Incidence of Colorectal Cancer and Extracolonic Cancers in Veteran Patients With Inflammatory Bowel Disease.

Background: The risk for colorectal cancer (CRC) and certain extracolonic cancers is thought to be increased in inflammatory bowel disease (IBD), but few recent US studies have evaluated this issue. We aimed to estimate the incidence of CRC and extracolonic cancers in IBD patients. Methods: In this case-control study, cases were all IBD patients treated in our Department of Veterans Affairs (VA) hospital who developed CRC or extracolonic cancers between 1996 and 2015. Controls were patients in the general VA population who developed these cancers during the same time. We compared cancer incidence rates (IRs) in cases and controls. Results: There was no significant difference between cases and controls in the 20-year IR for CRC (148/100 000 in IBD patients, 97/100 000 in controls; relative risk [RR], 1.53; 95% confidence interval [CI], 0.86-2.69). In contrast, IBD cases had a significantly higher 20-year IR for all extracolonic cancers than controls (2839/100 000 in IBD patients, 1960/100 000 in controls; RR, 1.45; 95% CI, 1.27-1.65). Site-specific analyses revealed that IBD patients had significantly elevated risks for nonmelanoma skin cancers (RR, 2.38; 95% CI, 1.99-2.85), melanoma skin cancers (RR, 2.85; 95% CI, 1.63-4.88), renal tumors (RR, 2.90; 95% CI, 1.46-5.84), prostate cancer (RR, 1.70; 95% CI, 1.28-2.27), and pancreatic cancer (RR, 4.23; 95% CI, 1.35-13.29). Conclusions: The incidence of CRC was not significantly higher in our veteran patients with IBD than in control patients in the general VA population. In contrast, our IBD patients had a significantly higher risk for extracolonic cancers than controls, including cancers of the skin, kidneys, prostate, and pancreas. 10.1093/ibd/izx046_video1Video 1.izx046_Mosher_Video5734484616001.

The Differential Effects of Human Immunodeficiency Virus and Hepatitis C Virus on Bone Microarchitecture and Fracture Risk.

Background: Human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected individuals have a significantly greater osteoporotic fracture risk than HIV-monoinfected persons, despite the fact that HIV/HCV coinfection has not been associated with lower bone mineral density (BMD) than HIV or HCV alone. To evaluate if changes in bone microarchitecture, measured by trabecular bone score (TBS), could explain these differences, we performed a prospective, cross-sectional cohort study of virologically suppressed HIV-infected subjects, untreated HCV-infected subjects, HIV/HCV-coinfected subjects, and uninfected controls. Methods: We enrolled 532 male subjects: 57 HIV/HCV coinfected, 174 HIV infected, 123 HCV infected, and 178 controls. We conducted analysis of covariance comparing BMD and TBS between groups, controlling for age, race, body mass index, and smoking. We used linear regression to evaluate predictors of BMD and TBS and evaluated the effects of severity of HCV infection and tenofovir disoproxil fumarate use. Results: Despite both infections being associated with decreased BMD, only HCV, but not HIV, was associated with lower TBS score. Also, HIV/HCV-coinfected subjects had lower TBS scores than HIV-monoinfected, HCV-monoinfected, and uninfected subjects. Neither the use of TDF or HCV viremia nor the severity of HCV liver disease was associated with lower TBS. Conclusions: HCV infection is associated with microarchitectural changes at the lumbar spine as assessed by the low TBS score, suggesting that microstructural abnormalities underlie some of the higher fracture risk in HCV infection. TBS might improve fracture risk prediction in HCV infection.

An effectiveness study of group psychoeducation for hepatitis C patients in community clinics.

OBJECTIVE: A successful psychoeducation program for serious mental illness, PsychoEducation Responsive to Families (PERF), was modified for hepatitis C virus (HCV). An effectiveness study was carried out comparing HCV-PERF with didactic education. PATIENTS AND METHODS: A sample of 309 adult HCV patients was recruited from three outpatient settings and randomized (60% HCV-PERF, 40% didactic control). Groups met for 90 min bimonthly for 6 months following separate structured protocols. HCV-PERF sessions included a didactic curriculum developed uniquely for groups by member choice, with group problem-solving and support interactions. Patients were assessed at baseline, after the intervention, and 1 year later. Demographic and HCV-related variables and structured diagnostic interview data were obtained. RESULTS: Both groups improved significantly on major depression and alcohol and drug use, quality of life, risk behaviors, and treatment satisfaction, and worsened on disability and perceived HCV-related problems. Intervention groups did not differ on outcomes. CONCLUSION: Even though the active intervention did not achieve a significant improvement relative to the control condition, the observable improvements in both conditions warrant further exploration of the contributions of education and support as potentially important elements of HCV behavioral intervention. Further study is needed to identify elements common to education interventions that may be contributory to the improved outcomes over time.

