PubMed Health⌕ Search

Biomedical subjects

Hugo R Rosen

Publications and source records attributed to Hugo R Rosen.

At least 19 recordsLinked to original sources
PubMed2007

A functional SNP of interferon-gamma gene is important for interferon-alpha-induced and spontaneous recovery from hepatitis C virus infection.

Cytokine polymorphisms are associated with disease outcome and interferon (IFN) treatment response in hepatitis C virus (HCV) infection. We genotyped eight SNPs spanning the entire IFN-gamma gene in two cohorts and assessed the association between those polymorphisms and treatment response or spontaneous viral clearance. The first cohort was composed of 284 chronically HCV-infected patients who had received IFN-alpha-based therapy and the second was 251 i.v. drug users who had either spontaneously cleared HCV or become chronically infected. A SNP variant located in the proximal IFN-gamma promoter region next to the binding motif of heat shock transcription factor (HSF), -764G, was significantly associated with sustained virological response [P = 0.01, odds ratio (OR) = 2.66 [corrected] (confidence interval 1.3-5.6)[corrected]]. The association was independently significant in multiple logistic regression (P = 0.04) along with race, viral titer, and genotype. This variant was also significantly associated with spontaneous recovery [P = 0.04, OR = 3.51 (1.0-12.5)] in the second cohort. Functional analyses show that the G allele confers a two- to three-fold higher promoter activity and stronger binding affinity to HSF1 than the C allele. Our study suggests that the IFN-gamma promoter SNP -764G/C is functionally important in determining viral clearance and treatment response in HCV-infected patients and may be used as a genetic marker to predict sustained virological response in HCV-infected patients.

Alleles↗
PubMed2006

Differential antigenic hierarchy associated with spontaneous recovery from hepatitis C virus infection: implications for vaccine design.

BACKGROUND: Cellular immune responses play a central role in the control of hepatitis C virus (HCV) infection, and in some individuals the adaptive immune response can spontaneously eradicate HCV infection. The development of vaccine candidates to prevent the spread of this infection remains a top priority; however, understanding the correlates of effective immunological containment is an important prerequisite. METHODS: Using 750 overlapping peptides, we directly characterized ex vivo total and subgenomic HCV-specific CD4(+) and CD8(+) T cell responses in a large cohort of participants with either chronic infection or spontaneously resolved infection. RESULTS: In chronic infection, the frequency of total CD4(+) T cells specific for HCV averaged 0.06%, compared with 0.38% in resolved infection. Total HCV-specific CD4(+) and CD8(+) T cell responses were strongly correlated in the setting of spontaneous resolution but not in the setting of viral persistence. NS3 protein-specific responses comprised a significantly greater proportion of the total response in resolved infection than in chronic infection, whereas responses to different regions comprised a larger proportion of responses in chronic infection. CONCLUSION: Because these data comprehensively define the breadth, specificity, and threshold of the T cell response associated with spontaneous recovery from HCV infection, they have important implications in the development of multigenic vaccine candidates for this common infection.

CD4-Positive T-Lymphocytes↗
PubMed2006

Identification of a hepatitis C virus-reactive T cell receptor that does not require CD8 for target cell recognition.

Hepatitis C virus (HCV) has been reported to elicit B and T cell immunity in infected patients. Despite the presence of antiviral immunity, many patients develop chronic infections leading to cirrhosis, hepatocellular carcinoma, and liver failure that can require transplantation. We have previously described the presence of HLA-A2-restricted, HCV NS3-reactive cytotoxic T lymphocytes (CTL) in the blood of HLA-A2- liver transplantation patients that received an HLA-A2+ liver allograft. These T cells are analogous to the "allospecific" T cells that have been described in hematopoietic stem cell transplantation patients. It has been speculated that allospecific T cells express high-affinity T cell receptors (TCRs). To determine if our HCV-reactive T cells expressed TCRs with relatively high affinity for antigen, we identified and cloned a TCR from an allospecific HLA-A2-restricted, HCV:NS3:1406-1415-reactive CD8+ T cell clone and expressed this HCV TCR in Jurkat cells. Tetramer binding to HCV TCR-transduced Jurkat cells required CD8 expression, whereas antigen recognition did not. In conclusion, based on the reactivity of the TCR-transduced Jurkat cells, we have identified a TCR that transfers anti-HCV reactivity to alternate effectors. These data suggest this high affinity HCV-specific TCR might have potential new immunotherapic implications.

