First case of Ethmoid Metastasis From an Induced Oropharyngeal Squamous Cell Carcinoma HPV, Interest of the P16 as a Diagnosis Aid.

We describe the first case of ethmoid metastasis from an oropharyngeal human papillomavirus-induced squamous cell carcinoma using the anti-P16 immunohistochemistry. The p16 overexpression can be a valuable aid in the differential diagnosis.

Antiphospholipid syndrome-induced ischemic stroke following pembrolizumab: Case report and systematic review.

Immune checkpoint inhibitors (ICI) improve the prognosis of patients with advanced non-small cell lung cancer. However, clinicians should be aware of potentially life-threatening immune-related adverse events (irAEs). We report a case of a 67-year-old man with lung adenocarcinoma who developed an acute ischemic stroke after the second administration of pembrolizumab. The patient benefited from thrombolysis and mechanical thrombectomy with improved neurological outcome. An anti-phospholipid syndrome (APS) was diagnosed. Simultaneously, he developed a grade IV autoimmune hepatitis. Bothmanifestations were considered irAEs and the ICI treatment was discontinued. Steroids were initiated resulting in irAEs resolution. Remarkably, the patient achieved a complete oncological response and persistent remission after one year follow-up despite early discontinuation of pembrolizumab. Of note, APS is rarely reported as irAE. To our knowledge, this is the first case reported in the context of lung cancer. A systematic review of the literature is provided.

Clinical application of targeted next-generation sequencing for colorectal cancer patients: a multicentric Belgian experience.

International guidelines made RAS (KRAS and NRAS) status a prerequisite for the use of anti-EGFR agents for metastatic colorectal cancer (CRC) patients. Daily, new data emerges on the theranostic and prognostic role of molecular biomarkers; this is a strong incentive for a validated, sensitive, and broadly available molecular screening test. Next-generation sequencing (NGS) has begun to supplant other technologies for genomic profiling. We report here our 2 years of clinical practice using NGS results to guide therapeutic decisions. The Ion Torrent AmpliSeq colon/lung cancer panel, which allows mutation detection in 22 cancer-related genes, was prospectively used in clinical practice (BELAC ISO 15189 accredited method). The DNA of 741 formalin-fixed paraffin-embedded CRC tissues, including primary tumors and metastasis, was obtained from 14 different Belgian institutions and subjected to targeted NGS. Of the tumors tested, 98% (727) were successfully sequenced and 89% (650) harbored at least one mutation. KRAS, BRAF and NRAS mutations were found in 335 (46%), 78 (11%) and 32 (4%) samples, respectively. These mutation frequencies were consistent with those reported in public databases. Moreover, mutations and amplifications in potentially actionable genes were identified in 464 samples (64%), including mutations in PIK3CA (14%), ERBB2 (0.4%), AKT1 (0.6%), and MAP2K1 (0.1%), as well as amplifications of ERBB2 (0.3%) and EGFR (0.3%). The median turnaround time between reception of the sample in the laboratory and report release was 8 calendar days. Overall, the AmpliSeq colon/lung cancer panel was successfully applied in daily practice and provided reliable clinically relevant information for CRC patients.

Nuclear localization of glutamate-cysteine ligase is associated with proliferation in head and neck squamous cell carcinoma.

Glutathione (GSH) is the keystone of the cellular response toward oxidative stress. Elevated GSH content correlates with increased resistance to chemotherapy and radiotherapy of head and neck (HN) tumors. The purpose of the present cross-sectional study was to evaluate whether the expression of glutamate-cysteine ligase (GCL) accounts for the increased GSH availability observed in HN squamous cell carcinoma (SCC). For that purpose, the messenger (m)RNA levels of the modifier (M) and catalytic (C) subunits of GCL and its putative regulators (namely, nuclear factor erythroid 2-related factor 2, heme oxygenase-1 and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) were monitored in 35 surgical resections of untreated HNSCC. The localization of GCLM was evaluated using in situ hybridization and immunohistochemistry. GCLM expression was significantly increased in tumor samples, compared with normal mucosa, both at the mRNA and protein level (P=0.029), but the pathway of GCLM activation remains to be elucidated. Protein expression of GCLM was detected in the cytoplasm and nucleus. GCLM and the proliferation marker Ki-67 displayed a similar distribution, being both mainly expressed at the periphery of tumor lobules. The present study reported increased expression of GCL and the rate-limiting enzyme of GSH synthesis, within HNSCC. The nuclear localization of GCLM and the concomitant expression of Ki-67 suggested that the localization of GSH synthesis contributes to the protection against oxidative stress within hotspots of cell proliferation.