An assessment of concurrent drug and alcohol use among patients seeking treatment for hepatitis C.

BACKGROUND: The purpose of this study was to assess the one-year prevalence of drug use and of concurrent alcohol use among hepatitis C (HCV) patients seeking treatment from specialty HCV clinics. METHODS: Patients with confirmed HCV RNA considering HCV treatment (N = 309) were recruited from university-affiliated and Veterans Affairs medical centers. RESULTS: The prevalence of current drug use in the last year was 65% (201/309) among patients considering HCV treatment. More than one-fourth of the sample used drugs at some time in their lives but none in the last year. Only 7% (22/309) of patients reported no lifetime drug use. The prevalence of concurrent drug and alcohol use in the last year was 72% (145/201) and 52% (105/201) in the last month. CONCLUSIONS: More than half of current drug users were still consuming alcohol in the last month despite the fact that they had all been informed of the potential for accelerated liver damage from continued alcohol use. This finding suggests that achieving abstinence from drug use does not necessarily imply that abstinence from alcohol has been obtained. Integration of substance treatment and HCV treatment into a unified disease management approach might increase treatment eligibility and compliance and improve disease outcomes.

Relationship of hepatic fibrosis, cirrhosis, and mortality with cholecystectomy in patients with hepatitis C virus infection.

OBJECTIVES: Studies have suggested that cholecystectomy is a risk factor for nonalcoholic fatty liver disease, but it is not known whether cholecystectomy is a risk factor for the progression of other chronic liver diseases such as hepatitis C virus (HCV) infection. The aim of this study was to assess whether cholecystectomy is associated with an increase in fibrosis, cirrhosis, and cirrhosis-related complications in patients with chronic HCV infection. METHODS: Among a total of 3989 HCV-positive patients at the VA North Texas Health Care System, we retrospectively reviewed the records of 88 patients who had undergone cholecystectomy between 1998 and 2013, followed up for a median of 4.9 years. We compared the outcomes of these patients with those of two age-matched, race-matched, and sex-matched cohorts: a cohort consisting of 129 HCV-positive patients without gallbladder disease (GBD) and a second cohort consisting of 178 HCV-positive patients with GBD who had not undergone cholecystectomy. Demographics, presence of metabolic syndrome, alcohol use, laboratory data, and clinical progression of liver disease were compared at study entry and 5 years later. RESULTS: Controlling for multiple factors associated with increase in liver fibrosis, analyses confirmed that a there was an increase in the proportion of patients who developed cirrhosis [odds ratio (OR)=3.24, 95% confidence interval (CI) 1.57-6.68, P=0.001] and ascites (OR=3.01, 95% CI 1.14-7.97, P=0.026) as well as in the incidence of death (OR=6.29, 95% CI 2.13-18.59, P=0.001) 5 years after cohort entry among HCV-positive patients with cholecystectomy compared with HCV-positive controls. The HCV-positive patient group with previous cholecystectomy showed an increased incidence of cirrhosis (OR=2.43, 95% CI 1.34-4.41, P=0.004), hepatocellular carcinoma (OR=2.85, 95% CI 1.11-7.36, P=0.030), and death (OR=3.31, 95% CI 1.50-7.28, P=0.003) 5 years after cohort entry compared with HCV-positive controls with GBD who had not undergone cholecystectomy. CONCLUSION: Cholecystectomy among HCV-positive patients is associated an increased incidence of fibrosis, cirrhosis, and its complications (ascites, hepatocellular carcinoma, and death) compared with HCV-positive controls and HCV-positive patients with GBD who have not undergone cholecystectomy.

Mechanisms of bone disease in HIV and hepatitis C virus: impact of bone turnover, tenofovir exposure, sex steroids and severity of liver disease.

