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Biomedical subjects

M B Oldstone

Publications and source records attributed to M B Oldstone.

At least 127 records · Page 7Linked to original sources
PubMed1994

Pancreatic islet production of murine interleukin-10 does not inhibit immune-mediated tissue destruction.

IL-10 inhibits macrophage-dependent antigen presentation, cytokine production, and generation of allospecific cells in vitro. These findings have lead to the widespread expectation that IL-10 may be a useful immunosuppressive agent to inhibit allograft rejection or autoimmunity in vivo. We used two experimental paradigms to study effects of murine IL-10 on in vivo immune responses. First, fetal pancreata or adult pancreatic islets from transgenic mice expressing IL-10 in pancreatic beta cells (Ins-IL-10 mice) were grafted across the MHC barrier to examine if IL-10 could inhibit allograft rejection. Second, Ins-IL-10 mice were crossed with transgenic mice expressing lymphocytic choriomeningitis virus (LCMV) antigens in pancreatic beta cells. These mice were infected with LCMV to elicit autoimmune diabetes, allowing us to ask if IL-10 protects islets from autoimmune destruction. We observed that allografts from IL-10-transgenic donors were rejected with comparable kinetics to the rejection of control nontransgenic allografts, indicating that IL-10 does not inhibit allograft rejection. After LCMV infection, IL-10 and LCMV antigen double transgenic mice developed diabetes earlier than LCMV antigen single transgenic littermates, suggesting that IL-10 does not inhibit islet antigen presentation or recognition. Our results contrast to in vitro observations and suggest that IL-10 cannot overcome immune-mediated tissue destruction within the pancreas.

Animals↗
PubMed1994

Islet inflammation and hyperplasia induced by the pancreatic islet-specific overexpression of interleukin-6 in transgenic mice.

Interleukin-6 (IL-6) is thought to be involved in the pathogenesis of autoimmune insulin-dependent diabetes mellitus. To examine this possibility, we developed two lines of transgenic mice (termed RIP-IL6) which overexpressed IL-6 in the pancreatic islet beta cells. RIP-IL6 mice, while showing a modest reduction in body weight, remained normoglycemic throughout their lives. Furthermore, insulin gene expression and glucose tolerance were similar to non-transgenic littermates. Histopathological examination revealed significant changes in the pancreas but not other organs of RIP-IL6 animals, with marked alterations in the architecture of the islets, in the islet cells, and in surrounding tissues. In younger animals these changes included islet hyperplasia with increased mitotic figures, neo-ductular formation, fibrosis, and a scant mononuclear cell infiltration (insulitis). In addition, immunostaining for islet hormones revealed changes in both the topography and density of beta and alpha cells. In older RIP-IL6 mice, a more florid insulitis was observed which was composed predominantly of B220+ B lymphocytes and, to a lesser extent, Mac-1+ macrophages and CD4+ and CD8+ T lymphocytes. Immunostaining for mouse IgG revealed significant numbers of plasma cells in the peri-islet infiltrates, which suggested that IL-6 induced differentiation of the recruited B lymphocytes. Therefore, islet overexpression of IL-6 produces a complex, localized host response implicating this cytokine in not only inflammatory processes that occur in autoimmune diabetes but also cellular neogenesis, which may indicate a role in tissue repair.

Animals↗
PubMed1993

CD2-deficient mice generate virus-specific cytotoxic T lymphocytes upon infection with lymphocytic choriomeningitis virus.

The major host response to many viral infections is the generation of virus-specific CTL. Many protein molecules on the surfaces of both CTL and target cells interact to mediate adhesion of the cells and generate signals that lead to T cell activation and proliferation of virus-specific CTL that then mediate lysis of infected cells. One such protein, CD2, has been shown to increase the binding affinity of CTL to infected cells, and, in addition, enhance CTL activation signals. To determine whether virus-specific CTL could be generated in the absence of CD2, mice lacking a functional CD2 gene were infected with lymphocytic choriomeningitis virus (LCMV), and the responses to the virus were monitored. CD2-deficient mice infected intracerebrally with LCMV died as a consequence of CTL-mediated choriomeningitis, similar to control littermates. Additionally, CD2-deficient mice inoculated i.p. with LCMV cleared the infection by 2 wk postinfection, as did control mice. Viral clearance in these mice was shown to be due to the generation of a vigorous virus-specific MHC-restricted CTL response. Finally, to determine whether CD2 is essential for the generation of memory CTL, we examined the ability of CD2-deficient mice to generate memory CTL to LCMV and found normal memory CTL responses. Our results indicate that CD2 is not required for the generation of an LCMV-specific CTL response in vivo, nor is CD2 required for the maintenance or activation of memory CTL.