Thyroid surgery with a harmonic scalpel: an experimental study.

BACKGROUND: The goal of the study was to determinate the safety of the harmonic scalpel, widely used in thyroidectomy, near the recurrent laryngeal nerve (RLN). METHODS: The study involved ten pigs of either sex. Twenty RLNs at risk were dissected using the new harmonic scalpel FOCUS. The distances between the nerve and the activated instrument were checked with a millimeter ruler. After dissection, the pigs were euthanized, and both RLNs were fixed in formol and examined by histology after staining with hematoxylin-eosin. Due to technical reasons, only 18 RLNs from the ten pigs could be examined. RESULTS: In the experiment that investigated the extent of heat injury, ultrasonic dissection did not cause any immediate damage of the nerve even close to the RLN (1 mm away from the RLN). CONCLUSION: The use of harmonic scalpel FOCUS for thyroid surgery is safe for the surrounding structures (nerves). Careful tissue applications of the device near the RLN (1 mm) did not cause any lesion histologically.

Assessment of oxidative stress in tumors and histologically normal mucosa from patients with head and neck squamous cell carcinoma: a preliminary study.

Over 90% of head and neck cancers are squamous cell carcinomas (HNSCC) and the overall 5-year survival rate is up to 50%. The redox status of these cancers is an important factor in carcinogenesis and plays a role in radioresistance and therefore locoregional recurrences. However, knowledge of the redox status is rather limited. Glutathione is the major reactive oxygen species scavenger in normal cells. We compared the levels of tissue redox potential in HNSCC tumor tissue and compared them with those of the adjacent, histologically cancer-free, mucosa. A total of 36 patients with HNSCC were included in the study. The redox status of tumor and normal adjacent tissue was measured by the oxidized/reduced glutathione (GSSG/GSH) ratio in capillary electrophoresis. The GSSG/GSH ratio in the tumor tissue was lower compared with adjacent normal tissue in 38% of the patients. Pretherapy HNSCC tumor tissue has variable GSH levels compared with adjacent cancer-free mucosa. This difference was not related to clinical and pathological parameters. Further studies are required to determine whether the GSSG/GSH ratio plays a role in carcinogenesis and could predict radioresistance.

Intraductal papillary mucinous neoplasms of the pancreas: clinicopathological features and long term outcome related to histopathological group.

BACKGROUND/AIMS: To investigate the clinicopathological features of intraductal papillary mucinous neoplasms and evaluate the prognosis between histopathological groups. METHODOLOGY: Retrospective review of 55 consecutive patients operated between 1991 and 2006, analysis of clinicopathological features and survival. RESULTS: Group I comprised of 9 mild and 14 moderate dysplasias, group II of 11 carcinomas in situ and group III of 21 invasive cancers. Age, diabetes, anorexia and jaundice were significantly more frequent in group III. Thirty-two patients (58.2%) presented main duct type which was more frequently associated with invasive carcinoma. Mean tumoral size progress from group I to group III (26.1mm vs. 27.4mm vs. 32.0mm p=0.015) as the mean size of the pancreatic duct (6.7mm vs. 7.9mm vs. 11.5mm p=0.008). Median follow-up was 154 months with 5-year survival rate of 60.7 %. For group I, II and III it was 76.3 %, 100 % and 25.8 % respectively (p=0.00007). Lymph node positivity was associated with poor outcome: 44.1% vs. 0% (N0 vs. N+) (p=0.0019). CONCLUSIONS: The prognosis of non-invasive intraductal papillary mucinous neoplasms of the pancreas is favourable. For patients with invasive cancer, nodal invasion is a factor of worst prognosis.

Lean non-alcoholic fatty liver disease (Lean-NAFLD): a major cause of cryptogenic liver disease.