OBJECTIVE: Both HIV and hepatitis C virus (HCV) infections are associated with higher osteoporotic fracture risk. Increased bone turnover, liver fibrosis, tenofovir (TDF) use or hormonal imbalances are possible underlying mechanisms. DESIGN: This prospective, cross-sectional study assessed 298 male volunteers with either virologically suppressed HIV or untreated HCV mono-infections, HIV/HCV co-infection and noninfected controls. METHODOLOGY: Study participants underwent bone mineral density (BMD) by dual-energy x-ray absorptiometry and measurement of bone turnover markers [BTM: C-telopeptide (CTX) and osteocalcin (OC)], insulin-like growth factor-1 (IGF-1), the sex steroids testosterone (T) and estradiol (E2), and the aspartate aminotransferase-to-platelet ratio index (APRI). Impact of HIV and HCV status on BMD was evaluated in multivariate models adjusting for APRI score, BTM, TDF exposure, IGF-1, and sex steroids. RESULTS: HIV and HCV status independently predicted lower BMD, controlling for age, race, BMI, and smoking (P = 0.017 and P = 0.010, respectively), whereas APRI did not (P = 0.84). HIV was associated with increased bone resorption (CTX: P < 0.001) and formation (OC: P = 0.014), whereas HCV infection was not associated with CTX (P = 0.30) or OC (P = 0.36). TDF exposure was associated with lower BMD (P < 0.01). IGF-1 was significantly decreased in HCV and increased in HIV. Tumor necrosis factor-α (P = 0.98), IGF-1 (P = 0.80), bioavailable T (P = 0.45) and E2 (P = 0.27) were not associated with BMD and did not attenuate the impact of HIV or HCV on BMD. CONCLUSION: HIV and TDF exposure decrease BMD through increased bone turnover, although the lower BMD in HCV is not explained by a high turnover state. Neither virus' effect on BMD is likely mediated through increased inflammation, liver fibrosis, IGF-1, or sex steroids.

Nonalcoholic fatty liver disease: a potential consequence of tumor necrosis factor-inhibitor therapy.

INTRODUCTION: Although tumor necrosis factor inhibitors (TNFi) might be expected to protect against nonalcoholic fatty liver disease (NAFLD), we have seen patients who appeared to develop NAFLD during TNFi treatment. We aimed to explore risk factors for this TNFi complication in a case-control study. METHODS: We reviewed clinic records at our VA hospital to identify patients with inflammatory diseases who developed aminotransferase elevations during TNFi therapy and who had liver biopsies showing NAFLD. These patients were matched with patients in each of three control groups: (i) inflammatory disease controls: patients on TNFi treatment with normal aminotransferase levels, (ii) nonalcoholic steatohepatitis (NASH) controls: patients with biopsy-proven NASH with no other inflammatory disease, and (iii) healthy controls. Genotyping was performed for PNPLA3, a gene predisposing to NASH. RESULTS: We identified eight cases (five steatohepatitis, three steatosis); elevated aminotransferase levels were first observed 1-63 months into TNFi therapy (average 12 months). TNFi therapy was stopped in five patients, whose aminotransferase levels then normalized within 2-8 months. There were no significant differences between cases and inflammatory disease controls in the frequency of features of metabolic syndrome. Cases had more methotrexate exposure than inflammatory controls (50 vs. 12.5%, P=0.28). PNPLA3 genotyping revealed mutations in 75% of cases, 38% of inflammatory controls, 88% of NASH controls, and 63% of healthy controls (P=NS). CONCLUSION: Our findings suggest that NAFLD can be a side effect of TNFi therapy, and that methotrexate exposure and PNPLA3 gene mutations might be risk factors. Further studies are needed to determine how TNFi causes NAFLD and to confirm these risk factors.

An empirical study of alcohol consumption by patients considering HCV treatment.