CD8 Antigens↗
PubMed2006

Loss of IL-7 receptor alpha-chain (CD127) expression in acute HCV infection associated with viral persistence.

Interleukin-7 (IL-7) is required for the establishment and maintenance of memory CD4(+) and CD8(+) T lymphocytes, and cells lacking IL-7Ralpha (CD127) demonstrate impaired IL-2 secretion and have a short life-span. Chronic HCV is characterized by T cells that are functionally impaired and exhibit an immature phenotype. To investigate the potential role of IL-7/IL-7Ralpha in the outcome of HCV infection, we used multiparameter flow cytometry to characterize patients with acute infection (n = 24), long-term chronic infection (12) and normal subjects (13). HCV infection per se resulted in downregulation of CD127 on total CD4(+) and CD8(+) T lymphocytes as compared to normal controls. Total expression was lowest in those patients who subsequently developed persistence and intermediate in those patients with acute-resolving infection. This reduction affected both naïve and effector/memory T cells. CD127 correlated phenotypically with upregulation of chemokine receptors CCR7 and CXCR4, expression of the anti-apoptotic molecule B cell leukemia/lymphoma 2 (Bcl-2), and enhanced IL-2 production. In six HLA A2-positive patients, we longitudinally tracked tetramer responses to HCV and CMV epitopes; at baseline, reflecting the expression of CD127 on whole T cell populations, viral-specific CTLs in patients who became chronic demonstrated lower CD127. In conclusion, CD127 is a useful marker of functional CD4(+) and CD8(+) T cells and its expression correlates with virologic outcome of acute HCV. These data provide a mechanistic basis for the observation that CTLs generated in early infection rapidly decline as chronicity is established; CD127 expression should be considered in the design of novel immunotherapeutic approaches.

Acute Disease↗
PubMed2006

Natural killer cells: primary target for hepatitis C virus immune evasion strategies?

Liver cirrhosis and hepatocellular carcinoma secondary to chronic hepatitis C virus (HCV) infection requiring transplantation represents a significant public health problem. The most remarkable feature of hepatitis C virus is the ability to establish chronic infection in the vast majority of cases. Efforts to define clinical correlates of HCV persistence have focused primarily on CD4 and CD8 T cell responses. Until recently, the role of innate immunity in determining the outcome of HCV infection had received relatively little attention. Natural killer (NK) cells are an important antiviral effector population eliminating virus through direct killing and cytokine production. Recent studies highlighting the cross-talk between NK cells, dendritic cells (DCs) and T cells have prompted reevaluation of the important role NK cells play in regulating and maintaining specific immune responses. Like many other viruses, HCV has evolved strategies to evade detection and elimination by NK cells. T cell defects observed in HCV infection may be a consequence of inhibition of NK:DC interactions. We propose a theoretical model for HCV persistence that places the NK cell at the center of HCV immune evasion strategies. While this model is only theoretical, it provides a plausible interpretation of many published observations and a useful working model to test the role of NK cells in HCV persistence. In conclusion, the role of innate immune cells and their regulation of antigen-specific responses by the initial innate response to the virus, in particular NK cells, may prove to be an informative and clinically relevant avenue of investigation.

Cell Communication↗
PubMed2006

Acute rejection in HCV-infected liver transplant recipients: The great conundrum.

KEY CONCEPTS: 1. In hepatitis C virus (HCV)-infected patients, treatment of acute rejection is associated with worse outcomes (increased risk of allograft cirrhosis and mortality). 2. Whether patients with HCV are at higher risk for rejection remains controversial. 3. The mechanisms mediating acute rejection and recurrence of HCV are distinct, and as such, it should be possible to develop techniques based on these molecular differences that are diagnostically useful. 4. Liver biopsy is considered the gold-standard for diagnosing acute rejection and recurrent HCV; however, given histopathological similarities between the two conditions, discrimination can be extremely difficult. 5. At the present time, there are no reliable, noninvasive tools available to distinguish between HCV recurrence alone and acute rejection plus HCV recurrence. 6. Mild rejection per se is not associated with graft loss and treatment of rejection with steroids and OKT3 is associated with worse outcome in HCV; thus, it seems logical that we should no longer treat mild rejection.

