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Biomedical subjects

Atul K Bhan

Publications and source records attributed to Atul K Bhan.

At least 19 recordsLinked to original sources
PubMed2006

Relationships between cellular immune responses and treatment outcomes with interferon and ribavirin in HIV/hepatitis C virus co-infection.

OBJECTIVE: To test the hypothesis that hepatitis C virus (HCV)-specific interferon (IFN)gamma immune responses are correlated with HCV virological response following treatment in subjects with HIV-1 and HCV co-infection. DESIGN: Immune responses were studied in a treatment trial comparing standard interferon alfa (IFN) to pegylated interferon alfa (PEG-IFN), each with ribavirin (R). METHODS: Using HCV antigens core, NS3 and NS5, and Candida, enzyme-linked immunosorbent spots on peripheral blood mononuclear cells measured IFNgamma and interleukin (IL)-10 production. Immunologic, virologic and clinical variables were modeled using recursive partitioning (CART) to identify factors associated with HCV virological response at week 24 (VR) and week 72 (SVR) in 108 patients. RESULTS: There were no significant differences in baseline IFNgamma immune responses and higher IL-10 to NS3 in subjects with VR versus non-responders. Subjects who had significant decreases in IL-10 responses at week 24 compared to baseline for NS3, NS5, or summed HCV responses were more likely to be VR. Using baseline immunological responses and clinical data in CART models, patients who were randomized to PEG-IFN/R and had high IL-10 responses to summed HCV proteins were more likely to be VR (73%), whereas those on IFN/R who had low IFNgamma responses to Candida were less likely to be VR (5%). The main correlate of SVR for genotype-1 subjects was maintenance of HCV-specific IFNgamma responses from baseline to week 72. CONCLUSIONS: In this cohort of subjects with HIV and HCV, a decrease in HCV-specific IL-10 responses and maintenance of IFNgamma responses during treatment with IFN were associated with week 24 or 72 virological response.

Adolescent↗
PubMed2006

A case for regulatory B cells.

B cells are typically characterized by their ability to produce Abs, including autoantibodies. However, B cells possess additional immune functions, including the production of cytokines and the ability to function as a secondary APC. As with T cells, the B cell population contains functionally distinct subsets capable of performing both pathogenic and regulatory functions. Recent studies indicate that regulatory B cells develop in several murine models of chronic inflammation, including inflammatory bowel disease, rheumatoid arthritis, and experimental autoimmune encephalomyelitis. The regulatory function may be directly accomplished by the production of regulatory cytokines IL-10 and TGF-beta and/or by the ability of B cells to interact with pathogenic T cells to dampen harmful immune responses. In this review, we make a case for the existence of regulatory B cells and discuss the possible developmental pathways and functional mechanisms of these B cells.

Animals↗
PubMed2006

CD48 controls T-cell and antigen-presenting cell functions in experimental colitis.

BACKGROUND & AIMS: The cell-surface receptor CD48 is a lipid-anchored protein expressed on all antigen-presenting cells and T cells. CD2 and 2B4 are known ligands for CD48, which themselves are expressed on the surface of hematopoietic cells. Here we examine the effect of CD48 in the development of chronic experimental colitis and how CD48 affects adaptive and innate immune functions. METHODS: The role of CD48 in experimental colitis was first assessed by transferring CD4(+)CD45RB(hi) cells isolated from either wild-type or CD48(-/-) mice into either Rag-2(-/-) or CD48(-/-) x Rag-2(-/-) mice. Development of chronic colitis in these adoptively transferred mice was assessed by disease activity index, histology, and production of interferon-gamma in mesenteric lymph nodes. Relevant functions of CD48(-/-)CD4(+) T cells and CD48(-/-) macrophages were examined using in vitro assays. In a second set of experiments, the efficacy of anti-CD48 in prevention or treatment of chronic colitis was determined. RESULTS: CD48(-/-)CD4(+) cells induced colitis when transferred into Rag-2(-/-) mice, but not when introduced into CD48(-/-) x Rag-2(-/-) recipients. However, both recipient mouse strains developed colitis upon adoptive transfer of wild-type CD4(+) cells. Consistent with a CD4(+) T-cell defect was the observation that in vitro proliferation of CD48(-/-)CD4(+) T cells was impaired upon stimulation with CD48(-/-) macrophages. In vitro evidence for a modest macrophage functional defect was apparent because CD48(-/-) macrophages produced less tumor necrosis factor alpha and interleukin 12 than wild-type cells upon stimulation with lipopolysaccharide. Peritoneal macrophages also showed a defect in clearance of gram-negative bacteria in vitro. Treatment of the CD4(+)CD45RB(hi)-->Rag-2(-/-) mice or the wild-type BM-->tg26 mice with anti-CD48 (HM48-1) ameliorated development of colitis, even after its induction. CONCLUSIONS: Both CD48-dependent activation of macrophages and CD48-controlled activation of T cells contribute to maintaining the inflammatory response. Consequently, T cell-induced experimental colitis is ameliorated only when CD48 is absent from both T cells and antigen-presenting cells. Because anti-CD48 interferes with these processes, anti-human CD48 antibody treatment may represent a novel therapy for inflammatory bowel disease patients.

