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Biomedical subjects

J W Hartley

Publications and source records attributed to J W Hartley.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1995

Impact of MHC class I gene on resistance to murine AIDS.

Development of murine AIDS in mice following infection with LP-BM5 murine leukaemia virus (MuLV) is highly strain dependent, with strain differences determined by genes within and outside H-2. Among H-2 genes, the Dd gene is the most closely associated with resistance to LP-BM5 MuLV infection. However, the Dd-mediated resistance is highly influenced by outside H-2 genes, i.e. A lineage strains are more resistant than mice strains of B6/B10 lineage. In this study, the mice having BALB background were analysed and, similarly to A lineage mice, only Dd gene products were found to be required to provide resistance to LP-BM5 MuLV infection. Furthermore, BALB/c Kh mice bearing both Dd and Ld genes clearly showed obviously higher resistance than BALB/c-H-2dm2 mice solely having the Dd gene. In addition, in the long-term observation of the effect of the Dd gene on B6/B10 background mice, D8 mice having the Dd gene as a transgene and expressing a high level Dd gene product showed higher resistance than naturally recombinant B10.A(18R) mice. These results suggest that the MAIDS resistance associated with the D end loci is dependent on the level of expression of an MHC class I gene.

Animals↗
PubMed1995

Effects of exogenous, nonleukemogenic, ecotropic murine leukemia virus infections on the immune systems of adult C57BL/6 mice.

Mouse AIDS (MAIDS) develops in mice infected with a mixture of replication-competent ecotropic and mink lung cell focus-inducing murine leukemia viruses and an etiologic replication-defective virus. Helper viruses are not required for induction of MAIDS, but the time course of disease is accelerated in their presence. To understand the possible contributions of ectropic murine leukemia viruses to MAIDS pathogenesis, we biologically cloned a series of viruses from the MAIDS-inducing LP-BM5 virus mixture. These viruses were examined for replication in tissues of infected mice and for effects on the immune system. All virus stocks replicated efficiently in mice. Infected animals showed slight lymphadenopathy and splenomegaly due primarily to B-cell proliferation associated with differentiation to immunoglobulin secretion resulting in twofold increases in serum immunoglobulin M levels; however, B-cell responses to helper T-cell-independent antigens were increased rather than decreased as in MAIDS. Analyses of CD8+ T-cell function showed that cytotoxic T-lymphocyte responses to alloantigens were comparable in control and infected mice. Finally, we showed that infection resulted in enhanced expression of transcripts for interleukin-10, interleukin-4, and gamma interferon. These cytokines can all contribute to B-cell activation and may promote the expansion of a target cell population for the MAIDS defective virus.

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↗
PubMed1993

Infection of human cells with murine amphotropic replication-competent retroviruses.

Replication of the murine wild-type 4070A amphotropic retrovirus and a recombinant amphotropic replication-competent retrovirus arising from the PA12 packaging cell line varied considerably among the primate cell types tested. Medium from infected primate fibroblasts and endothelial cells contained the highest viral titers [10(4)-10(5) focus-forming units (ffu)/ml], while most hematopoietic cell lines, such as K562 and MOLT4, were associated with viral titers in the range of 10(3)-10(4) ffu/ml. Interestingly, HTLV-1-transformed T cell lines (TJF-2 and HM) and primary tumor infiltrating lymphocytes (TIL) had very low viral titer (0-10(1) ffu/ml). The low production of virus was not due to low infectivity and, in contrast to the virus, retroviral vectors were expressed without difficulty. Because screening for replication-competent retrovirus (RCR) is an important component of human retroviral-mediated gene therapy clinical protocols, a variety of assays were tested for their ability to detect RCR in virus-exposed cell lines. A biologic assay (3T3 amplification) and polymerase chain reaction (PCR) for the 4070A viral envelope are effective screening methods for RCR, even in cell lines associated with low virus production.

Animals↗
PubMed1993

Retrovirus-induced lymphoproliferation as a model for developing diagnostic criteria for malignant lymphoma in mice.

