Robert M. Hoffmann

Possible mechanism involving T-lymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection

In acute hepatitis C virus (HCV) infection only 20-50% of patients spontaneously clear the virus. To characterise the immune reaction during that phase we studied the response of peripheral blood mononuclear cells (PBMC) to the recombinant HCV proteins core, non-structural protein 3 (NS3), NS4, and NS5 in 14 patients with acute hepatitis C. All eight patients with self-limited disease compared with two of six with evolving chronic infection showed an NS3- specific PBMC response (p = 0.015). Of 65 patients with established chronic hepatitis C, five showed a PBMC response to NS3. NS3-specific CD4 T-cell clones from patients with self-limited infection predominantly produced interferon-gamma and may thus support cytotoxic effector mechanisms important for viral clearance.

Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T-cell response in acute hepatitis C

BACKGROUND & AIMS The prospective comparison of patients with acute hepatitis C virus (HCV) who spontaneously clear the virus with those who cannot achieve viral elimination and progress to chronic hepatitis offers the unique opportunity to analyze natural mechanisms of viral elimination. METHODS We studied the HCV-specific CD4(+) T-cell response in 38 patients with acute HCV and correlated the clinical course with the antiviral immune response. The individual HCV-specific T-cell response was assessed in a proliferation assay ((3)H-thymidine uptake) and an enzyme-linked immunospot assay. RESULTS Patients were classified according to their clinical course and pattern of CD4(+) T-cell responses in 3 categories: first, patients mounting a strong and sustained antiviral CD4(+)/Th1(+) T-cell response who cleared the virus (HCV RNA-negative; n = 20); second, patients who were unable to mount an HCV-specific CD4(+) T-cell response and developed chronic disease (n = 12); and third, patients who initially displayed a strong CD4(+) T-cell response and eliminated the virus (HCV PCR-negative) but subsequently lost this specific T-cell response (n = 6). The loss of the HCV-specific CD4(+) T-cell response was promptly followed by HCV recurrence. CONCLUSIONS The results indicate that a virus-specific CD4(+)/Th1(+) T-cell response that eliminates the virus during the acute phase of disease has to be maintained permanently to achieve long-term control of the virus. The induction and/or maintenance of virus-specific CD4(+) T cells could represent a promising therapeutic approach in HCV infection.

Association of Hepatitis C Virus—Specific CD8+ T Cells with Viral Clearance in Acute Hepatitis C

CD8+ T lymphocytes play a major role in antiviral immune defense. Their significance for acute hepatitis C is unclear. Our aim was to correlate the CD8+ T cell response with the outcome of infection. Eighteen patients with acute hepatitis C and 19 normal donors were studied. Hepatitis C virus (HCV)-specific CD8+ T cells were identified in the enzyme-linked immunospot assay by their interferon-gamma (IFN-gamma) production after specific stimulation. The highest numbers of IFN-gamma-producing HCV-specific CD8+ T cells were found in patients with acute hepatitis C and a self-limited course of disease during the first 6 months after onset of disease, but these numbers dropped thereafter to undetectable levels. The differences in responsiveness between patients with self-limited disease versus patients with a chronic course were statistically significant (P<.001). Our data show that the number of IFN-gamma-producing HCV-specific CD8+ T cells during the first 6 months after onset of disease is associated with eradication of the HCV infection.

Hepatitis B virus antigen-specific T-cell activation in patients with acute and chronic hepatitis B

Since the hepatitis B virus is noncytopathic, it is generally believed that the individual specific immune response determines the course of infection. The lack of data about hepatitis B virus-specific T-cell reactions in acute infection led us to investigate the specific cellular immune response of infected individuals in terms of proliferation, and gamma-interferon and lymphotoxin production. Our results demonstrate that peripheral blood mononuclear cells (PBMNC) from patients with acute and chronic hepatitis B respond weakly to HBsAg. In contrast, patients with acute hepatitis show a vigorous response to the nucleocapsid antigen (HBcAg) in terms of proliferation and lymphokine production, while only few chronic virus carriers gave a proliferative response. Either of the antigens could activate lymphocytes to produce gamma-interferon and lymphotoxin, cytokines which may modulate antiviral immune response.

Sarcoidosis associated with interferon-α therapy for chronic hepatitis C

BACKGROUND/AIMS Pulmonary side effects of interferon-alpha therapy of chronic hepatitis C seem to be rare. So far, only two cases of sarcoidosis in association with interferon-alpha treatment of chronic hepatitis C have been described. METHODS/CASES We report on three patients who were treated with recombinant interferon-alpha2a for chronic hepatitis C, two of them in combination with ribavirin. These patients developed pulmonary sarcoidosis 12, 20 and 21 weeks, respectively, after beginning interferon therapy, one patient with Löfgrens syndrome. In one patient sarcoidosis emerged only after discontinuation of interferon therapy because of treatment failure. Clinical symptoms of sarcoidosis in the three patients were suggestive of side effects of interferon-alpha. Interferon therapy was discontinued and spontaneous remission was observed in all three cases 5, 6, and 8 months, respectively, after the onset of symptoms. CONCLUSION The occurrence of sarcoidosis in association with interferon-alpha therapy for chronic hepatitis C may have been underestimated so far. This could be due to the fact that symptoms of sarcoidosis and common side effects of interferon are similar, and sarcoidosis may occur after the end of interferon therapy. We hypothesize that interferon-alpha as a potent stimulator for T-helper 1 (Th1) immune responses may trigger the compartmentalized Th1 reaction that has been shown to take place in sarcoidosis.