Animals↗
PubMed2005

Antigen-specific immune responses and liver histology in HIV and hepatitis C coinfection.

OBJECTIVE: To test the hypothesis that antigen-specific interferon (IFN)gamma responses are correlated with milder liver disease in subjects coinfected with HIV-1 and hepatitis C virus (HCV). DESIGN: Cellular immune responses were studied in a cohort with HIV/HCV coinfection (n = 107) who underwent liver biopsy. METHODS: We measured HCV-specific and recall responses in peripheral blood mononuclear cells using IFNgamma and interleukin (IL)-10 ELISpots, and correlated these immune responses with liver histology. The relationship of immunologic, virologic and clinical variables to inflammation and fibrosis was modeled using recursive partitioning. RESULTS: There were significant negative correlations between inflammatory scores and IFNgamma production in response to the HCV proteins core, NS5 and summed HCV responses. Lower fibrosis scores were also correlated with higher IFNgamma production in response to NS5 and summed HCV proteins. Higher IFNgamma production in response to Candida was significantly associated with lower inflammatory and fibrosis scores. In multivariable models, factors associated with severe fibrosis were lower IFNgamma responses to Candida and summed HCV proteins. Factors associated with severe inflammation were detectable HIV viral load and lower HCV viral load, while predictors of mild inflammation included undetectable HIV viral load and higher IFNgamma response to Candida. CONCLUSIONS: In this cohort of subjects coinfected with HIV and HCV, antigen-specific IFNgamma responses are correlated with milder inflammation and fibrosis. Immunological responses best predicted severity of fibrosis, while clinical variables and recall antigen responses best predicted severity of inflammation.

Adolescent↗
PubMed2005

Associations among clinical, immunological, and viral quasispecies measurements in advanced chronic hepatitis C.

The relationships among host immune and viral factors and the severity of liver disease due to hepatitis C virus (HCV) are poorly understood. Previous studies have focused on individual components of the immune response to HCV, often in relatively small numbers of patients. We measured HCV-specific lymphoproliferation (LP), intrahepatic cytotoxic T lymphocyte (CTL), and neutralizing antibody (NA) responses and HCV quasispecies (QS) diversity and complexity in a large cohort of subjects with advanced liver fibrosis (Ishak stages 3-6) on entry into the HALT-C (Hepatitis C Antiviral Long-term Treatment against Cirrhosis) trial. We correlated LP, CTL, NA, and QS results with clinical characteristics, including serum alanine aminotransferase (ALT), HCV RNA level, HCV genotype, and hepatic histopathology. LP, CTL, and NA responses were detected in 37%, 22%, and 22% of subjects tested, respectively. The only association that was statistically significant was higher mean serum ALT values in patients with detectable HCV-specific CTL responses (P = .03). In conclusion, immune responses to HCV and viral diversity showed little relationship to clinical or histological features at a single time point in this selected population of patients with advanced chronic hepatitis C for whom prior interferon treatment had failed.

Adult↗
PubMed2005

In vivo generation of oligoclonal colitic CD4+ T-cell lines expressing a distinct T-cell receptor Vbeta.

