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Biomedical subjects

A W Hügin

Publications and source records attributed to A W Hügin.

At least 19 recordsLinked to original sources
PubMed2000

CD8(+) T cells secreting type 2 lymphokines are defective in protection against viral infection.

Effector T cells secreting type 1 and/or type 2 lymphokines (Tc1, Tc0, Tc2) were generated in vitro from CD8(+) T cells of mice with a transgenic TCR recognizing lymphocytic choriomeningitis virus (LCMV) glycoprotein to compare their effector function in vitro and in vivo. Tc1, Tc2, and Tc0 showed similar Fas- and perforin-mediated cytotoxicity in vitro. Upon adoptive transfer, Tc2 and Tc0 effectors were less efficient than Tc1 at controlling LCMV or recombinant vaccinia virus expressing the LCMV glycoprotein in vivo. Tc2 and Tc0 had decreased surface VLA-4 density and deficient activation-induced LFA-1/ICAM-1-dependent homotypic adhesion in vitro. Therefore, the reduced antiviral activity in vivo of Tc2 and Tc0 compared with Tc1 is not due to reduced cytotoxic activity or IFN-gamma secretion but may be explained by defective homing to the target organ due to decreased expression and/or lower activity of adhesion molecules.

Adoptive Transfer↗
PubMed2000

The autoimmune accelerating yaa mutation does not accelerate murine AIDS.

Murine acquired immunodeficiency syndrome (MAIDS) is characterized by lymphoproliferation, polyclonal B cell activation resulting in the production of autoantibodies, and a progressive immunodeficiency. These are all hallmarks of some autoimmune diseases. Yaa is a Y-chromosome-linked gene that accelerates autoimmune diseases in some autoimmune-prone strains of mice. To further elucidate a possible relationship with autoimmunity, the effect of the Yaa gene on MAIDS was investigated. Analysis of phenotypic and functional disease parameters revealed that Yaa does not accelerate MAIDS disease. This is probably due to the generalized activation of most or all lymphoid cells in MAIDS, which cannot be enhanced by the Yaa gene. This result is in accordance with the selective enhancing effect of the Yaa gene on the immune response against self and foreign antigens in a specific genetic background. It suggests that the autoimmune response associated with MAIDS is a secondary phenomenon. Interestingly, even in wild-type C57BL/6 mice, autoantibody production may contribute overproportionally to the hypergammaglobulinemia associated with MAIDS.

Animals↗
PubMed2000

Poxvirus as a vector to transduce human dendritic cells for immunotherapy: abortive infection but reduced APC function.

Dendritic cells (DC) are potent antigen-presenting cells (APC). Ongoing preclinical and clinical studies exploit this capacity for the immunotherapy of tumors. We tested vaccinia virus (VV) as a vector to transduce human DC. Immature and mature DC were prepared from blood monocytes and infected with (1) recombinant VV expressing GFP to analyze infection rates, virus replication in DC and the effect of infection on DC phenotype and (2) recombinant VV expressing beta-galactosidase (betaGAL) under the control of viral early, intermediate and late promoters to analyze the poxvirusdriven gene expression. While the infection rate in DC was comparable to a permissive fibroblast cell line, viral betaGAL gene expression was limited to early promoters. Genes under the control of virus late promoters were not expressed by VV in DC, indicating an abortive infection. VV infection selectively reduced the surface expression of the costimulatory molecule CD80 and the DC maturation marker CD83 on mature DC while other surface molecules including CD86 and MHC remained unchanged. In line with this finding, there was a pronounced reduction in the capacity of VV-infected DC to stimulate allogeneic or autologous T cells in mixed lymphocyte reactions. Furthermore, VV infection inhibited the maturation of immature DC after exposure to proinflammatory cytokines. These results indicate that VV-derived vectors may have complex effects on their target cells. In the case of DC used for immunotherapy, this may be detrimental to their function as potent APC and particularly their capacity to activate T helper cells.

Antigen Presentation↗
PubMed1999

Protective immunity from naive CD8+ T cells activated in vitro with MHC class I binding immunogenic peptides and IL-2 in the absence of specialized APCs.

Ag-specific CTL can protect against tumors and some viral infections and may be useful for adoptive immunotherapy. Here, we show that purified CD8+ T cells from naive C57BL/6 mice can be primed in vitro with different immunogenic peptides, which bind to MHC class I gene products, and IL-2 to exhibit specific and MHC-restricted effector function in vitro and in vivo protection against lymphocytic choriomeningitis virus infection and B16.F10 melanoma lung metastases. Limiting dilution assays in the absence of feeder cells with highly purified CD8+ T cells from two transgenic mice strains, each expressing a different MHC class I-restricted TCR, indicated that only peptide and IL-2, but not TCR- cells, were required for the growth of naive CD8+ T cells. These alternative minimal requirements for the activation and expansion of specific CD8+ T lymphocytes, without the need for professional APC, may be exploited for adoptive immunotherapy.

Adoptive Transfer↗
PubMed1999

An immunochemical focus assay to quantify replication competent and defective viruses involved in murine acquired immunodeficiency syndrome.