Acute Disease↗
PubMed2006

Diagnosis and management of allograft failure.

The article focuses on diagnosis and management of allograft failure in four main categories: (1) ischemic-reperfusion injury (primary nonfunction), (2) technical complications (hepatic artery and portal vein thrombosis), (3) chronic rejection, and (4) recurrent disease. It also discusses the complex problems involved in retransplantation for allograft failure.

Graft Rejection↗
PubMed2006

Liver transplantation for hepatocellular carcinoma: a survey of practices.

GOAL: To survey physician practices regarding liver transplantation for patients with hepatocellular carcinoma (HCC). BACKGROUND: Many issues surrounding liver transplantation for HCC are controversial and physician practices have not been well characterized. METHODS: Transplant physicians and surgeons were electronically surveyed regarding surveillance, diagnosis, selection criteria for deceased and living donor transplantation, and use of adjunctive therapy for HCC. RESULTS: Eighty-nine of 174 (51%) physicians completed the survey (39 hepatologists, 41 transplant surgeons, and 9 others). Most respondents were from large US transplant centers. All reported screening for HCC during transplant evaluation, and 98% surveyed patients awaiting transplant. Sixty percent of respondents would biopsy lesions under selective conditions, whereas 32% never biopsy lesions, and 8% biopsy all lesions. Eighty two percent of respondents claimed to adhere to the Milan criteria (single lesion </=5 cm or no more than 3 lesions each </=3 cm without vascular invasion) for patient selection, however, 36% would transplant patients with tumors that invade a small portal branch. Forty one percent of respondents would consider living donor transplantation for patients with tumors exceeding the Milan criteria. Ninety-six percent of respondents treat HCC before transplantation, and 87% would transplant patients down-staged to meet the Milan criteria. CONCLUSIONS: There is consistency related to HCC surveillance and treatment in liver transplant candidates. Variations of responses regarding biopsy of lesions, patient selection for deceased donor and living donor transplantation highlight a need for evidence-based guidelines.

Biopsy↗
PubMed2005

Immune evasion versus recovery after acute hepatitis C virus infection from a shared source.

Acute infection with hepatitis C virus (HCV) rarely is identified, and hence, the determinants of spontaneous resolution versus chronicity remain incompletely understood. In particular, because of the retrospective nature and unknown source of infection in most human studies, direct evidence for emergence of escape mutations in immunodominant major histocompatibility complex class I-restricted epitopes leading to immune evasion is extremely limited. In two patients infected accidentally with an identical HCV strain but who developed divergent outcomes, the total lack of HCV-specific CD4+ T cells in conjunction with vigorous CD8+ T cells that targeted a single epitope in one patient was associated with mutational escape and viral persistence. Statistical evidence for positive Darwinian selective pressure against an immunodominant epitope is presented. Wild-type cytotoxic T lymphocytes persisted even after the cognate antigen was no longer present.

Acute Disease↗
PubMed2005

Reconstitution of hepatitis C virus-specific T-cellmediated immunity after liver transplantation.