BACKGROUND & AIMS: Transplantation of wild-type (H-2k) bone marrow into tg epsilon26 mice (BM-->tg epsilon26) induces colitis, characterized by T-helper cell type 1 activation in the lamina propria. Here we determined whether pathogenic T-cell clones could be derived by serial adoptive transfers into healthy tg epsilon26 recipients, starting with the population of CD4+ cells in the mesenteric lymph nodes of BM-->tg epsilon26 mice. METHODS: CD4+ cells purified from the mesenteric lymph nodes of colitic BM-->tg epsilon26 mice were adoptively transferred into a second group of healthy tg epsilon26 recipients. Mesenteric lymph node CD4+ cells from the second group of mice were then used for consecutive transfers. Lamina propria CD4+ cells isolated from each mouse with colitis were analyzed for their cytokine profile and for their T-cell receptor Vbeta repertoire. RESULTS: CD4+ T cells maintained a dominant T-helper 1 phenotype after multiple transfers (< or = 8) into recipient tg epsilon26 mice. A single T-cell receptor Vbeta was enriched (as much as 90%) in 8 CD4+ T-cell lines: Vbeta8S3, Vbeta8S1/2, Vbeta10S1, or Vbeta14. Sequence analyses of the T-cell receptor Vbetas showed clonality or the presence of a very restricted number of clones within each line. Adoptive transfers of the oligoclonal lines into either C3H x Rag-/- or severe combined immunodeficiency disease mice (H-2k) also induced colitis, whereas transfers into BALB/c x Rag-/- or severe combined immunodeficiency disease mice (H-2d) did not. CONCLUSIONS: Colitis-inducing CD4+ T-helper 1 cell clones can be obtained by enrichment through sequential adoptive transfers of CD4+ cells from mesenteric lymph nodes. Distinct dominant T-cell receptor Vbetas in each cell line responded to antigens presented by class II major histocompatibility complex.

Adoptive Transfer↗
PubMed2004

Cadherin-11 provides specific cellular adhesion between fibroblast-like synoviocytes.

Cadherins are integral membrane proteins expressed in tissue-restricted patterns that mediate homophilic intercellular adhesion. During development, they orchestrate tissue morphogenesis and, in the adult, they determine tissue integrity and architecture. The synovial lining is a condensation of fibroblast-like synoviocytes (FLS) and macrophages one to three cells thick. These cells are embedded within the extracellular matrix, but the structure is neither an epithelium nor an endothelium. Previously, the basis for organization of the synovium into a tissue was unknown. Here, we cloned cadherin-11 from human rheumatoid arthritis (RA)-derived FLS. We developed L cell transfectants expressing cadherin-11, cadherin-11 fusion proteins, and anti-cadherin-11 mAb. Cadherin-11 was found to be expressed mainly in the synovial lining by immunohistologic staining of human synovium. FLS adhered to cadherin-11-Fc, and transfection of cadherin-11 conferred the formation of tissue-like sheets and lining-like structures upon fibroblasts in vitro. These findings support a key role for cadherin-11 in the specific adhesion of FLS and in synovial tissue organization and behavior in health and RA.

Animals↗
PubMed2004

I kappa B kinase 2 deficiency in T cells leads to defects in priming, B cell help, germinal center reactions, and homeostatic expansion.

Signal transduction from proinflammatory stimuli leading to NF-kappa B-dependent gene expression is mediated by the I kappa B kinase 2 (IKK2/IKK beta). Therefore, IKK2 has become an important drug target for treatment of inflammatory conditions. T cells, whose activation depends to a large extent on the activity of NF-kappa B transcription factors, play important roles in inflammation and autoimmunity. Ablation of IKK2 specifically in T cells in CD4cre/Ikk2(FL) mice allows their survival and activation by polyclonal stimuli in vitro, suggesting that IKK2 is dispensable for T cell activation. We report in this study that IKK2-deficient T cells expand efficiently in response to superantigen administration in vivo, but are completely deficient in recall responses, most likely due to inefficient priming. IKK2-deficient T cells provide suboptimal B cell help and fail to support germinal center reactions. Finally, IKK2 is essential for homeostatic expansion of naive T cells, reflected by the inability of IKK2-deficient T cells to induce colitis in lymphopenic hosts.