Murine acquired immunodeficiency syndrome is a lymphoproliferative disease with a concurrently developing immunodeficiency. The disease is induced after injection of supernatant of a chronically infected cell line that releases a mixture of two replication competent virus classes and a replication incompetent virus species responsible for pathogenicity. An immunochemical detection assay for virus infected foci on cell monolayers has been developed. This assay allows quantification of all three types of virus.

Animals↗
PubMed1997

Control of immunodeficiency and lymphoproliferation in mouse AIDS: studies of mice deficient in CD8+ T cells or perforin.

CD8+ T cells were previously shown to be important in preventing lymphoproliferation and immunodeficiency following infection of murine AIDS (MAIDS)-resistant mice with the LP-BM5 mixture of murine leukemia viruses. To further evaluate the mechanisms contributing to MAIDS resistance, we studied mice lacking CD8+ T cells or deficient in perforin due to knockout of the beta2-microglobulin (beta2M) or perforin gene, respectively. In contrast to wild-type, MAIDS-resistant controls, B10.A mice homozygous for the beta2M mutation and B10.D2 mice homozygous for the perforin mutation were diagnosed as having MAIDS by 5 to 8 weeks after infection by the criteria of lymphoproliferation, impaired proliferative responses to mitogens, and changes in cell populations as judged by histopathology and flow cytometry. Unexpectedly, there was no progression of lymphoproliferation through 24 weeks, even though immune functions were severely compromised. Expression of the defective virus responsible for MAIDS was enhanced in spleens of the knockouts in comparison with wild-type mice. These results demonstrate that perforin-dependent functions of CD8+ T cells contribute to MAIDS resistance but that other, non-CD8-dependent mechanisms are of equal or greater importance.

Animals↗
PubMed1995

Variability in the growth sustaining capacity of medium batches.

Medium batches, analysed in various spontaneous and mitogen induced proliferation assays, revealed heterogeneity in their growth promoting activity. This can critically affect test results and suggests that culture media can be a source of variability and problems in cell culture work. The manufacturers of media should broaden their quality control of medium batches.

3T3 Cells↗
PubMed1995

Contribution of B cell subsets to delayed development of MAIDS in xid mice.

C57BL/6 (B6) mice develop a syndrome of progressive lymphoproliferation and immunodeficiency, murine AIDS (MAIDS), when infected with an etiologic replication-defective virus termed BM5def. Induction of MAIDS requires the presence of CD4+ T cells and B cells. B6 mice with altered conventional B cell function and a deficit in CD5+ B cells due to the xid mutation develop disease with a greatly prolonged latency. The association of this mutation with resistance to MAIDS was confirmed in studies of P.xid mice. To test the hypothesis that conventional B cells are required for rapid induction of disease, B6.xid mice were injected with spleen cells from nude mice or were given bone marrow from aged donors. Both sets of recipients developed advanced disease by 10 weeks post infection, suggesting that resistance to MAIDS in xid mutants may be due to effects of B cells other than the CD5+ subset.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1994

Mice with an acquired immunodeficiency (MAIDS) develop a persistent infection after injection with Listeria monocytogenes.

Mice with a retrovirus-induced immunodeficiency were challenged with Listeria monocytogenes and resistance to this facultative intracellular bacterium was analyzed. Early innate immunity was unaltered or enhanced. Although immunodeficient mice had reduced bacterial titers after these reached their peak on Day 3, infection with L. monocytogenes generally resulted in a low-grade persistent infection and occasionally there was a delayed resolution of bacterial infection. Endogenous cytokines are important in the containment of bacteria as mice often developed a high load of bacteria or succumbed to infection in the absence of cytokine action. There was a substantial heterogeneity in disease after bacterial challenge which probably reflects the variability found in retrovirus-infected mice during the later stages of this immunodeficiency syndrome.

Animals↗
PubMed1994

The epidermal growth factor receptor is not a receptor for vaccinia virus.

It has been suggested that the epidermal growth factor receptor (EGFR) is a receptor for vaccinia virus. Other reports, although not specifically addressing this question, did not support such a role for the EGFR. We addressed this issue by using wild-type virus and a virus growth factor deletion mutant, as well as sets of cells that do not express EGFR or have been transfected with the human gene for EGFR. The expression of virus growth factor by vaccinia virus or of EGFR by the target cells influenced neither virus adsorption to cells nor penetration. These results indicate that the EGFR is not a receptor for vaccinia virus.

3T3 Cells↗
PubMed1993

Clearance of recombinant vaccinia virus expressing IL-2: role of local host immune responses.

Recombinant vaccinia viruses that express the human or mouse IL-2 gene are rapidly eliminated from immunoincompetent nude mice whereas control viruses cause lethal infections. To understand the role that virus-encoded IL-2 plays in attenuation, we investigated the mechanism of virus elimination from nude mice. Survival correlated with accelerated clearance of the virus. Treatment of infected mice with antibodies to eliminate NK cells or to neutralize interferon-gamma suggested that both are involved in the elimination of IL-2-producing virus. However, lytic activity of NK cells was not necessary as shown by studies with beige mice. Coinfection with IL-2-expressing and control virus resulted in lethal infection of nude mice, indicating the absence of significant systemic immunity. Focally acting immunopotentiating and chemotactic activities of virus-encoded IL-2 and host-derived interferon-gamma seem to confer protection in this novel approach to virus attenuation.