Hepatitis C virus (HCV)-related liver failure is the leading indication for liver transplantation worldwide. After transplantation, virological recurrence is the rule, but the spectrum of histological injury is wide, ranging from the development of allograft cirrhosis within a few years to minimal hepatitis despite long-term follow-up. The immunological correlates of this variable natural history are poorly understood. Here, we studied the kinetics of the cellular immune responses, viral replication, and allograft histology in 24 patients who had undergone liver transplantation for HCV-related liver failure. Using direct ex vivo methodologies (i.e., interferon-gamma ELISPOT and major histocompatibility complex class I-peptide tetrameric complexes), we found that patients who experienced viral eradication after antiviral therapy showed restoration of HCV-specific T-cell responses, whereas patients with progressive HCV recurrence that failed to respond to therapy showed declining frequencies of these viral-specific effector cells. The cytotoxic T lymphocytes that peripherally reconstituted after transplantation were clonotypically identical to those present within the recipient explant liver, defined at the level of the T-cell receptor beta chain (one epitope/one clone). Moreover, the subset of patients who spontaneously demonstrated minimal histologic recurrence had more vigorous CD4+ T-cell responses in the first 3 months, particularly targeting nonstructural proteins. We provide evidence that T-cell responses emerge after liver transplantation, and their presence correlates with improved histological and clinical outcomes. In conclusion, these results may help identify patients more likely to develop severe HCV recurrence and therefore benefit from current antiviral therapy, as well as provide a rationale for the future use of novel immunotherapeutic approaches. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience. wiley.com/jpages/0270-9139/suppmat/index.html).

Adult↗
PubMed2005

Liver retransplantation for hepatitis C virus recurrence: a survey of liver transplant programs in the United States.

BACKGROUND & AIMS: Hepatitis C virus (HCV)-related liver failure is the leading indication for liver transplantation (LT). The number requiring re-LT is expected to grow as patients live long enough to develop graft failure and recurrent disease. Numerous factors have been identified as influencing survival after re-LT. To gain insight into how transplant centers are dealing with this issue and whether published prognostic factors are being used, we conducted a survey of liver transplant centers across the US in late 2003. METHODS: Surveys consisting of 6 multiple-choice questions were sent to all 96 adult transplant medical directors in the U.S. RESULTS: Fifty-five (57%) surveys were returned. Of these respondents, 95% would offer re-LT for allograft failure caused by recurrent HCV. A little more than half believed age >60 years and development of allograft cirrhosis after <2 years should exclude a patient from re-LT. However, less than half thought international normalized ratio (INR), Model for End-Stage Liver Disease (MELD), and bilirubin were important factors. After initial LT, 40% of the respondents do not have a protocol for managing HCV recurrence, and 33% responded that they treat only those who develop severe recurrence. In contrast, for re-LT, 67% preemptively treat HCV recurrence. Compared to 5 years ago, 75% believe practice patterns have changed in respect to retransplanting patients with HCV: Most were less likely to offer re-LT because of associated poor long-term survival in these patients. CONCLUSIONS: As of late 2003, nearly all surveyed transplant medical directors in the U.S. would offer re-LT to recurrent HCV. Perceived practice patterns for re-LT are at variance with published outcome data.

Health Care Surveys↗
PubMed2004

Cutting edge: identification of hepatitis C virus-specific CD8+ T cells restricted by donor HLA alleles following liver transplantation.

By necessity, human liver transplantation is performed across HLA barriers. As a result, intracellular infection of the allograft presents a unique immunologic challenge for the recipient's immune system. In this study, we describe the presence of HLA-A2-restricted, hepatitis C virus (HCV)-specific CD8+ T cells in liver transplant recipients in whom the allograft is HLA-A2 positive and the recipient is HLA-A2 negative. These memory-effector T cells are recipient derived and recognize HCV peptide uniquely in the context of HLA-A2. Furthermore, these cells were absent before the transplant, suggesting that the allograft is capable of selectively expanding naive CD8+ T cells. The in vitro specificity to donor HLA allele-restricted CD8+ T cells suggests that these cells may function to control HCV spread in the allograft.

Alleles↗
PubMed2004

Direct enumeration and functional assessment of circulating dendritic cells in patients with liver disease.