Animals↗
PubMed2004

Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is a cause of major complications in persons who are also infected with the human immunodeficiency virus (HIV). However, the treatment of HCV infection in such persons has been associated with a high rate of intolerance and a low rate of response. We conducted a multicenter, randomized trial comparing peginterferon plus ribavirin with interferon plus ribavirin for the treatment of chronic hepatitis C in persons coinfected with HIV. METHODS: A total of 66 subjects were randomly assigned to receive 180 microg of peginterferon alfa-2a weekly for 48 weeks, and 67 subjects were assigned to receive 6 million IU of interferon alfa-2a three times weekly for 12 weeks followed by 3 million IU three times weekly for 36 weeks. Both groups received ribavirin according to a dose-escalation schedule. At week 24, subjects who did not have a virologic response (those who had an HCV RNA level greater than or equal to 60 IU per milliliter) underwent liver biopsy, and medications were continued in subjects with either a virologic response or histologic improvement. RESULTS: Treatment with peginterferon and ribavirin was associated with a significantly higher rate of sustained virologic response (an HCV RNA level of less than 60 IU per milliliter 24 weeks after completion of therapy) than was treatment with interferon and ribavirin (27 percent vs. 12 percent, P=0.03). In the group given peginterferon and ribavirin, only 14 percent of subjects with HCV genotype 1 infection had a sustained virologic response (7 of 51), as compared with 73 percent of subjects with an HCV genotype other than 1 (11 of 15, P<0.001). Histologic responses were observed in 35 percent of subjects with no virologic response who underwent liver biopsy. CONCLUSIONS: In persons infected with HIV, the combination of peginterferon and ribavirin is superior to the combination of interferon and ribavirin in the treatment of chronic hepatitis C. These regimens may provide clinical benefit even in the absence of virologic clearance. The marked discrepancy in the rates of sustained virologic response between HCV genotypes indicates that strategies are needed to improve the outcome in persons infected with HCV genotype 1.

Adult↗
PubMed2004

Impaired IgA class switching in APRIL-deficient mice.

The tumor necrosis factor (TNF) family member APRIL binds to the receptors BCMA on B cells and TACI on B and T cells. To investigate the role of APRIL in immunity, we generated APRIL-deficient mice. APRIL(-/-) mice have normal T and B lymphocyte development, normal T and B cell proliferation in vitro, but increased numbers of CD44(hi)CD62L(lo) CD4(+) effector/memory T cells and increased IgG responses to T-dependent antigens. Serum IgA levels were significantly decreased, and serum IgA antibody responses to mucosal immunization with TD antigens and to type 1 T-independent antigens were impaired in APRIL(-/-) mice. APRIL by itself induced IgA as well as IgG1 isotype switching in CD40-deficient IgM(+)IgD(+) sorted B cells. These results suggest that APRIL down-regulates T cell-dependent antibody responses and promotes IgA class switching.

Animals↗
PubMed2004

Pegylated interferon alpha-2b plus ribavirin in the treatment of post-liver transplant recurrent hepatitis C.

BACKGROUND: Histological recurrence of the hepatitis C virus (HCV) occurs in the majority of persons transplanted for cirrhosis as a result of HCV. Herein we analyze our experience with the use of both conventional and pegylated (PEG) interferon (IFN) in combination with ribavirin (RBV) in liver transplant recipients with recurrent HCV. METHODS: Patients transplanted between 1992 and 2001 with post-orthotopic liver transplantation (OLT) histological recurrence of HCV, and who were treated with at least 6 months of IFN or PEG-IFN in combination with RBV were included in this analysis. A retrospective chart review was performed. RESULTS: A total of 31 patients were included. Fifteen were treated with IFN/RBV and 16 with PEG-IFN/RBV. Of these 16, 11 had been begun on IFN/RBV and were changed to PEG-IFN/RBV because of persistent viremia. Three patients (20%) in the IFN/RBV group and six patients (37.5%) in the PEG-IFN/RBV group experienced a virologic response (VR) on therapy. Of the six patients experiencing VR in the PEG-IFN/RBV group, three (50%) were IFN/RBV non-responders. There were two sustained VRs (SVR). The 65.6% of all patients experienced a biochemical response (BR) on therapy. Seven deaths were observed. Dose modifications of IFN or PEG-IFN (87.1%) and RBV (80.6%) and the requirement for hematopoietic growth factors were frequent. CONCLUSIONS: Treatment of recurrent HCV infection with combination of IFN or PEG-IFN and RBV produced an on-therapy VR in 29% and BR in 65% of patients. Hematologic toxicity and dose modifications were frequent. Our experience with antiviral therapy for HCV post-OLT remains disappointing but PEG-IFN + RBV appears to produce VR in a sizable portion of IFN + RBV non-responders.