The role of hepatitis C virus specific CD4 + T lymphocytes in acute and chronic hepatitis C

Abstract Since the discovery of hepatitis C virus it has become clear that chronic hepatitis C is a major health problem throughout the world. Because antiviral agents are of limited value in the treatment of chronic hepatitis C, research has focused on the antiviral immune response for the development of both a protective vaccine and effective immunotherapies for established chronic infection. Antiviral antibodies are present in almost all patients with chronic hepatitis C but do not seem to be virus neutralizing, probably due to the high mutational rate of viral envelope proteins. Studies on the antiviral T cell response have revealed the presence of virus-specific CD4+ helper and CD8+ cytotoxic T cells in a substantial proportion of patients with chronic hepatitis C. Recent studies describe an association between strong CD4+ T helper cell activity to certain hepatitis C virus antigens and a self-limited course of acute hepatitis C and possibly also a sustained response to treatment with interferon-α. Therapeutic manipulation of the virus-specific T cell response may thus develop into a new approach for prevention and treatment of hepatitis C virus infection.

A vigorous virus-specific CD4+ T cell response may contribute to the association of HLA-DR13 with viral clearance in hepatitis B

A strong virus‐specific CD4+ and CD8+ T lymphocyte response to hepatitis B virus (HBV) has been associated with viral clearance, but little is known about factors determining the individuals ability to mount such a T cell response. Recently a strong association between the HLA class II allele DR13 and a self‐limited course of HBV infection has been described. In the present study of 33 patients with acute hepatitis B we show that individuals carrying HLA‐DR13 mount a more vigorous CD4+ T cell response to HBV core (5706 ct/min (25th/75th percentile 3239 ct/min; 10 552 ct/min)) than patients without HLA‐DR13 (1365 ct/min (490 ct/min; 5334 ct/min); P = 0.006). However, peptide epitopes aa 50–69, aa 61–85, and aa 81–105 were recognized most frequently by both patient groups. Moreover, among 14 HBV core‐specific CD4+ T cell clones from two patients with HLA‐DR13, only one T cell clone was HLA‐DR13‐restricted. Our data suggest that the beneficial effect of the HLA‐DR13 alleles on the outcome of HBV infection could be explained by a more vigorous HBV core‐specific CD4+ T cell response, which may either be due to more proficient antigen presentation by the HLA‐DR13 molecules themselves or a linked polymorphism in a neighbouring immunoregulatory gene.

Chronic Diarrhea As A Result Of Intestinal Microsposidiosis In A Liver Transplant Recipient

Background. Microsporidia are common pathogens among patients infected with human immunodeficiency virus. They account for a substantial proportion of chronic diarrhea and malabsorption in acquired immune deficiency syndrome, but their appearance after solid organ transplantation has only rarely been reported. Methods. We report what we believe is the first case of documented Enterocytozoon bieneusi infection in a liver transplant recipient. Results. Our patient presented with chronic diarrhea and colicky abdominal pain. Although symptoms were severe, only mild microscopical mucosal changes were found in the intestinal tract. A modified trichrome stain of stool specimens revealed microsporidial spores, and species differentiation by restriction fragment length polymorphism polymerase chain reaction identified Enterocytozoon bieneusi. Albendazole therapy brought symptomatic relief but no microbiological clearance. Conclusions. Enterocytozoon bieneusi may cause chronic diarrhea not only in immunosuppression as a result of human immunodeficiency virus infection but also among patients with therapeutic immunosuppression after organ transplantation. Therefore, microsporidial infection should be considered in immunosuppressed patients with otherwise unexplained diarrhea.

Shock-wave therapy of gastric outlet syndrome caused by a gallstone

A patient with gastric outlet syndrome (Bouverets syndrome) caused by a large gallstone impacted in the duodenal bulb was successfully treated by extracorporeal shock-wave lithotripsy. Thus, open abdominal surgery could be avoided. For disintegration of the stone, three consecutive lithotripsy procedures were necessary. Thereafter, stone fragments could be extracted endoscopically. Extracorporeal shock-wave lithotripsy could become a non-surgical alternative in patients with obstruction of the duodenum caused by a gallstone.

T lymphocytes from patients with primary biliary cirrhosis produce reduced amounts of lymphotoxin, tumor necrosis factor and interferon-γ upon mitogen stimulation

Primary biliary cirrhosis (PBC) is considered an autoimmune disease characterized by destruction of small intrahepatic bile ducts by lymphocytes. Altered functions of these lymphocytes might reflect an abnormal immune response leading to tissue damage. We investigated lymphokine secretion by mitogen-stimulated T lymphocytes from the liver biopsies of patients with PBC and for comparison also peripheral blood. In PBC, diminished synthesis of lymphotoxin (TNF beta), tumor necrosis factor (TNF alpha) and interferon-gamma (IFN gamma) was found both in T-cell lines from liver tissue and in peripheral blood. The reduction was most prominent for TNF beta in early histological stages of PBC, and appeared to be a stable phenomenon when T cells were tested after long-term tissue culture. Analysis of mRNA levels indicates a possible link between reduced TNF beta production and a defect in interleukin-2 transcription. The data suggest that diminished lymphokine production in patients with PBC may play an important role in the immunopathogenesis of this disease.