PD-L1 Expression on Circulating CD34+ Hematopoietic Stem Cells Closely Correlated with T-cell Apoptosis in Chronic Hepatitis C Infected Patients

BACKGROUND AND OBJECTIVES: Lack of understanding of the interplay between hematopoietic stem cells (HSCs) and the immune system has severely hampered stem cell research. Programmed death-1 (PD-L1) has been reported on parenchymal cells in patients with chronically inflamed livers and found to play an essential role in T cell homeostasis regulation. However, the bidirectional interaction between HSCs and lymphocytes remains elusive. Here, we aimed to get more insight into circulating CD34+ HSCs PD-L1 expression and T cell apoptosis in chronic HCV infected patients. METHODS: CD34+ HSCs were isolated and purified by immunomagnetic separation. PD-L1 expression was analyzed by quantitative PCR and flow cytometry. Furthermore, co-culture experiments between CD34+ HSCs and T-lymphocytes were established. T-cell lymphocyte apoptosis in peripheral blood and in cultures was detected. RESULTS: CD34+ HSCs constitutively express low levels of PD-L1. Its expression is up-regulated in chronic HCV infected patients. Moreover, PD-L1 expression on circulating CD34+ HSCs enhanced T cell apoptosis in peripheral blood and co-culture. CONCLUSION: Our results suggest novel bidirectional interplay between HSCs and lymphocytes mediated by PD-L1 expression on CD34+ HSCs. PD-L1 expression correlated with T-cell lymphocyte apoptosis. This may contribute to immunomodulatory properties of HSCs which improves its use for allogeneic transplantation.

Histopathological changes in anti-HCV positive subjects with persistently normal aminotransferase levels

Approximately 30% of patients with chronic hepatitis C have normal serum alanine transaminase [ALT] levels; most of those patients have mild degrees of inflammation with mild or no fibrosis and the rate of disease progression is reduced compared to that in patients with elevated ALT levels. Is to study the histopathological characteristics of anti-HCV positive subjects with persistently normal aminotransferase levels in comparison with those patients having elevated aminotransferase levels. A comparative case control study was conducted on 80 patients who asked medical advice in outpatient clinics of National Liver Institute, Menoufiya University and Specialized Medical Hospital, Mansoura University. They were classified into two groups. Group I: were forty anti-HCV-positive subjects with normal enzymes. They were 28 males, 12 females. Their age ranged from 18 to 50 years with a mean age of 31 +/- 8.47 years. Group II: were forty chronic hepatitis C patients [31 males and 9 females] their age ranged between 17-53 years with a mean age 32.12 +/- 7.70 years with elevated ALT levels [one and half or more times of the upper limit of normal for at least six months], Both groups were subjected to thorough history taking and physical examination, complete blood counts [CBC], routine liver tests, abdominal ultrasound and percutaneous ultrasound guided liver biopsy to assess the severity of the necro-inflammatory process using histological activity index [HAT] of Knodell et al. and modification of Ishak et al. This research showed that the majority of anti-HCV positive patients with persistently normal ALT have histological features of minimal to mild necro-inflammation [HAT]. The severity of histological necro-inflammation is reduced in anti-HCV positive patients with persistently normal ALT compared with that of patients with elevated ALT levels. Also they have no or minimal to mild stage of fibrosis compared with that in patients with elevated ALT levels. Persistently normal ALT patients with steatosis had higher HAT grades and fibrosis stages than patients without steatosis and a significant correlation was found between steatosis and increased BMI. Moderate significant correlation was found between low platelet counts and fibrosis stage in patients with elevated ALT levels. The majority of anti-HCV positive patients with persistently normal ALT have histological-pathological changes of variant degrees of severity specially patients having steatosis. So it is recommended that patients with chronic hepatitis C should not be excluded from therapy based on ALT levels alone and the treatment must be individualized according to each patient

Interferon alfa-2B with and without ribavirin for the treatment of chronic hepatitis C genotype IV

Interferon alfa is the only effective treatment for chronic hepatitis C. Forty percent of patients have an initial response to this therapy but most subsequently relapse. The effect of interferon alone was compared with that of interferon plus oral ribavirin for the treatment of chronic hepatitis C genotype N. A total of 47 patients with chronic hepatitis C doses were assigned to receive standard doses of recombinant interferon alfa - 2b and 45 patients were assigned to receive interferon alpa-26 with ribavirin [1000 to 1200 mg orally per day, depending on body weight] for six months. At the completion of treatment, HCV-RNA was undetected in d 9 of the 45 patients who were treated with interferon and ribavirin and in 11 of the 47 patients who were treated with interferon alone [42.2% As compared with. 23.4%, p<0.0751. Serum HCV-RNA remained undetected 24 weeks after the end of treatment in 12 patients [26.65%] in the combination therapy group, but only 3 patients [6.3%] in the interferon group [p>0.010].Sustained normalization of serum alanine aminotransferase [ALT] and histologic improvement were highly correlated with virologic response. Combined therapy caused a predictable fall in hemoglobin concentrations but otherwise had a safety profile similar to that of interferon alone. In conclusion, in patients with chronic hepatitis C genotype W therapy with interferon and oral ribavirin resulted in higher rates of sustained virologic, biochemical response than treatment with interferon alone

