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Adrian F Ochsenbein

Publications and source records attributed to Adrian F Ochsenbein.

7 recordsLinked to original sources
PubMed2006

Elimination of chronic viral infection by blocking CD27 signaling.

Neutralizing antibody (nAb) responses to lymphocytic choriomeningitis virus (LCMV) in mice and immunodeficiency virus and hepatitis C virus in humans are usually weak and slow to develop. This may be the result of structural properties of the surface glycoprotein, a low frequency of B cells with neutralizing specificity, and the necessity of prolonged affinity maturation of specific nAbs. In this study, we show that during LCMV infection, CD27 signaling on CD4+ T cells enhances the secretion of interferon-gamma and tumor necrosis factor-alpha. These inflammatory cytokines lead to the destruction of splenic architecture and immunodeficiency with reduced and delayed virus-specific nAb responses. Consequently, infection with the otherwise persistent LCMV strain Docile was eliminated after CD27 signaling was blocked. Our data provide a novel mechanism by which LCMV avoids nAb responses and suggest that blocking the CD27-CD70 interaction may be an attractive strategy to prevent chronic viral infection.

Adoptive Transfer↗
PubMed2006

Imatinib mesylate selectively impairs expansion of memory cytotoxic T cells without affecting the control of primary viral infections.

Imatinib mesylate (imatinib) is a potent inhibitor of defined tyrosine kinases (TKs) and is effective in the treatment of malignancies characterized by constitutive activation of these TKs such as chronic myeloid leukemia and gastrointestinal stromal tumors. TKs also play an important role in T-cell receptor (TCR) signal transduction. Inhibitory as well as stimulating effects of imatinib on T cells and dendritic cells have been described. Here, we analyzed the effects of imatinib treatment on antiviral immune responses in vivo. Primary cytotoxic T-cell (CTL) responses were not impaired in imatinib-treated mice after infection with lymphocytic choriomeningitis virus (LCMV) or after immunization with a tumor cell line expressing LCMV glycoprotein (LCMV-GP). Similarly, neutralizing antibody responses to vesicular stomatitis virus (VSV) were not affected. In contrast, secondary expansion of LCMV-specific memory CTLs was reduced in vitro and in vivo, resulting in impaired protection against reinfection. In addition, imatinib treatment delayed the onset of diabetes in a CTL-induced diabetes model. In summary, imatinib treatment in vivo selectively inhibits the expansion of antigen-experienced memory CTLs without affecting primary T- or B-cell responses. Therefore, imatinib may be efficacious in the suppression of CTL-mediated immunopathology in autoimmune diseases without the risk of acquiring viral infections.

Animals↗
PubMed2005

Immunological ignorance of solid tumors.

Many peripheral solid tumors such as sarcomas and carcinomas express tumor-specific antigens that can serve as targets for immune effector T cells. Nevertheless, the immune surveillance against clinically manifest carcinomas and sarcomas seems relatively inefficient. Naïve cytotoxic T cells are activated exclusively in secondary lymphoid organs including the spleen and lymph nodes. Tumor antigen might be either cross-presented to naïve cytotoxic T cells by professional antigen-presenting cells (pAPC), or presented directly by tumor cells that migrated to secondary lymphoid organs. Direct priming is quite inefficient during early tumor development because metastasis to lymphoid organs is usually limited to advanced stage diseases. Similarly, the process of cross-priming by pAPC seems to depend on relatively large antigen amounts and on maturation stimuli for dendritic cells, and both requirements may be limiting during initial tumorigenesis. Therefore, the immunosurveillance of solid tumors may fail because they are ignored for too long by the immune system. However, these situations may prove promising for the induction of tumor-specific T cell immunity by vaccination, as the T cell repertoire against these antigens has a naïve phenotype and is not yet affected by tolerance mechanisms.

Animals↗
PubMed2005

Virus-induced polyclonal B cell activation improves protective CTL memory via retained CD27 expression on memory CTL.