AIMS: Non-alcoholic fatty liver disease (NAFLD) is strongly associated to obesity and type 2 diabetes, but may occur in the absence of these factors. Based on a large series of liver biopsies, we have evaluated the clinical, biochemical, metabolic and pathological characteristics of a new entity, which we refer to as "lean-NAFLD". METHODS: Among 1,777 patients, who underwent liver biopsy for chronic liver disease, Lean-NAFLD, defined as patients with NAFLD without obesity (BMI < 30 kg/m2) and without diabetes was found in 50 of them (2.8%), being the most frequent cause (38%) of cryptogenic liver disease. Thirty-one patients from the Lean-NAFLD group were compared to 48 Obese-NAFLD patients diagnosed during the same period and 8 healthy control patients. Insulin resistance was determined using the homeostasis model assessment method. RESULTS: In the Lean-NAFLD group as compared to the obese-NAFLD group, patients were younger : median 40 vs. 49 years, p = 0.047, with male predominance: 71 vs. 46%, p = 0.037. Fasting glucose and HbA1c were lower, as was insulin sensitivity: 1.7 vs. 3.0, p = 0.049. Blood pressure was significantly lower (p = 0.001) while triglycerides and HDL-cholesterol were similar. Although there was less inflammation (p = 0.038) and fibrosis (p = 0.029), non-alcoholic steatohepatitis and fibrosis were present in 61% and 55% of the Lean-NAFLD group, respectively. Compared to healthy controls, Lean-NAFLD were less insulin sensitive, with a insulin sensitivity index of 59 vs. 110 (p = 0.015), and more hypertriglyceridemic (p = 0.003). CONCLUSIONS: Lean-NAFLD is a new unrecognized clinicopathological entity, a frequent cause of cryptogenic liver disease.

Putative contribution of CD56 positive cells in cetuximab treatment efficacy in first-line metastatic colorectal cancer patients.

BACKGROUND: Activity of cetuximab, a chimeric monoclonal antibody targeting the epidermal growth factor receptor, is largely attributed to its direct antiproliferative and proapoptotic effects. Antibody-dependent cell-mediated cytotoxicity (ADCC) could be another possible mechanism of cetuximab antitumor effects and its specific contribution on the clinical activity of cetuximab is unknown. METHODS: We assessed immune cells infiltrate (CD56, CD68, CD3, CD4, CD8, Foxp3) in the primary tumor of metastatic colorectal cancer (mCRC) patients treated with a first-line cetuximab-based chemotherapy in the framework of prospective trials (treatment group) and in a matched group of mCRC patients who received the same chemotherapy regimen without cetuximab (control group). The relationship between intra-tumoral immune effector cells, the K-ras status and the efficacy of the treatment were investigated. We also evaluated in vitro, the ADCC activity in healthy donors and chemonaive mCRC patients and the specific contribution of CD56+ cells. RESULTS: ADCC activity against DLD1 CRC cell line is maintained in cancer patients and significantly declined after CD56+ cells depletion. In multivariate analysis, K-ras wild-type (HR: 4.7 (95% CI 1.8-12.3), p = 0.001) and tumor infiltrating CD56+ cells (HR: 2.6, (95%CI:1.14-6.0), p = 0.019) were independent favourable prognostic factors for PFS and response only in the cetuximab treatment group. By contrast CD56+ cells failed to predict PFS and response in the control group. CONCLUSIONS: CD56+ cells, mainly NK cells, may be the major effector of ADCC related-cetuximab activity. Assessment of CD56+ cells infiltrate in primary colorectal adenocarcinoma may provide additional information to K-ras status in predicting response and PFS in mCRC patients treated with first-line cetuximab-based chemotherapy.

Neuroendocrine tumors of pancreas: how can we apply the 2006 TNM proposal?

BACKGROUND/AIMS: In 2006, a TNM system for foregut neuroendocrine tumors has been proposed. Our study aimed to present the management of neuroendocrine tumors of pancreas according to this classification and to highlight some of its limitations. METHODOLOGY: Clinical, biochemical, radiological, surgical and pathological data were retrospectively collected on 22 consecutives patients, who underwent surgery for neuroendocrine tumors of pancreas between November, 1991 and September, 2005. These data were used to set the TNM. RESULTS: After excluding 5 patients, the remaining 17 patients were analyzed. In 9 patients, with a mean age of 39 years, tumors were benign with a mean size of 1.8 cm, classed at stage I-IIa, whereas for 8 patients with a mean age of 57 years, tumors were malignant with a mean size of 6cm and were classed at stage IIb-IV. There were 3 deaths in stage IIb-IV, and none in stage I-IIa. CONCLUSION: TNM may be considered as a useful tool for prognostic stratification, but true benign tumors need to be excluded in order to improve the classification. Size and age appeared as variables affecting malignant behavior and the prognosis.