Response to ribavirin treatment in patients with chronic hepatitis C

Ribavirin is a nucleosi.de analogue with a broad spectrum of antiviral action. 17 patients with chronic hepatitis C were treated with oral ribavirin at a dose of 15 mg/Kg per day for 6 months. S e m alanine aminotransferase [ALT] activities decreased significantly [P<0.005] during ribavirin treatment [mean ALT before treatment was 117.01 +/- 50.3 1 U/ ml and 65.01 +/- 31.09 U/ml by the end of treatment]. ALT levels became normal in 5 cases [29.5%], significantly decreased in 8 cases [47%], but did not significantly change in the remaining 4 cases [23.5%]. Serum ALT in all the responding patients returned to pretreatment levels 2 months after stopping the treatment. Before treatment, serum hepatitis C virus [HCVRNA was detected by polymerase chain reaction [PCR] in all 17 patients. At the end of treatment, 5 of these 17 patients had become negative for HCV - RNA but they became positive again 3 months after discontinuation of treatment. The response to ribavirin was not correlated with HCV genotypes and liver histopathology in all patients and there was no significant difference between responders and non-responders. Ribavirin treatment resulted in mild, reversible hemolysis and none of the patients exhibited symptomatic anemia. These findings suggest that ribavirin has a beneficia1 effect on patients with chronic hepatitis C, although further studies are needed to determine how ribavirin can be best used

Serum leptin level in chronic hepatitis

This study was planned to evaluate serum leptin levels in patients with chronic viral hepatitis or liver cirrhosis. The study included 80 patients with chronic viral hepatitis [chronic hepatitis C positive group [41 patients]. 23 non-cirrhotic and 18 patients post HCV cirrhosis. Chronic hepatitis B patient [25 patients] 10 patients non-cirrhotic and 15 post HBV cirrhosis. Chronic hepatitis B and C virus positive group. [14 patients] 6 non-cirrhotic and 8 patients post HBV and HCV cirrhosis. 10 healthy subjects of matched age and sex as a control group. The study showed that serum leptin levels was significantly elevated with non-cirrhotic and cirrhotic cases [chronic hepatitis] than the control while the highest concentration being seen in cirrhotic patients. There was a non significant difference in serum leptin levels with the different etiology of non-cirrhotic chronic viral hepatitis. Serum leptin levels showed a non significant difference between different Child classes. Serum leptin levels are sex dependent, higher in females than males. Serum leptin levels correlated positively with [BMI], this correlation was significant in females while not significant in males. Serum leptin was correlated positively with serum bilirubin, on the other hand serum leptin levels was inversely correlated significantly with serum albumin but no correlation with SGPT or SGOT. It can be concluded that in the course of chronic viral liver disease, serum leptin levels may reflect the extent of liver dysfunction Serum leptin levels is higher in patients with chronic hepatitis and is significantly increased in cirrhotic than non-cirrhotic and there is no correlation between BMI and its level

Does schistosomiasis interfere with application of knodell score for assessment of chronic hepatitis C?

Schistosoma mansoni [SM] is a significant etiology of liver disease in many countries. Chronic hepatitis C is a major health problem worldwide. Association of schistosomiasis and chronic hepatitis C is not uncommon especially in areas where the two diseases are prevalent. The possible synergistic relationship between both conditions is a point of controversy. Also, the assessment of degree of necroinflammatory injury and stage of fibrosis in patients with mixed schistosomiasis and chronic hepatitis C is not a settled issue. The present study is a trial to highlight this problem. 185 individuals [25] pure schistosomal affection, [100] pure HCV, and [60] mixed HCV and schistosomal [HCV+S] were included. These were selected from 222 biopsied patients with chronic liver disease attending the liver unit of Internal Medicine Department, Mansoura University July 1999-May 2000. They were subjected to rectal snip and serological test for schistosomiasis, liver functions, HBV, HCV serological markers, serum qualitative PCR and liver biopsy. .Masson trichrome stain was performed to assess fibrosis. Immunohistochemical staining for HBsAg and HBcAg were performed. Modified Knodell score was applied to assess the biopsy. Five out of the 25 pure schistosomal and only 2 of the mixed group revealed schistosomal granuloma. 30% of pure HCV and 33% of mixed [HCV+S] patients were found to be cirrhotic. No significant statistical difference was identified between the two groups as regard necroinflammatory injury and Knodell score [p= 0.81]. Also, no significant difference was identified as regard stage of fibrosis [p=0.77]. Schistosomal hepatic affection does not lead to more severe or progressive disease in patients with chronic hepatitis C. Also, it does not interfere with assessment of necroinflammatory injury or fibrosis stage as determined by Knodell score