Antiviral Agents↗
PubMed2004

Colitis is associated with thymic destruction attenuating CD4+25+ regulatory T cells in the periphery.

BACKGROUND & AIMS: Syngeneic bone marrow transplantation into the adult tgepsilon26 mouse results in severe wasting disease and colitis. On transplantation, the rudimentary thymus of the adult tgepsilon26 mouse repopulates briefly but quickly regresses in temporal association with the onset of colitis. The aim of this study is to test the hypothesis that treatment of colitis restores thymic capability to generate regulatory T cells (CD4+25+ T(R) cells). METHODS: Colitis was induced by bone marrow transplantation into adult irradiated tgepsilon26 mice. Colitis was prevented by 3 distinct modalities. CD4+25+ T cells were collected from both the thymus and spleen and studied for regulatory function by an in vitro suppression assay. RESULTS: CD4+25+ T(R) cells do not develop efficiently in the thymus of bone marrow transplanted adult tgepsilon26 mice, which have a developmental arrest affecting thymic epithelium. By contrast, the thymic epithelium of neonatal tgepsilon26 mice supports development of T(R) cells. Consequently, colitis develops only in adult transplanted mice but not in the neonatally transplanted mice. Treatment of colitis prevents destruction of the thymus of adult transplanted tgepsilon26 mice and T(R) cells are produced. CONCLUSIONS: The negative impact of colitis on T(R) development in the thymus, which was confirmed in a second model of colitis, has profound implications for the pathogenesis and treatment of human inflammatory bowel disease.

Animals↗
PubMed2004

Blocking inducible co-stimulator in the absence of CD28 impairs Th1 and CD25+ regulatory T cells in murine colitis.

Several autoimmune disease models depend on an imbalance in the activation of aggressor T(h)1 and CD4(+)CD25(+) regulatory T (T(reg)) cells. Here we compare the requirement for signals through the co-stimulatory molecules CD28 and inducible co-stimulator (ICOS) in chronic murine colitis, a model for inflammatory bowel disease. We used a colitis model in which disease-causing CD45RB(hi) T cells alone or in combination with CD4(+)CD25(+) T cells from either CD28-deficient or wild-type donors were transferred into T cell-deficient animals, half of which were treated with ICOS-blocking reagents. Blocking ICOS on the surface of CD28-deficient T(h)1 cells abrogated development of colitis, whereas blocking CD28 or ICOS alone had little to no effect on disease induction. In contrast to T(h)1 cells, regulatory T cell functioning depended mostly on CD28 signaling with only a minor contribution for ICOS. We conclude that CD28 and ICOS collaborate to development of murine colitis by aggressor T(h)1 cells, and that CD28 is required for T(reg) cells, which should caution against the use of CD28-blocking reagents in inflammatory bowel disease.

Animals↗
PubMed2003

Colonic epithelial functional phenotype varies with type and phase of experimental colitis.