BACKGROUND: Alcohol accelerates the course of hepatitis C (HCV) infection and liver damage. Little is known about recency of alcohol use among patients with HCV. OBJECTIVES: Alcohol consumption recency was compared among HCV patients with and without alcohol use disorders and current and lifetime alcohol use histories. METHODS: Patients considering antiviral treatment for HCV (n = 309) recruited from university-affiliated and VA liver and infectious disease clinics were assessed for lifetime and current-year psychiatric disorders and alcohol-use patterns. Full diagnostic interviews, self-report surveys, medical record review, and urine screening for recent alcohol and drug use were conducted. RESULTS: 60% used alcohol in the last year. Besides alcohol history, those who stopped using alcohol in the past year differed from those with no lifetime use only in gender (60% vs. 22%); however, patients no longer using alcohol in the last year were less likely than those still using to have a current drug use disorder (16% vs. 3%) or last-month drug use (52% vs. 30%), and had fewer current risky behaviors (1.3 vs. 0.6). Among patients with last-year alcohol use, those with past alcohol use disorders differed from those without only by higher prevalence of drug use disorder (84% vs. 47%) and drug use after HCV diagnosis (67% vs. 43%). CONCLUSIONS: Patients who had stopped using alcohol for at least a year were much like those who never used alcohol in regard to other drug use, psychiatric history, smoking, and risky behaviors. These findings indicate that HCV patients with at least a year of abstinence from alcohol, including those with a history of alcohol use disorder, should be considered HCV treatment candidates.

Hepatitis C co-infection and severity of liver disease as risk factors for osteoporotic fractures among HIV-infected patients.

Osteoporosis is increasingly reported in the aging HIV-positive population, and co-infection with hepatitis C virus (HCV) may further increase the risk of osteoporosis. However, it remains unclear whether HCV-related increased fracture risk is a function of the severity of liver disease. We calculated the time-updated alanine aminotransferase to platelet ratio index (APRI) score (an indirect marker of hepatic fibrosis) in all HIV-infected patients enrolled in the Veterans Affairs' Clinical Case Registry between 1984 and 2009. The association between HCV co-infection and incident osteoporotic fracture (defined as closed wrist, vertebral, or hip fracture) was assessed in univariate and multivariate Cox survival models adjusting for traditional risk factors for osteoporosis and APRI score or the presence of cirrhosis. A total of 772 osteoporotic fractures were identified among 56,660 HIV-infected patients (98.1% male; 31.3% HCV co-infected; median age 44.0 years) contributing 305,237 patient-years of follow-up. Fracture rates were significantly higher among HIV/HCV patients than HIV-only patients (2.57 versus 2.07/1000 patient-years, relative risk = 1.24, p < 0.0001). In a Cox multivariable model including age, race, smoking, drug use, body mass index, and antiretroviral therapy, HCV co-infection remained an independent predictor of osteoporotic fractures after controlling for presence of cirrhosis (hazard ratio [HR] = 1.32; p <0.001) or APRI score (HR = 1.30; p = 0.003). Among HIV/HCV co-infected patients, cirrhosis strongly predicted osteoporotic fractures (HR = 1.65; 95% confidence interval [CI] 1.11-2.44; p = 0.012), but APRI score was a weaker predictor (HR = 1.008; 95% CI 1.002-1.014; p = 0.015). In conclusion, among HIV-infected patients, severity of liver disease partly explains the HCV-associated increased risk of osteoporotic fractures. Other determinants of this increased risk remain to be defined.

Second infections independently increase mortality in hospitalized patients with cirrhosis: the North American consortium for the study of end-stage liver disease (NACSELD) experience.

UNLABELLED: Bacterial infections are an important cause of mortality in cirrhosis, but there is a paucity of multicenter studies. The aim was to define factors predisposing to infection-related mortality in hospitalized patients with cirrhosis. A prospective, cohort study of patients with cirrhosis with infections was performed at eight North American tertiary-care hepatology centers. Data were collected on admission vitals, disease severity (model for endstage liver disease [MELD] and sequential organ failure [SOFA] scores), first infection site, type (community-acquired, healthcare-associated [HCA] or nosocomial), and second infection occurrence during hospitalization. The outcome was mortality within 30 days. A multivariate logistic regression model predicting mortality was created. 207 patients (55 years, 60% men, MELD 20) were included. Most first infections were HCA (71%), then nosocomial (15%) and community-acquired (14%). Urinary tract infections (52%), spontaneous bacterial peritonitis (SBP, 23%) and spontaneous bacteremia (21%) formed the majority of the first infections. Second infections were seen in 50 (24%) patients and were largely preventable: respiratory, including aspiration (28%), urinary, including catheter-related (26%), fungal (14%), and Clostridium difficile (12%) infections. Forty-nine patients (23.6%) who died within 30 days had higher admission MELD (25 versus 18, P < 0.0001), lower serum albumin (2.4 g/dL versus 2.8 g/dL, P = 0.002), and second infections (49% versus 16%, P < 0.0001) but equivalent SOFA scores (9.2 versus 9.9, P = 0.86). The case fatality rate was highest for C. difficile (40%), respiratory (37.5%), and spontaneous bacteremia (37%), and lowest for SBP (17%) and urinary infections (15%). The model for mortality included admission MELD (odds ratio [OR]: 1.12), heart rate (OR: 1.03) albumin (OR: 0.5), and second infection (OR: 4.42) as significant variables. CONCLUSION: Potentially preventable second infections are predictors of mortality independent of liver disease severity in this multicenter cirrhosis cohort.

