T cells, a cell population potentially involved in endothelial damage. CD4+CD28null T cell clones isolated from RA patients with vasculitis were found to express killer cell immunoglobulin–like receptors (KIRs) with the stimulatory KIR2DS2 often present in the absence of opposing inhibitory receptors with related specificities. To test the hypothesis that the KIR2DS2 gene is involved in the development of vasculitis, association studies were performed. The KIR2DS2 gene was significantly enriched among patients with rheumatoid vasculitis compared with normal individuals (odds ratio 5.56, P = 0.001) and patients with RA but no vasculitis (odds ratio 7.96, P = 0.001). Also, the distribution of human histocompatibility leukocyte antigen (HLA)-C, the putative ligand for KIRs, was significantly different in patients with rheumatoid vasculitis in comparison with the control populations. These data suggest that HLA class I–recognizing receptors and HLA class I genes are genetic risk determinants that modulate the pattern of RA expression. Specifically, KIR2DS2 in conjunction with the appropriate HLA-C ligand may have a role in vascular damage by regulating CD4+CD28null T cells.