Different viruses elicit distinct phenotypes of memory cytotoxic T lymphocytes (CTL). This is reflected in differential expression of homing receptors and costimulatory molecules like CD27. Memory CTL retained CD27 following lymphocytic choriomeningitis virus (LCMV) infection, but not after immunization with recombinant vaccinia virus or tumor cells expressing LCMV glycoprotein. Stable CD27 expression on memory CTL required ligation by CD70 expressed on polyclonally activated B cells during the contraction phase. The functional consequence of CD27 expressed on virus-specific CTL was analyzed in CD27-deficient mice. LCMV infection of CD27(-/-) mice revealed that primary CTL activation and expansion as well as elimination of the virus were independent of CD27 expression. In contrast, ligation of CD27 on memory CTL upon secondary antigen encounter increased clonal expansion and improved protection against re-infection. This points to novel B cell-CTL interactions during viral infection and to a beneficial role of polyclonal B cell activation that represents a characteristic of murine LCMV, human immunodeficiency virus and human hepatitis B and C virus infection.

Animals↗
PubMed2004

CD27 expression promotes long-term survival of functional effector-memory CD8+ cytotoxic T lymphocytes in HIV-infected patients.

Human immunodeficiency virus (HIV)-specific CD8(+) T cells persist in high frequencies in HIV-infected patients despite impaired CD4(+) T helper response to the virus, but, unlike other differentiated effector cytotoxic T lymphocytes, most continue to express the tumor necrosis factor receptor family member CD27. Because the ligand for CD27 (CD70) is also overexpressed in HIV-infected hosts, we examined the nature of expression and potential functional consequences of CD27 expression on HIV-specific CD8(+) T cells. Analysis of CD27(+) and CD27(-) T cells derived from the same HIV-specific clone revealed that retention of CD27 did not interfere with acquisition of effector functions, and that after T cell receptor stimulation, CD27(+) cells that concurrently were triggered via CD27 exhibited more resistance to apoptosis, interleukin 2 production, and proliferation than CD27(-) T cells. After transfer back into an HIV-infected patient, autologous HIV-specific CD27(-) T cells rapidly disappeared, but CD27(+) T cells derived from the same clone persisted at high frequency. Our findings suggest that the CD27-CD70 interaction in HIV infection may provide CD27(+) CD8(+) T cells with a survival advantage and compensate for limiting or absent CD4(+) T help to maintain the CD8 response.

Adoptive Transfer↗
PubMed2002

Principles of tumor immunosurveillance and implications for immunotherapy.

Although antigen loss variants, major histocompatibility (MHC) class I down-regulation, or the expression of inhibitory molecules may explain the failure of immunosurveillance against some tumors, this seems not to apply for many other solid peripheral or lymphohematopoietic tumors. Why then is immunosurveillance so ineffective and can it be improved? This review focuses on one important aspect of tumor immunity, namely the relevance of antigen dose and localization. Immune responses in vivo are induced in organized lymphoid tissues, i.e., in lymph nodes and spleen. The antigen dose that reaches secondary lymphoid organs over time is a crucial parameter that drives antiviral and antitumoral immune responses. Tumors use various strategies to prevent efficient presentation of their antigens in lymphoid organs. A major obstacle to the induction of an endogenous tumor-specific cytotoxic T lymphocyte (CTL) response is the inefficient presentation of tumor antigen on MHC class I molecules of professional antigen-presenting cells. Peripheral solid tumors that develop outside lymphoid organs are, therefore, often ignored by the immune system. In other situations, tumors - especially of lymphohematopoietic origin - may tolerize specific CTLs. Understanding tumor immunosurveillance is key to the design of efficient antitumor vaccines. Attempts to improve immunity to tumors include vaccination strategies to (a) provide the tumor antigen to secondary lymphoid organs using recombinant viruses or dendritic cells as carriers, (b) express costimulatory signals on tumor cells, or (c) improve the efficiency of cross-priming.

Animals↗