Chronic liver disease has been shown to be associated with diminished humoral and cellular immune function. Although antigen-presenting cells (APC) that initiate immune responses include various cells (B cells, endothelial cells, macrophages, etc.), the dendritic cell (DC) is a professional APC that activates naive T cells most efficiently. To examine the frequency and function of DCs in chronic liver disease, we studied circulating DCs from a cohort of 112 subjects (23 normal subjects, 29 subjects who had spontaneously recovered from hepatitis C virus [HCV] infection, 30 chronically infected HCV patients, and 30 patients with liver disease unrelated to HCV infection). Our analyses revealed significant reduction in both circulating myeloid (mDC) and plasmacytoid dendritic cells (pDC) in patients with liver disease. In contrast, examination of subjects with spontaneously resolved HCV infection revealed no significant difference in either circulating mDCs or pDCs. We found an inverse correlation with serum alanine aminotransferase (ALT) levels and both mDCs and pDCs frequency. In a subset of patients for whom intrahepatic cells were available, paired analysis revealed enrichment for DCs within the intrahepatic compartment. Interferon alfa (IFN-alpha) production in response to influenza A and poly (I:C) correlated with the frequency of circulating DCs, although IFN-alpha production was comparable on a per-DC basis in patients with liver disease. In conclusion, patients with liver disease exhibit a reduction in circulating DCs. Considering that DCs are essential for initiation and regulation of innate and adaptive immunity, these findings have implications for both viral persistence and liver disease.

Adult↗
PubMed2004

An immunomodulatory role for CD4(+)CD25(+) regulatory T lymphocytes in hepatitis C virus infection.

The CD4(+)CD25(+) regulatory T lymphocytes have been implicated in suppressing T cell immune responses. Our aim was to characterize the frequency, phenotype, function, and specificity of CD4(+)CD25(+) T cells in hepatitis C virus (HCV) infection. Peripheral CD4(+)CD25(+) cells from recovered (n = 15), chronic infected (n = 30), and normal control (n = 15) subjects were analyzed ex vivo for quantitation, phenotype, and effect on HCV-specific interferon gamma production and proliferation. CD4(+)CD25(+) specificity was determined by intracellular cytokine staining for interleukin 10 (IL-10). A higher proportion of CD4(+)CD25(+) were found in chronic infection (mean, 3.02%) when compared with recovered (1.64%, P = .001) and normal controls (2.27%, P = .02). CD4(+)CD25(+) cells display CD45RO(high), CD45RA(low), CD28(high), CD62L(high), and CD95(high) phenotype. HCV-specific interferon gamma activity was enhanced in peripheral blood mononuclear cells depleted of CD4(+)CD25(+) and suppressed in peripheral blood mononuclear cells enriched with CD4(+)CD25(+). Depletion of CD4(+)CD25(+) cells also enhanced HCV-specific CD4(+) and CD8(+) T cell proliferation. Cytokine analysis suggested CD4(+)CD25(+) cells secrete transforming growth factor beta (TGF-beta(1)) and IL-10. The inhibitory role for TGF-beta(1) was confirmed by anti-TGF-beta(1). Transwell studies showed CD4(+)CD25(+) mediated suppression to be dose dependent and requiring cell contact. CD4(+)CD25(+) cells showed HCV-specificity through IL-10 production, with a frequency ranging from 1.9% to 5.3%. A positive correlation was detected between CD4(+)CD25(+) T cell frequency and HCV RNA titer, whereas an inverse relation was found with liver inflammatory activity. In conclusion, CD4(+)CD25(+) T lymphocytes constitute a highly differentiated population and appear to play a role in viral persistence by suppressing HCV-specific T cell responses in a cell-cell contact manner.

Antibodies↗
PubMed2004

Retransplantation for recurrent hepatitis C in the MELD era: maximizing utility.

1. Retransplantation (re-LT) for hepatitis C virus (HCV) recurrence is controversial. Although re-LT accounts for 10% of all liver transplants (LTs), the number of patients requiring re-LT is expected to grow as primary LT recipients survive long enough to develop graft failure from recurrent disease. 2. Utility, as applied to the medical ethics of transplantation, refers to allocating organs to those individuals who will make the best use of them. The utility function (U) of liver transplantation is represented by the product of outcome (O = 1-year survival with LT) times emergency (E = 3-month mortality without LT), i.e., U = O x E. 3. For primary LT, maximal U is achieved by allocating organs at the highest model for end-stage liver disease (MELD) score (i.e., "sickest first"). No significant differences exist between HCV and non-HCV diagnoses. 4. For re-LT, maximal utility for HCV and non-HCV diagnoses are achieved at MELD scores of 21 and 24, respectively. Utility starts to decline at MELD scores above 28. 5. The current allocation system (MELD) fails to maximize utility with regard to re-LT.

Decision Support Techniques↗