BACKGROUND & AIMS: Colonic crypt elongation occurs during both chronic colitis and in the recovery phase of acute colitis. The impact of these alterations on epithelial cell functions is not fully defined. METHODS: DNA microarray analysis of freshly isolated colonic epithelial cells (CECs) from acute and chronic colitis was performed, and the results were confirmed by reverse transcription polymerase chain reaction. Localization of the selected molecules was examined by immunohistochemistry using newly generated antibodies. The function of selected molecules detected in this study was examined by administering the specific inhibitors in dextran sodium sulfate (DSS) colitis. RESULTS: Several detoxification-associated molecules, which contribute to prevent inflammation by regulating physiological balance under normal conditions, were markedly down-regulated, and anti-inflammatory molecules, which are not normally expressed, were up-regulated in the CEC under the chronic colitis. Among the detoxification-associated molecules, carbonic anhydrase IV was specifically down-regulated in CEC of Th2- but not Th1-mediated colitis. Functionally, inhibition of carbonic anhydrase activity led to the enhancement of recovery from DSS-induced acute colitis by directly stimulating CEC proliferation. Increased expression of regeneration-associated molecules such as regenerating gene-III gamma was detectable in the CEC of acute and chronic colitis but not in the recovery phase of colitis. The expression of this molecule was restricted in surface epithelium and upper crypts but not lower crypts. CONCLUSIONS: These studies suggest that functional alterations, which result in either the exacerbation or the suppression of colitis, coexist in the CEC during chronic colitis. CEC functions are likely to be differentially regulated in the context of the stage and mechanism of colitis.

Animals↗
PubMed2003

Recurrent allograft HCV presenting as acute cellular rejection: successful management with interferon and ribavirin alone.

Hepatitis C virus (HCV) is currently the leading indication worldwide for orthotopic liver transplantation. However, the majority of patients receiving transplant for HCV eventually develop histopathologic evidence of recurrent allograft HCV and approximately 10% die or require retransplantation within the first 5 post-operative years because of accelerated graft injury and cirrhosis. Traditional induction immunosuppressive regimens and intensive immunosuppression used to treat episodes of acute cellular rejection (ACR) are associated with enhanced viral replication and higher likelihood and severity of recurrent HCV. At our institution, therefore, we have used low-dose steroid therapy in an effort to limit HCV replication. However, this practice has been associated with frequent early presentations consistent with ACR. Here, we present three cases consistent with histologic ACR treated with conventional antirejection therapy that improved transiently, but evolved rapidly to progressive HCV. A fourth patient with a similar presentation experienced dramatic improvement in aminotransferases when treated solely with interferon and ribavirin. We propose that histologic characteristics traditionally associated with ACR may, in fact, represent early recurrent HCV as both processes share common immunopathogenetic mechanisms, or alternatively, that both ACR and recurrent HCV may be present simultaneously. We conclude that in cases suggestive of ACR, careful consideration should be given to treatment for recurrent HCV in lieu of or in concert with intensive immunosuppression.

Acute Disease↗
PubMed2003

Role of the CD5 molecule on TCR gammadelta T cell-mediated immune functions: development of germinal centers and chronic intestinal inflammation.

Although CD4(+) T cells form a major subset of TCRalphabeta T cells, only a small number of TCRgammadelta T cells express CD4. Factors contributing to the down-regulation of CD4(+) TCRgammadelta T cells have not been identified. The CD5 molecule is expressed on most TCRgammadelta T cells in the spleen, whereas only a few intestinal intraepithelial TCRgammadelta T cells express this molecule in wild-type mice and TCRbeta mutant (beta(-/-)) mice. Unexpectedly, in the present studies, the lack of CD5 led to a remarkable increase of a CD4(+) TCRgammadelta T cell subset in CD5(-/-)beta(-/-) mice. The CD4(+) TCRgammadelta T cells were also detectable in MHC II(-/-)CD5(-/-)beta(-/-) triple-mutant mice. This CD4(+) TCRgammadelta T cell subset provided help in Mycobacterium-induced germinal center (GC) formation and showed a T(h)-like cytokine profile. In contrast, CD5(+) TCRgammadelta T cells suppressed the CD4(+) TCRgammadelta T cell-mediated GC formation, presumably by eliminating this CD4(+) subset. Unlike intraepithelial gammadelta T cells, >30% of TCRgammadelta T cells in the colonic lamina propria (LP) expressed CD5. The lack of CD5 also led to increased numbers of CD4(+) TCRgammadelta T cells in the colonic LP and increased susceptibility to development of chronic colitis in beta(-/-) mice. Cell transfer studies suggest that CD5(+) TCRgammadelta T cells are capable of selectively eliminating CD4(+) TCRgammadelta T cells in the intestine. The CD4(+) TCRgammadelta T cells possess immune functions similar to CD4(+) TCRalphabeta T cells.

Animals↗