Animals↗
PubMed1993

Effects of immunization with the p12 proteins of LP-BM5 defective and ecotropic viruses on development of MAIDS.

Among murine leukemia viruses (MuLV) present in the LP-BM5 virus mixture, the agent etiologic for an acquired immunodeficiency syndrome (MAIDS) is replication defective, containing only a single open reading frame which includes all of gag. The Gag polyprotein encoded by the defective virus, termed BM5def, differs most in p12 from that of nonpathogenic ecotropic virus (BM5eco). As one approach to examining the role of p12 in disease, the ecotropic and defective virus forms of the protein, synthesized in bacteria, were used to immunize three strains of mice differing in their sensitivity to MAIDS. In each strain, both proteins elicited substantial antibody responses that were cross-reactive with either p12 and recognized the proteins as part of intact viral Gag polyproteins. Immunization with either p12 before infection with LP-BM5 viruses had no effect on the sensitivity or resistance of mice to MAIDS or on the extent of helper virus spread. The variant p12 of BM5def, when presented on its own, is thus not a crucial antigenic determinant of disease. Alternative mechanisms by which BM5def may contribute to MAIDS are discussed.

Amino Acid Sequence↗
PubMed1992

CD4+ subset regulation in viral infection. Preferential activation of Th2 cells during progression of retrovirus-induced immunodeficiency in mice.

Progressive lymphoproliferation and increasingly severe immunodeficiency are prominent features of a syndrome, designated mouse AIDS, which develops in susceptible strains of mice infected with the mixture of murine leukemia viruses, termed LP-BM5. Development of splenomegaly and lymphadenopathy, caused primarily by increases in B cell immunoblasts, requires the presence of CD4+ T cells and is assumed to be mediated by lymphokines produced by these cells inasmuch as progression of disease is markedly inhibited by treatment of infected mice with cyclosporin A. Studies of spleen cells from infected mice revealed spontaneous production of cytokines (IFN-gamma, IL-2, IL-4, IL-5, and IL-10) characteristic of Th0 (or a mixture of Th1 and Th2) T helper cells at 1 wk after infection. At later times, IFN-gamma and IL-2, characteristic products of Th1 helper clones, were expressed poorly, either spontaneously or after stimulation of cells with Con A. In contrast, IL-4, IL-5, IL-6, and IL-10, cytokines typically synthesized by Th2 cells, were produced in response to Con A or spontaneously through 18 wk post-infection. Increased serum IgE levels and enhanced IL-10 mRNA expression were consistent with expression of Th2 cytokines at biologically significant levels in vivo. Selective depletion of T cell subsets before stimulation with Con A showed that CD4+ T cells were the primary source of IL-2, IL-4, IL-10, and, to a lesser extent, IFN-gamma in spleens and lymph nodes of normal or infected mice. These results suggest that persistent activation of CD4+ T cells with the lymphokine profile of Th2 helper clones is responsible for chronic B cell stimulation, down-regulation of Th1 cytokines, and impaired CD8+ T cell function in mouse AIDS. This provides the first demonstration that, like many parasitic infections, viruses encoding potent antigenic stimuli can markedly affect the balance of Th subset expression.

Animals↗
PubMed1991

A virus-encoded "superantigen" in a retrovirus-induced immunodeficiency syndrome of mice.

The development of an immunodeficiency syndrome of mice caused by a replication-defective murine leukemia virus (MuLV) is paradoxically associated with a rapid activation and proliferation of CD4+ T cells that are dependent on the presence of B cells. The responses of normal spleen cells to B cell lines that express the defective virus indicated that these lines express a cell surface determinant that shares "superantigenic" properties with some microbial antigens and Mls-like self antigens. This antigen elicited a potent proliferative response that was dependent on the presence of CD4+ T cells and was associated with selective expansion of cells bearing V beta 5. This response was markedly inhibited by a monoclonal antibody specific for the MuLV gag-encoded p30 antigen.

Animals↗
PubMed1990

B cells are required for induction of T cell abnormalities in a murine retrovirus-induced immunodeficiency syndrome.

The role of B cells in induction of phenotypic and functional abnormalities of T cells in a murine retrovirus-induced immunodeficiency syndrome, MAIDS, was evaluated in mice depleted of mature B cells from birth with anti-IgM antibodies (mu-suppressed) and infected at 4 wk of age. Multicolor FACS analyses of CD4+ T cell subsets showed that development of phenotypic abnormalities of these cells at 9 wk after infection was completely inhibited by mu-suppression. Furthermore, induction of impaired proliferative responses to Con A and alloantigens and CTL responses to alloantigens was fully blocked in antibody-treated animals. The extent of virus replication was comparable in spleens of untreated and mu-suppressed mice. Retroviral induction of T cell dysfunction in MAIDS is thus dependent on the presence of B cells, and high level virus expression in mice without B cells has little or no effect on T cell function.

Animals↗