Animals↗
PubMed1993

Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6.

Cytokines are thought to be important mediators in physiologic and pathophysiologic processes affecting the central nervous system (CNS). To explore this hypothesis, transgenic mice were generated in which the cytokine interleukin 6 (IL-6), under the regulatory control of the glial fibrillary acidic protein gene promoter, was overexpressed in the CNS. A number of transgenic founder mice and their offspring exhibited a neurologic syndrome the severity of which correlated with the levels of cerebral IL-6 expression. Transgenic mice with high levels of IL-6 expression developed severe neurologic disease characterized by runting, tremor, ataxia, and seizure. Neuropathologic manifestations included neuro-degeneration, astrocytosis, angiogenesis, and induction of acute-phase-protein production. These findings indicate that cytokines such as IL-6 can have a direct pathogenic role in inflammatory, infectious, and neurodegenerative CNS diseases.

Animals↗
PubMed1993

Autoimmune diabetes can be induced in transgenic major histocompatibility complex class II-deficient mice.

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease marked by hyperglycemia and mononuclear cell infiltration of insulin-producing beta islet cells. Predisposition to IDDM in humans has been linked to the class II major histocompatibility complex (MHC), and islet cells often become aberrantly class II positive during the course of the disease. We have used two recently described transgenic lines to investigate the role of class II molecules and CD4+ T cells in the onset of autoimmune insulitis. Mice that are class II deficient secondary to a targeted disruption of the A beta b gene were bred to mice carrying a transgene for the lymphocytic choriomenigitis virus (LCMV) glycoprotein (GP) targeted to the endocrine pancreas. Our results indicate that class II-deficient animals with and without the GP transgene produce a normal cytotoxic T lymphocyte response to whole LCMV. After infection with LCMV, GP-transgenic class II-deficient animals develop hyperglycemia as rapidly as their class II-positive littermates. Histologic examination of tissue sections from GP-transgenic class II-deficient animals reveals lymphocytic infiltrates of the pancreatic islets that are distinguishable from those of their class II-positive littermates only by the absence of infiltrating CD4+ T cells. These results suggest that in this model of autoimmune diabetes, CD4+ T cells and MHC class II molecules are not required for the development of disease.

Animals↗
PubMed1993

Virus-induced immunosuppression. 1. Age at infection relates to a selective or generalized defect.

Viruses that persist must develop strategies to escape immunologic surveillance in order to survive. Investigation of lymphocytic choriomeningitis virus (LCMV)-induced persistence has indicated that this virus avoids immune clearance mainly by aborting the viral specific cytotoxic T lymphocyte (CTL) response, a response that is necessary for terminating viral infection. This study demonstrates that persistence established in immunologically immature newborns selectively depletes the LCMV-specific CTL response but does not hinder CTL responses to the RNA and DNA viruses influenza, vaccinia, or herpes simplex. In contrast, persistence established in immunologically mature adults leads not to selective but rather to generalized immunosuppression during which CTL responses to LCMV, influenza, vaccinia, and herpes simplex viruses are all ablated or down-regulated. These results indicate that the state of maturity of the immune system at the time of virus-induced immunosuppression can result in two distinct phenotypes. These observations may account for the differing patterns of infection caused by hepatitis B virus or human immunodeficiency virus initiated in the neonatal period compared to that initiated in adulthood.

Aging↗
PubMed1993

Cytotoxic T lymphocytes cleanse viral gene products from individually infected neurons and lymphocytes in mice persistently infected with lymphocytic choriomeningitis virus.