Proton pump inhibitors increase the incidence of bone fractures in hepatitis C patients.

BACKGROUND: While proton pump inhibitors (PPI) may increase the risk of bone fractures, the incidence of new bone fractures in a chronic hepatitis C virus (HCV) infected cohort, with or without PPI exposure, has not been explored. METHODS: A retrospective cohort study of the incidence of bone fractures over 10 years in 9,437 HCV antibody positive patients in the Dallas VA Hepatitis C Registry was performed. The study endpoint was the incidence of verified new bone fractures per patient-years (pt-yrs) in PPI users compared to non-PPI users. PPI use was defined as those taking a PPI for ≥360 days. Pt-yrs of exposure for PPI users began on the first PPI prescription date, and pt-yrs of exposure for non-PPI users began with first date of any non-PPI prescription. For both HCV groups, the final date of patients' study duration was defined by end of PPI exposure, bone fracture occurrence, death or end of study evaluation period. Exclusion criteria included use of bone health modifying medications ≥30 days. Statistical differences in fracture incidence between groups were determined by multivariate regression analysis. RESULTS: Among the total study population analyzed (n = 2,573), 109 bone fractures occurred. Unadjusted bone fracture incidences were 13.99/1,000 pt-yrs vs. 5.86/1,000 pt-yrs in PPI and non-PPI users, respectively. The adjusted hazard ratio for new bone fractures was 3.87 (95 % CI 2.46-6.08) (p < 0.001) in PPI users. CONCLUSIONS: In patients with chronic HCV, use of PPI for >1 year increased the risk of new bone fractures by more than threefold.

Tumor necrosis factor is critical for cytolytic T cell activity against allospecific hepatocytes and splenic targets in major histocompatibility complex class I disparate graft versus host disease.

The present studies determined the role of tumor necrosis factor (TNF)/tumor necrosis factor receptor (TNFR) interactions on cytolytic (CTL) activity of splenic and intrahepatic lymphocytes (IHL) isolated from mice undergoing graft versus host disease, induced by transfer of B6 T cells to major histocompatibility complex (MHC) class I disparate bm1 × B6 F1 mice. Allospecific killing of anti-H-2(bm1) splenic and hepatocyte targets was assessed by 4-h (51)Cr release and 16-h DNA lysis assays, respectively, utilizing spleen cells (SpC) and IHL isolated (1) from sublethally irradiated bm1 × B6 F1 who had received B6 spleen and bone marrow cells, and a control adenovirus (Adv-ßgal) or a TNF inhibitor expressing adenovirus (Adv-TNFi), or (2) from bm1 × B6 F1 recipients of B6, B6.129-Tnfrsf1a(tm1Mak)/J (TNFR1(-/-)), B6.129S2-Tnfrsf1b(tm1Mwm)/J (TNFR2(-/-)), or B6.129S-Tnfrsf1a(tm1Imx) Tnfrsf1b(tm1Imx)/J (TNFR(-/-)) SpC and bone marrow cells, or (3) from in vitro-activated SpC. Splenic and IHL from bone marrow transplant recipients who had received Adv-TNFi at the time of transplant displayed lower allospecific CTL activity than controls. Addition of TNFR-Ig or a TNF antibody before the CTL activity assay further reduced allospecific killing against bm1 SpC blast targets. Both TNF/TNFR1 and TNF/TNFR2 interactions were critical for the development of optimal CTL activity against allospecific hepatocyte targets. Further, TNFR1- and TNFR2-deficient SpC from MHC class I disparate mixed lymphocyte cultures displayed lower CTL activity and expression of effector molecules than control B6 SpC. TNF/TNFR interactions were critical for the development of optimal CTL activity of IHL and splenic cytotoxic T cells against MHC class I disparate SpC blast and hepatocyte targets in MHC class I disparate graft versus host disease.