Acute liver transplant rejection upon immunosuppression withdrawal in a tolerance induction trial: potential role of IFN-gamma-secreting CD8+ T cells.

We designed a pilot trial in cadaveric liver transplantation to determine whether induction with antithymocyte globulins (ATG) and sirolimus would allow immunosuppression withdrawal. Patients received ATG 3.75 mg/kg per day from day 1 to 5 after transplantation followed by sirolimus for 4 to 6 months. We monitored interleukin (IL)-7 serum levels, interferon (IFN)-gamma, and IL-2 mRNA accumulation in mixed leukocyte reaction and intragraft IFN-gamma mRNA expression. In the first three patients, immunosuppression discontinuation was followed by reversible acute rejection occurring on days 280, 246, and 163 posttransplantation, corresponding to days 140, 40, and 39 after drug withdrawal, respectively. At the time of rejection, blood CD8+ T-cells counts had returned to or above pretransplant levels in two of three patients, whereas CD4+ T-cell count remained low. IL-7 serum levels rose in all three patients in the first months after transplantation and IFN-gamma mRNA accumulated in mixed leukocyte reaction between recipient T cells and donor spleen cells at the time of rejection. High levels of IFN-gamma mRNA were consistently detected in liver biopsy performed at the time of rejection. In conclusion, lymphopenia-induced IL-7 production after induction with ATG and sirolimus might lead to emergence of IFN-gamma-secreting CD8+ T-cells responsible for acute rejection after immunosuppression withdrawal.

Expression of galectin-3 in the tumor immune response in colon cancer.

The role of tumor-associated macrophages (TAMs) is controversial. Although most studies on different cancer types associate them with a poorer prognosis, interestingly in colon cancer, most articles indicate that TAMs prevent tumor development; patients with high TAMs have better prognosis and survival rate. M1-polarized macrophages produce high level of tumor necrosis factor-alpha, interleukin-1 beta or reactive oxygen species, which can effectively kill susceptible tumor cells. In contrast, M2-polarized macrophages can secrete different factors that promote tumor cell growth and survival or favor angiogenesis and tissue invasion. Considering the beneficial role of TAMs in colon cancer, we speculated that they may not display the M2 polarization commonly observed in tumor microenvironment, but rather develop M1 properties. Therefore, we used an in vitro model to analyze the effects of supernatants from M1-polarized macrophages on DLD-1 colon cancer cells. Our data indicate that the conditioned medium from LPS-activated macrophages (CM-LAM) contains a high level of granulocyte-macrophage colony-stimulating factor, interleukins-1 beta, -6, -8 and tumor necrosis factor-alpha, and that it exerts a marked growth inhibitory activity on DLD-1 cells. Prolonged exposure to CM-LAM results in cell death by apoptosis. Such exposure to CM-LAM leads to the modulation of gal-3 expression: we observed a marked downregulation of gal-3 mRNA and protein expression following CM-LAM treatment. We also describe that the knockdown of gal-3 sensitizes DLD-1 cells to CM-LAM. These data suggest an involvement of gal-3 in the response of colon cancer cells to proinflammatory stimuli, such as the conditioned medium from activated macrophages.

Expression of galectins-1, -3 and -4 varies with strain and type of experimental colitis in mice.

Galectins are increasingly the focus of biomedical research. Although they are involved at different stages in inflammation, data on galectins in colitis remain scarce. The aim of this study was to determine and compare the expression of galectins in acute and chronic experimental colitis in mice. Immunohistochemistry for galectins-1, -3 and -4 was performed on colon tissue from C57BL/6 and BALB/c mice with acute dextran sodium sulphate colitis and from 129 Sv/Ev IL-10 knock-out (IL-10(-/-)) mice. From these three mouse strains, we first detected major differences in galectin expression related to the genetic background in the control animals. With regard to inflammation, chronic colitis in IL-10(-/-) mice was associated with increased galectin-4 expression; in contrast with the two other models, no galectin-1 and -3 alterations were observed in IL-10(-/-) mice. Acute colitis in C57BL/6 and BALB/c mice showed increased galectin-3 expression in the lamina propria and the crypt epithelium, together with a decreased nuclear expression. These results suggest an involvement of galectins in the development and perpetuation of colonic inflammation and illustrate that the choice of the mouse strain for studying galectins might influence the outcome of the experiments.

Chemokine receptor CCR5 deficiency exacerbates cerulein-induced acute pancreatitis in mice.