Lymphocytes and/or monocytes/macrophages carry viral genetic information in most, if not all, persistent and latent viral infections, and serve as potential reservoirs for maintaining or reintroducing the infection. Similarly, neurons can be persistently infected by several DNA and RNA viruses whose continued presence can alter the physiologic function of these cells, leading to disorders in neurotransmitters and disease. Here, we document that adoptive transfer of virus-specific cytotoxic T lymphocytes clears virus and viral nucleic acid sequences, in vivo, from individually infected lymphocytes, macrophages, and neurons. By plaquing, infectious center, Northern blot, and in situ hybridization at the single cell level, virus was efficiently removed from these cells.

Animals↗
PubMed1993

Trafficking of activated cytotoxic T lymphocytes into the central nervous system: use of a transgenic model.

We have used cell or tissue-specific promoters to express lymphocytic choriomeningitis virus (LCMV) proteins in selected cells in independent lines of transgenic mice. Upon adoptive transfers into these mice, MHC-restricted LCMV-specific cytotoxic T lymphocytes homed specifically to either the choroid plexus (SV40 promoter) or beta cells of the islets of Langerhans (rat insulin promoter). The availability of promoters specific for neurons, oligodendrocytes and astrocytes makes this approach compelling for evaluating T cell trafficking into the CNS and for analyzing antigen presentation in vivo in the CNS.

Amino Acid Sequence↗
PubMed1993

Molecular mimicry accompanying HIV-1 infection: human monoclonal antibodies that bind to gp41 and to astrocytes.

Monoclonal antibodies that bound to HIV gp41 and cross-reacted with astrocytes were recovered from the blood of three patients infected with HIV-1. Mapping of the specificity of these monoclonal antibodies, using synthetic gp41 peptides, located their epitope to amino acids 644-663 and established their conformation dependence. Six other human monoclonal anti-HIV antibodies were found to bind to HIV gp41 or gp120 but not to reactive astrocytes in brain tissue. Sharing of linear or conformational protein determinants between disparate viral and host proteins is termed molecular mimicry. The consequences of such mimicry by anti-viral antibodies interacting with astrocytes may play a role in the dementia of AIDS patients since a major function of astrocytes is to maintain the appropriate milieu for neuronal function. The finding of such cross-reactive antibodies adds to the evidence for a possible autoimmune pathogenesis in some of the disease manifestations accompanying HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1993

A "string-of-beads" vaccine, comprising linked minigenes, confers protection from lethal-dose virus challenge.

We have previously demonstrated that induction of antiviral cytotoxic T lymphocytes (CTL), in the absence of antiviral antibodies, can confer protection against a lethal-dose virus challenge. Here we extend those findings as follows. First, three discrete viral CTL epitopes expressed from minigenes encoding peptides as short as 12 amino acids can be recognized when expressed from recombinant vaccinia virus; second, concentrating on two of the three epitopes, we show that these vaccinia virus recombinants can confer protection in a major histocompatibility complex (MHC)-restricted manner; third, the minigenes can be fused to generate a "string of beads," and the close proximity of the two epitopes within one oligopeptide does not disrupt recognition of either epitope; fourth, this string-of-beads vaccine, in contrast to the single epitope vaccines, can protect on both MHC backgrounds; and, fifth, CTL to different epitopes may act synergistically, as protection is improved when the vaccine contains more than one CTL epitope for a given MHC background.

Amino Acid Sequence↗
PubMed1993

Replication of lymphocytic choriomeningitis virus is restricted in terminally differentiated neurons.

We have investigated the replication of lymphocytic choriomeningitis virus (LCMV) before and after the nerve growth factor (NGF)-induced transdifferentiation of PC12 cells from the chromaffin to the neuron-like phenotype. Untreated and NGF-treated cells were equally susceptible to LCMV infection; however, the viral yield was found to be 1,000-fold lower in NGF-differentiated PC12 cells. The reduced viral yield correlated with restricted LCMV replication and transcription within the infected cell, which was not caused by the lack of cell proliferation in the NGF-treated cells but rather was related to the induction or changes in expression levels of specific gene product(s) associated with the cell commitment to a neuronal phenotype. The return to the chromaffin phenotype after withdrawal of NGF restored normal LCMV yields as well as levels of viral replication and transcription. The finding of reduced viral replication in terminally differentiated neuronal cells has important implications for understanding the mechanism by which neurotropic viruses, such as LCMV, are able to establish a long-term persistent infection in the central nervous system in the absence of severe pathological changes.