Tumor necrosis factor receptor 1 expression is upregulated in dendritic cells in patients with chronic HCV who respond to therapy.

The present studies assessed the level of tumor necrosis factor receptor (TNFR) expression in peripheral blood mononuclear cells (PBMCs) subsets from patients with chronic HCV undergoing interferon α/ribavirin-based therapy (Ifn/R). Methods. TNFR family member mRNA expression was determined using quantitative real-time PCR assays (RTPCRs) in PBMC from 39 HCV+ patients and 21 control HCV- patients. Further subset analysis of HCV + patients (untreated (U), sustained virological responders (SVR), and nonresponders (NR)/relapsers (Rel)) PBMC was performed via staining with anti-CD123, anti-CD33, anti-TNFR1 or via RTPCR for TNFR1 mRNA. Results. A similar level of TNFR1 mRNA in PBMC from untreated HCV+ genotype 1 patients and controls was noted. TNFR1 and TNFR2 mRNA levels in PBMC from HCV+ patients with SVR were statistically different than levels in HCV(-) patients. A significant difference was noted between the peak values of TNFR1 of the CD123+ PBMC isolated from SVR and the NR/Rel. Conclusion. Upregulation of TNFR1 expression, occurring in a specific subset of CD123+ dendritic cells, appeared in HCV+ patients with SVR.

Abatacept therapy for rheumatoid arthritis in the setting of hepatitis C infection.

Chronic hepatitis C in the setting of rheumatoid arthritis may be an obstacle to optimal management because of potential hepatotoxicity and adverse effects from immune suppression in these patients with a chronic infection. There are no reports in the literature discussing the use of abatacept, a T-cell costimulatory blocker, in patients with chronic hepatitis C. This article is the first report to describe the use of abatacept in 2 patients with rheumatoid arthritis and concomitant hepatitis C with favorable outcome.

Effects of recognizing depression with a standardized questionnaire (CES-D) versus patient reporting of depression after a single-standardized question on the outcomes of treatment for hepatitis C with pegylated interferon-α-2b and ribavirin.

BACKGROUND: Depression may worsen during antiviral treatment for hepatitis C virus, resulting in noncompliance treatment. AIM: The aim was to compare the response and compliance rates between the groups of veteran patients using two different methods of identifying depression, either the Centers for Epidemiology Studies for Depression Scale (group A) questionnaire or the report of symptoms of depression after a single-standardized question by the health care provider (group B). METHODS: One hundred and twenty-nine patients were randomly assigned to the two groups before the treatment. RESULTS: No statistical differences were noted in baseline characteristics between the groups. Depression was common in both the groups. No difference between initial Centers for Epidemiologic Studies Depression Scale scores and diagnosis of depression between the two groups was noted. Furthermore, the number of patients diagnosed with depression during the treatment was similar in each group. There were no significant differences between the groups in rates of sustained viral response (30% group A, 35% group B) or in rates of overall compliance with patients receiving more than 90% of prescribed PegIntronA therapy (44% group A, 39% group B), and ribavirin (32% group A and 37% group B). CONCLUSION: The use of the Centers for Epidemiology Studies for Depression Scale questionnaire to recognize depression had no significant advantage over patient reporting of depression symptoms after a single-standardized question on the hepatitis C virus clearance and the treatment compliance rates in veteran populations.

Disparate role of LIGHT in organ-specific donor T cells activation and effector molecules in MHC class II disparate GVHD.