Several methods for evaluating lymphoproliferative lesions in mice were compared. The model systems included spontaneous lymphomas arising in CWD mice and NFS mice congenic for ecotropic murine leukemia virus (MuLV) induction loci and a series of transplants in mice with severe combined immunodeficiency disease mutation of cells derived from mice infected with LP-BM5 MuLV. Primary lymphomas and donor tissues and transplants were examined using histopathology, flow cytometry, and Southern blot analysis of DNA for rearrangements of immunoglobulin and T-cell receptor genes and for viral integrations. The use of flow cytometric analysis, to establish cell lineage and define population size, and DNA analysis, for cell lineage and clonality determination, allowed the identification of malignant lymphoproliferations. Histologic evaluation did not define clonal populations of particular lineage but did provide other indications of malignancy such as invasiveness and presence of a dominant morphologic cell type. Thus, the precision of diagnosis of mouse lymphomas can be considerably enhanced by augmenting histopathologic examination with antigenic and molecular characterizations that can define malignant populations.

Animals↗
PubMed1993

High expression of NK-1.1 antigen is induced by infection with murine AIDS virus.

Spleen cells from mice infected with LP-BM5 MuLV, a causative agent of murine acquired immunodeficiency syndrome (MAIDS), were tested for frequency of NK-1.1+ cells and natural killer (NK) activity. During the first 3 weeks following infection, NK activity was well conserved, but by 9-12 weeks post-infection (p.i.), killer activity was depressed; however, the frequency of NK-1.1+ cells increased within 4 weeks of infection and remained elevated thereafter, even following the decline in functional killing activity. Since the absolute number of NK-1.1+ cells increased after infection, the ability of each NK-1.1+ cell to kill the targets seems drastically impaired. Extraordinary expansion of NK-1.1-positive cells was induced by infection with LP-BM5-defective virus (BM5def), a crucial element for MAIDS induction, but not with a helper non-pathogenic virus. With advance of MAIDS the NK-1.1 antigen (Ag) was preferentially expressed on B220+ and Thy-1+ cells, in contrast to CD4+ and CD8+ cells, and among activated large cells a higher proportion was NK-1.1+ than NK-1.1-. Mice with graft-versus-host disease (GVHD) due to class II major histocompatibility complex (MHC) Ag disparity showed a high frequency of NK-1.1 expression in association with other phenotypic alterations, very similar to those seen in mice with MAIDS. In contrast, B6-lpr/lpr mice developed similar activation of B cells but did not exhibit enhanced expression of the NK-1.1 marker. Thus, enhanced expression of the NK-1.1 Ag might be associated with chronic activation of lymphocytes through a common but not universal pathway.

Animals↗
PubMed1993

Early divergence of erythroid lineage suggested by gene rearrangements in mouse hematopoietic neoplasms.

A total of 113 primary murine hematopoietic neoplasms, including those of erythroid, granulocytic, and T and B lymphoid lineages, were examined for rearrangement of immunoglobulin heavy (IgH) and kappa light chain (IgK) and T cell receptor beta and gamma (TcR-beta and TcR-gamma) genes. There was a total absence of Ig or TcR gene rearrangements in erythroid leukemias. In contrast, overlaps of IgH rearrangements were observed in myeloid and T cell as well as B cell neoplasms. In a minority of B cell lymphomas, rearrangements of TcR-beta or TcR-gamma genes were detected. This evidence of shared recombinase activity for myeloid, T cell, and B cell-lineage tumors and the absence of such activity in erythroid tumors suggest early divergence of the erythroid pathway.

Animals↗
PubMed1992

Impaired calcium mobilization in CD4+ and CD8+ T cells in a retrovirus-induced immunodeficiency syndrome, murine AIDS.

After infection with LP-BM5 murine leukemia viruses, susceptible strains of mice develop a severe and progressive immunodeficiency disease, termed murine AIDS (MAIDS), features of which include markedly impaired T cell response to mitogens or specific Ag stimulation and decreased production of IL-2. Since an elevation of intracellular calcium concentration resulting from binding of Ag to the TCR is associated with IL-2 production, T cells from mice either uninfected or infected with LP-BM5 murine leukemia viruses were examined by a calcium mobilization assay. Both CD4+ and CD8+ T cells from infected mice manifested impaired calcium mobilization responses upon in vitro stimulation with anti-CD3 mAb or Con A. The abnormalities appeared early after virus inoculation and showed no difference in time course between subsets of T cells. Frequencies of prestimulation calcium-positive cells among both CD4+ and CD8+ cells in mice with MAIDS were significantly higher than those for uninfected mice. These abnormalities were associated with presence of the MAIDS-inducing defective virus genome, but were not induced by infection of mice genetically resistant to development of MAIDS or with nonpathogenic helper murine leukemia virus, a virus component that induces high spontaneous proliferation of T cells, even in MAIDS-resistant mice.