Acute pancreatitis (AP) is an inflammatory disease involving the production of different cytokines and chemokines and is characterized by leukocyte infiltration. Because the chemokine receptor CCR5 and its ligands [the CC chemokines CCL3/MIP-1alpha, CCL4/MIP-1beta, and CCL5/regulated upon activation, normal T cell expressed and secreted (RANTES)] regulate leukocyte chemotaxis and activation, we investigated the expression of CCR5 ligands and the role of CCR5 and its ligands in experimental AP in mice. AP was induced by hourly intraperitoneal injections of cerulein in CCR5-deficient (CCR5(-/-)) or wild-type (WT) mice. Induction of AP by cerulein resulted in an early increase of pancreatic CCL2, CCL3, and CCL4 mRNA expression, whereas CCL5 mRNA expression occurred later. CCR5(-/-) mice developed a more severe pancreatic injury than WT mice during cerulein-induced AP, as assessed by a more pronounced increase in serum amylase and lipase levels and by more severe pancreatic edema, inflammatory infiltrates (mainly neutrophils), and necrosis. CCR5(-/-) mice also exhibited increased production of CCL2/MCP-1, CCL3/MIP-1alpha, and CCL4/MIP-1beta during the course of cerulein-induced AP. In vivo simultaneous neutralization of CC chemokines with monoclonal antibodies in CCR5(-/-) mice reduced the severity of cerulein-induced AP, indicating a role of CC chemokines in exacerbating the course of AP in the absence of CCR5. Moreover, simultaneous neutralization of CCR5 ligands in WT mice also reduced the severity of cerulein-induced AP. In conclusion, lack of the chemokine receptor CCR5 exacerbates experimental cerulein-induced AP and leads to increased levels of CC chemokines and a more pronounced pancreatic inflammatory infiltrate, suggesting that CCR5 expression can modulate severity of AP.

Differential liver sensitization to toll-like receptor pathways in mice with alcoholic fatty liver.

Gut-derived, endotoxin-mediated hepatocellular damage has been postulated to play a crucial role in the pathogenesis of alcohol-induced liver injury in rodents. Endotoxins induce production of tumor necrosis factor alpha (TNF-alpha) by Kupffer cells via Toll-like receptor (TLR) 4 and contribute to liver injury. This study addressed the contribution of other TLRs and ligands to alcoholic fatty liver. C57Bl6/J mice were fed a modified Lieber-DeCarli diet. Serum aminotransferase measurements, histological analysis, and quantification of liver TNF-alpha and TLR1-9 messenger RNA (mRNA) were performed. The effect of TLR ligands on liver injury was assessed in vivo. Neomycin and metronidazole or diphenyleneiodonium sulfate (DPI) were administered to evaluate the role of gut bacteria and NADPH oxidase activity, respectively, in hepatic TLR expression. Enteral ethanol (EtOH) exposure induced steatosis and increased liver weight, aminotransferase levels, and expression of TLR1, 2, 4, 6, 7, 8, and 9 liver mRNA. Injection of lipoteichoic acid, peptidoglycan (PGN), lipopolysaccharide (LPS), loxoribine, and oligonudeotide containing CpG (ISS-ODN) increased TNF-alpha mRNA expression more in the livers of EtOH-fed mice than in control mice. PGN, LPS, flagellin, and ISS-ODN induced liver inflammatory infiltrate in EtOH-fed mice but not control mice. Addition of antibiotics reduced the severity of alcoholic fatty liver without affecting TLR expression, whereas daily DPI injections reduced the EtOH-mediated upregulation of TLR2, 4, 6, and 9 mRNA. In conclusion, EtOH-fed mice exhibited an oxidative stress dependent on upregulation of multiple TLRs in the liver and are sensitive to liver inflammation induced by multiple bacterial products recognized by TLRs.

Primary antibiotic resistance and effectiveness of Helicobacter pylori triple therapy in ulcero-inflammatory pathologies of the upper digestive tract.