Animals↗
PubMed1993

Virus and cytotoxic T lymphocytes: crucial role of viral peptide secondary structure in major histocompatibility complex class I interactions.

Viral antigens are presented to cytotoxic T lymphocytes (CTLs) by H-2-restricted major histocompatibility complex (MHC) glycoproteins. Binding of the endogenously processed viral peptides (epitopes) to their specific MHC molecules is an early intracellular event in the recognition process and is necessary for subsequent killing of virus-infected cells by virus-specific CTLs. It is now well established that interaction between a viral antigenic peptide and MHC is dependent on the primary structure (length and amino acid sequence) of that antigen. Here we show, using the H-2Db-restricted epitope GP277-286 of lymphocytic choriomeningitis virus as a model, that the secondary structure (conformation) of the viral sequence also plays a crucial role in the binding of a viral antigen to MHC glycoprotein and in its subsequent presentation to virus-specific CTLs.

Amino Acid Sequence↗
PubMed1993

Vaccination to prevent persistent viral infection.

Persistent virus infections are increasingly being recognized as a significant cause of human morbidity and mortality. To establish persistence, a virus must establish infection and evade eradication by the host immune response, in particular by cytotoxic T lymphocytes (CTL). We have studied a virus that establishes persistence in part by suppressing the CTL response of the infected host. The virus persists in many cell types, including lymphocytes and macrophages. We show that prior immunization with a vaccine designed to induce CTL (in the absence of antiviral antibody) confers complete protection against subsequent establishment of persistence in all tissues analyzed. The vaccine can be designed to express as few as 10 amino acids of a viral protein that comprise the CTL epitope. Further, two CTL epitopes for two discrete MHC haplotypes can be successfully used in a single vaccine that protects both strains of mice. Hence, a "string of CTL epitopes" (beads) concept for vaccination is feasible. Finally, the CTL vaccine provided protection against the establishment of persistence by an immunosuppressive virus.

Amino Acid Sequence↗
PubMed1993

Mechanism and consequence of viral persistence in cells of the immune system and neurons.

Viral persistence depends on a virus having a non-lytic strategy of replication and the ability to escape immune surveillance. Cells of the immune system (lymphocytes/monocytes/macrophages) and central nervous system (neurons) are most often infected by DNA and RNA viruses that persist. Cytotoxic T lymphocytes (CTL) are the primary host defense that aborts or prevents viral persistence. Viral interaction with these specialized cells and of such infected cells with CTL is explored in this paper.

Animals↗
PubMed1993

Astrocytes are the primary source of tissue factor in the murine central nervous system. A role for astrocytes in cerebral hemostasis.

Hemostasis in the brain is of paramount importance because bleeding into the neural parenchyma can result in paralysis, coma, and death. Consistent with this sensitivity to hemorrhage, the brain contains large amounts of tissue factor (TF), the major cellular initiator of the coagulation protease cascades. However, to date, the cellular source for TF in the central nervous system has not been identified. In this study, analysis of murine brain sections by in situ hybridization demonstrated high levels of TF mRNA in cells that expressed glial fibrillary acidic protein, a specific marker for astrocytes. Furthermore, primary mouse astrocyte cultures and astrocyte cell lines from mouse, rat, and human constitutively expressed TF mRNA and functional protein. These data indicated that astrocytes are the primary source of TF in the central nervous system. We propose that astrocytes forming the glia limitans around the neural vasculature and deep to the meninges are intimately involved in controlling hemorrhage in the brain. Finally, we observed an increase in TF mRNA expression in the brains of scrapie-infected mice. This modulation of TF expression in the absence of hemorrhage suggested that TF may function in processes other than hemostasis by altering protease generation in normal and diseased brain.

Animals↗