Animals↗
PubMed1992

Analysis of role of CD8+ T cells in resistance to murine AIDS in A/J mice.

The mixture of retroviruses termed LP-BM5 murine leukemia virus (MuLV) contains a replication-defective genome (BM5def), the crucial element for induction of murine AIDS (MAIDS), as well as helper B-tropic ecotropic and mink cell focus-forming MuLV. Among Fv-1b mouse strains, C57BL mice are sensitive to infection by these viruses and to development of MAIDS, but A/J mice are highly resistant to all viral components and to induction of disease. Inasmuch as previous genetic studies indicated a major role in susceptibility for the H-2D locus within the MHC, the effect of CD8+ T cells in A/J resistance to MAIDS was analyzed by depletion of this subset using mAb. A/J mice treated with anti-CD8 mAb beginning soon after inoculation with LP-BM5 MuLV developed disease within 5 wk after virus inoculation. Histopathologic and flow cytometry alteration of tissues and cells from the mAb-treated mice were identical to those seen in virus-infected MAIDS-sensitive strains, and assays for MuLV demonstrated high-level expression of ecotropic MuLV and integration of BM5def. Parallel studies of A/J mice treated with anti-CD4 mAb after infection revealed enhanced expression of ecotropic MuLV but no integration of BM5def, and no signs of MAIDS were detected. These observations indicate that CD8+ T cells are critical in the resistance of A/J mice to LP-BM5 MuLV replication and development of disease and suggest that CD4+ T cells play a role in regulation of ecotropic virus replication.

Animals↗
PubMed1992

Central nervous system infection in a murine retrovirus-induced immunodeficiency syndrome.

Astrocyte-enriched primary glial cultures (AGC) from C57BL/6 mice were found to be highly susceptible to infection with the replication competent components of LP-BM5, consisting of the ecotropic and mink cell focus-inducing (MCF) helper murine leukemia viruses (MuLVs). The presence in infected AGC of defective LP-BM5 MuLV genome, a critical component for induction of the disease referred to as murine AIDS, was confirmed by Southern blot hybridization using a probe reactive with the p12 gag sequence of the 4.9 kb defective genome. Electron microscopic studies demonstrated C-type retrovirus particles in both astrocytes and microglial cells. In vivo studies demonstrated that the ecotropic MuLVs and the defective genome could be detected within AGC obtained form either 14-day-old mice following intraperitoneal inoculation or 7-day-old mice following intracranial inoculation. These findings suggest that: (1) the central nervous system (CNS) infection is present at an early stage in murine AIDS, (2) both astrocytes and microglial cells are possible CNS targets in which helper MuLVs replicate, and (3) these cells can harbor the defective genome that is a critical component for disease induction.

Animals↗
PubMed1992

Opportunistic infections and retrovirus-induced immunodeficiency: studies of acute and chronic infections with Toxoplasma gondii in mice infected with LP-BM5 murine leukemia viruses.

Mice infected with LP-BM5 murine leukemia viruses develop a syndrome, termed mouse AIDS (MAIDS), characterized by increasingly severe immunodeficiency and progressive lymphoproliferation. Virus-infected mice were examined for the ability to resist acute infection and to control chronic infection with the protozoan Toxoplasma gondii, a major opportunistic pathogen of individuals infected with human immunodeficiency virus. Mice infected with the retroviruses for 2 or 4 weeks responded normally to challenge with the parasite, but mice inoculated with the protozoan 8 or 12 weeks after viral infection died with acute disease due to T. gondii. Increased sensitivity to acute infection was associated with a reduced ability to produce gamma interferon (IFN-gamma) and with established changes in CD4+ T-cell function. Mice latently infected with T. gondii and then inoculated with the retrovirus mixture were found to reactivate the parasite infection, with 30 to 40% of dually infected animals dying between 5 and 16 weeks after viral infection. Reactivation was associated with reduced proliferation and impaired production of IFN-gamma in response to stimulation with soluble T. gondii antigens or to concanavalin A. Continuing resistance to lethal reactivation in the remaining mice was shown to require CD8+ T cells and expression of IFN-gamma. In addition, it was found that chronic infection with T. gondii altered the course of MAIDS by inhibiting the progression of splenomegaly and immunodeficiency and reducing the expression of both the helper and etiologic defective viruses. These results support previous studies which indicate that infection with T. gondii is controlled by synergistic interactions between CD4+ and CD8+ T cells, the functions of which are progressively impaired during the course of MAIDS.

Acute Disease↗