OBJECTIVES: To determine firstly, the rates of primary antimicrobial resistance for Helicobacter pylori-associated upper-digestive lesions in relation to the success rate of triple therapy; and secondly, the performance of HpSA stool antigen detection test for control of eradication after treatment. METHODS: Prospective open study of 436 patients who underwent upper-digestive tract endoscopy with biopsies for histological examination and culture between January 1 and July 31, 2002 at a University hospital in Brussels, Belgium. The primary resistance to antibiotics of H. pylori isolates was determined by disc diffusion method. Seventy of 164 infected patients agreed to be included in the treatment study with standard triple therapy with amoxicillin + clarithromycin + omeprazole adjusted on the basis of antibiogram results. Control of eradication was tested by 14C-Urea breath test and H. pylori Stool Antigen test (HpSA test). RESULTS: Primary resistance to clarithromycin and metronidazole was observed in 3% and 31% of the isolates, respectively. No primary resistance to amoxicillin and tetracycline was observed. By intention to treat analysis, H. pylori was eradicated in 56 (80%) patients included in the therapeutic study. Three (4%) patients were lost to follow-up. The rate of eradication failure was 20% (14/70), included 11 cases documented by a positive control test (14C-Urea breath test). In comparison with 14C-Urea breath test, the H. pylori Stool Antigen test showed a sensitivity of 100%, a specificity of 91%, PPV of 69%, and NPV of 100%. CONCLUSION: Standard triple therapy achieved 80% bacterial eradication in this patient population with a low prevalence of H. pylori primary antibiotic resistance. Our data confirm that the H. pylori Stool Antigen test displays a diagnostic performance similar to the breath test for control of eradication.

Regulatory role of host CD8+ T lymphocytes in experimental graft-versus-host disease across a single major histocompatibility complex class II incompatibility.

BACKGROUND: CD8+ T cells are known to regulate type 2 helper T cell (Th2) alloreactive immune responses but their mode of activation is unclear. We investigated the role of host CD8+ T cells in experimental Th2-type graft-versus-host disease (GVHD) where donor/recipient disparity is restricted to a single major histocompatibility complex (MHC) class II antigen. METHODS: Immunoglobulin (Ig) E serum levels, eosinophilia and lymphoid tissue hyperplasia were compared after injection of bm12 CD4+ T cells in either wild-type or CD8+ T cell-deficient (CD8-/-) C57BL/6 mice. In vitro, we explored effects of the addition of CD8+ T cells from wild-type or IFN-gamma-/- mice in mixed leukocyte cultures prepared with beta2 microglobulin-deficient (beta2m-/-) CD4+ T cells as responders or beta2m dendritic cells as stimulators. RESULTS: HyperIgE resolved after 3 weeks in wild-type hosts whereas it persisted for 6 weeks in CD8-/- hosts. Eosinophil infiltrates in lymph nodes were significantly enhanced in CD8-/- hosts. Increased serum levels of IL-5 and IL-13 in CD8-/- hosts confirmed the enhancement of Th2-type responses in the context of recipient CD8+ T cell deficiency. Hyperplasia of lymph nodes and spleen were similar in both groups, as well as in vivo proliferation of donor CD4+ T cells. In vitro, CD8+ T cell regulation of the alloreactive Th2 response depended on their production of IFN-gamma and did not require expression of beta2m on CD4+ T cells or antigen-presenting cells. CONCLUSIONS: Host CD8+ T cells regulate alloreactive Th2 responses during graft-versus-host disease through an IFN-gamma dependent pathway, independently of the recognition of beta2m-associated MHC class I molecules.

CCR5 deficiency exacerbates T-cell-mediated hepatitis in mice.

Experimental T-cell-mediated hepatitis induced by concanavalin A (Con A) involves the production of different cytokines and chemokines and is characterized by leukocyte infiltration. Because the chemokine receptor CCR5 and its ligands (CCL3, CCL4, and CCL5) regulate leukocyte chemotaxis and activation, we investigated the role of CCR5 during Con A-induced liver injury. Serum levels of CCR5 ligands and their hepatic transcript levels were significantly increased after Con A injection, whereas CCR5+ liver mononuclear cells were recruited to the liver. CCR5-deficient (CCR5-/-) mice disclosed increased mortality and liver injury following Con A administration compared with wild-type mice. CCR5-/- mice also exhibited increased production of interleukin 4, tumor necrosis factor alpha, CCL3, CCL4, and CCL5, and a prominent liver mononuclear cell infiltrate, among which many cells were CCR1+. In vivo neutralization of CCR5 ligands in CCR5-/- mice afforded a protection against hepatitis only when CCL5 was neutralized. In conclusion, CCR5 deficiency exacerbates T-cell-mediated hepatitis, and leads to increased levels of CCR5 ligands and a more pronounced liver mononuclear infiltrate, suggesting that CCR5 expression can modulate severity of immuno-mediated liver injury.