BACKGROUND: The present studies determined the role of LIGHT on organ-specific cytokine and effector molecules in acute graft-versus-host disease. METHODS: Cytokine and effector molecules were assessed by flow cytometry and quantitative PCR. RESULTS: More CD4+ spleen cells (SpC) expressing interferon-gamma (IFNgamma) and interleukin-2 were noted in SpC isolated from lethally irradiated bm12 X B6 F1 recipients of B6 donor SpC and T cell-depleted bone marrow cells and control Adv-betagal than in transplant (bone marrow transplantation (BMT)) recipients who had received Adv-LTbetaR-Ig or Adv-herpes simplex virus entry mediator (HVEM)-Ig. IFNgamma RNA levels from SpC, small intestines, and large intestines of control BMT recipients were significantly higher than those who had received Adv-HVEM-Ig. Granzyme B levels from SpC and small intestines of control BMT recipients were significantly higher than those that had received the Adv-LTbetaR-Ig. In contrast, BMT recipients of Adv-HVEM-Ig had lower granzyme A levels than controls in their large intestines. DISCUSSION: LIGHT inhibition differentially affects cytokines and effector molecules in SpC, small intestines, and large intestines, implicating different organ-specific pathways.

The role of TNF in hepatic histopathological manifestations and hepatic CD8+ T cell alloresponses in murine MHC class I disparate GVHD.

Transfer of B6 T cells to major histocompatibility complex (MHC) class I disparate bm1 x B6 F1 mice leads to the development of hepatic graft-versus-host disease (GVHD) characterized by an active hepatitis with portal and lobular inflammation as well as bile duct inflammation and venulitis. The present studies determined the role of tumor necrosis factor (TNF) in hepatic GVHD. B6 responder cells were cultured with irradiated MHC class I disparate bm1 or syngeneic spleen cells (SpC) in the presence or absence of TNF receptor inhibitor [TNFR-immunoglobulin (Ig)]. Recipient bm1 x B6 F1 mice were irradiated (600 cGy) and reconstituted with 5 x 10(6) T cell-depleted B6 bone marrow cells and 1 x 10(7) B6 SpC. Mice were injected with an adenovirus encoding TNFR-Ig [TNF inhibitor-encoding adenovirus (Adv-TNFi)] or beta-galactosidase (Adv-betagal). Severity of liver GVHD was assessed by a composite histopathological score consisting of the sum of scores for venulitis, lobular hepatitis, and bile duct inflammation. Addition of TNFR-Ig reduced cell proliferation in mixed lymphocyte cultures using B6 responder SpC by 71% +/- 12.8% and interferon-gamma responses by 78% +/- 18%. GVHD-induced "wasting disease" was reduced in Adv-TNFi recipients [4.4%+/-5.2% weight loss (n=11)] compared with Adv-betagal recipients [16.1%+/-7.6% weight loss (n=11; P=0.0004)] 9 days post-transplant. Composite histopathological scores and individual venulitis scores were reduced with the addition of Adv-TNFi. Hepatic CD8+ T cells in the recipients of Adv-TNFi were reduced as compared with recipients of Adv-betagal. In conclusion, Adv-TNFi reduces MHC class I disparate alloproliferative responses and hepatic GVHD.

IL-12-independent LIGHT signaling enhances MHC class II disparate CD4+ T cell alloproliferation, IFN-gamma responses, and intestinal graft-versus-host disease.

Inhibition of LIGHT (a cellular ligand for herpes virus entry mediator and lymphotoxin receptor)/herpes simplex virus entry mediator (HVEM) and LIGHT/lymphotoxin beta receptor (LT beta R) interactions decreases mortality in MHC class I and II disparate graft-vs-host disease (GVHD). The present studies assessed the effects of these interactions on the generation of CD4+ T cell alloresponses in MHC class II-disparate MLC and GVHD. An inhibitor protein of LIGHT and LT alpha beta2 (LT beta R-Ig) and an inhibitor protein of LIGHT (HVEM-Ig) caused similar decreases in alloresponses of control B6 or B6.129S1-IL12rb2(tm1Jm) (B6.IL12R-/-) spleen cells (SpC) in a MHC class II-disparate MLC. GVHD-induced wasting disease in MHC class II-disparate recipients of B6 CD4+ SpC who received either the LT beta R-Ig-encoding adenovirus (LT beta R-Ig Adv; 13.1 +/- 10.9%; n = 10; p = 0.0004) or the HVEM-Ig-encoding adenovirus (HVEM-Ig Adv; 16.4 +/- 9.9%; n = 13; p = 0.0008) was significantly reduced compared with that in recipients of a control adenovirus (30.4 +/- 8.8%; n = 13). Furthermore, gut GVHD histologic scores of recipients of B6 CD4+ SpC who received the LT beta R-Ig Adv (0.8 +/- 0.8; n = 5; p = 0.0007) or the HVEM-Ig Adv (1.4 +/- 0.5; n = 5; p = 0.008) were reduced compared with scores of recipients of a control adenovirus (2.5 +/- 0.75; n = 11). In the intestine, both LT beta R-Ig Adv and HVEM-Ig Adv decreased CD4+ T cells (0.35 +/- 0.4 x 10(6) (n = 6) vs 0.36 +/- 0.02 x 10(6) (n = 9); p = 0.03 and p = 0.007) compared with control adenovirus (0.86 +/- 0.42 x 10(6); n = 9). LIGHT is critical for optimal CD4+ T cell alloresponses in MHC class II-disparate MLC and GVHD.

The role of TNF-TNFR2 interactions in generation of CTL responses and clearance of hepatic adenovirus infection.

Deficiency or inhibition of tumor necrosis factor (TNF) significantly prolongs hepatic expression of recombinant adenoviral vectors. To explore mechanisms responsible for this observation, the present studies examined the effects of TNF versus TNF receptor 1 (TNFR1) or TNFR2 deficiency on the course of antiviral-immune responses to a replication-deficient, beta-galactosidase-encoding recombinant adenovirus (AdCMV-lacZ). Clearance of AdCMV-lacZ was significantly delayed in TNF-deficient mice. Less pronounced but significant delays in AdCMV-lacZ clearance were observed in TNFR2-deficient but not TNFR1-deficient mice. Numbers of interferon-gamma expressing intrahepatic lymphocytes (IHL) were similar in AdCMV-lacZ-infected, TNF-deficient, TNFR1-deficient, TNFR2-deficient, and control mice. However, IHL isolated from AdCMV-lacZ-infected, TNF-deficient or AdCMV-lacZ-infected, TNFR2-deficient mice exhibited decreased levels of FasL expression and adenovirus-specific cytolytic T lymphocyte (CTL) activity. Similar defects in allo-specific killing of Fas-sensitive hepatocyte targets by TNF-deficient or TNFR2-deficient but not TNFR1-deficient CTL were also noted. No defects in generation of allo-specific cytotoxicity directed against perforin-sensitive target cells were noted in TNF-, TNFR1-, or TNFR2-deficient lymphocytes. These findings indicate that TNF/TNFR2 interactions facilitate generation of FasL-dependent CTL effector pathways that play an important role in in vivo antiviral-immune responses in the liver.

TNF enhances CD4+ T cell alloproliferation, IFN-gamma responses, and intestinal graft-versus-host disease by IL-12-independent mechanisms.

Inhibition of TNF/TNFR2 interactions ameliorates intestinal graft-vs-host disease (GVHD) and Th1 cytokine responses induced by transfer of B6 CD4(+) spleen cells into irradiated MHC class II disparate B6.C-H-2(bm12) (bm12) x B6 F(1) recipients. The present studies examined whether these effects of TNF are IL-12 dependent. T cell proliferative responses of B6.129S1-IL-12rb2(tm1Jm) (B6.IL-12R(-/-)) responder spleen cells were found to be comparable to those of control B6 spleen cells. TNF inhibition reduced T cell proliferation and IFN-gamma production in supernatants of MLC using either B6.IL-12R(-/-) or control B6 responder cells. GVHD induced wasting disease in recipients of B6.IL-12R(-/-) CD4(+) spleen cells that received a TNF inhibitor-encoding adenovirus (5.4 +/- 6.5% weight loss (n = 7)) was significantly reduced compared with levels of weight loss observed in recipients that had received a control adenovirus (25.7 +/- 12.2% weight loss (n = 11), p = 0.001). Furthermore, TNF inhibition was associated with a reduction in colonic GVHD scores (p = 0.039) and in the percentage of the splenic CD4(+) T cells that expressed IFN-gamma (16 vs 6%). These findings indicate that TNF promotes CD4(+) T cell alloproliferation, IFN-gamma responses, and intestinal GVHD by IL-12-independent mechanisms.