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Biomedical subjects

H W Virgin

Publications and source records attributed to H W Virgin.

50 records · Page 3Linked to original sources
PubMed1992

A severe combined immunodeficient (SCID) mouse model for infection with Entamoeba histolytica.

We used severe combined immunodeficient (SCID) mice to study resistance to invasive infection with Entamoeba histolytica. Seven of seven SCID mice developed liver abscesses when challenged intrahepatically with virulent HM1:IMSS strain E. histolytica trophozoites. Only one of seven similarly challenged immunocompetent congenic C.B-17 mice developed an abscess. Adoptive transfer of polyclonal rabbit anti-E. histolytica antiserum, but not preimmune rabbit serum, completely protected 7 of 12 SCID mice from intrahepatic challenge with ameba. These results demonstrate that lymphocyte-based immunity is important in protection against amebic liver abscess, and that anti-E. histolytica antibody can protect against amebic infection in this system. The SCID mouse may provide a powerful model for studying the components of protective immunity to invasive amebiasis.

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PubMed1991

Role of immune cells in protection against and control of reovirus infection in neonatal mice.

We studied the role of T cells in resistance to reovirus intestinal and central nervous system infection. Transfer of reovirus-immune adult spleen cells protected neonatal mice from (i) lethal infection with reovirus serotype 3 Dearing (T3D, footpad inoculation) and serotype 3 clone 9 (T3C9, oral inoculation) and (ii) hydrocephalus caused by serotype 1 Lang (T1L, intracranial [i.c.] inoculation). Cell-mediated protection was not serotype specific. While immune cells protected against T1L i.c., they failed to protect against 1/5,000 of the dose of T3D i.c. Two types of experiments showed that both CD4 and CD8 T cells are involved in reovirus resistance. First, immune cell-mediated protection against T3D was abrogated by in vivo treatment with anti-CD4 monoclonal antibody (MAb) and significantly inhibited by in vivo treatment with anti-CD8 MAb. Second, T3C9-infected neonatal mice treated with anti-CD4 and/or anti-CD8 developed a novel disease phenotype, an oily hair syndrome, associated with severe hepatobiliary pathology and increased viral titer in heart and liver. Immune cells and an MAb to the cell attachment protein sigma 1 (MAb G5) protected by different mechanisms. Immune cells were more effective than sigma 1 MAb G5 at controlling primary replication, while sigma 1 MAb G5 was more effective than immune cells at inhibiting neural spread of virus. We conclude that both CD4 and CD8 T cells are important for reovirus resistance, that cells and antibody act preferentially at different stages in pathogenesis in vivo, and that adoptively transferred immune cells can protect both the central nervous system and intestine.

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PubMed1991

Monoclonal antibodies to reovirus reveal structure/function relationships between capsid proteins and genetics of susceptibility to antibody action.

Thirteen newly isolated monoclonal antibodies (MAbs) were used to study relationships between reovirus outer capsid proteins sigma 3, mu 1c, and lambda 2 (core spike) and the cell attachment protein sigma 1. We focused on sigma 1-associated properties of serotype specificity and hemagglutination (HA). Competition between MAbs revealed two surface epitopes on mu 1c that were highly conserved between reovirus serotype 1 Lang (T1L) and serotype 3 Dearing (T3D). There were several differences between T1L and T3D sigma 3 epitope maps. Studies using T1L x T3D reassortants showed that primary sequence differences between T1L and T3D sigma 3 proteins accounted for differences in sigma 3 epitope maps. Four of 12 non-sigma 1 MAbs showed a serotype-associated pattern of binding to 25 reovirus field isolates. Thus, for reovirus field isolates, different sigma 1 proteins are associated with preferred epitopes on other outer capsid proteins. Further evidence for a close structural and functional interrelationship between sigma 3/mu 1c and sigma 1 included (i) inhibition by sigma 3 and mu 1c MAbs of sigma 1-mediated HA, (ii) enhancement of sigma 1-mediated HA by proteolytic cleavage of sigma 3 and mu 1c, and (iii) genetic studies demonstrating that sigma 1 controlled the capacity of sigma 3 MAbs to inhibit HA. These data suggest that (i) epitopes on sigma 3 and mu 1c lie in close proximity to sigma 1 and that MAbs to these epitopes can modulate sigma 1-mediated functions, (ii) these spatial relationships have functional significance, since removal of sigma 3 and/or cleavage of mu 1c to delta can enhance sigma 1 function, (iii) in nature, the sigma 1 protein places selective constraints on the epitope structure of the other capsid proteins, and (iv) viral susceptibility to antibody action can be determined by genes other than that encoding an antibody's epitope.

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PubMed1989

Antibody inhibits defined stages in the pathogenesis of reovirus serotype 3 infection of the central nervous system.

The mammalian reoviruses provide a model for studying specific aspects of the immunopathogenesis of viral infection. We have used two serotype 3 reoviruses to define stages in the pathogenesis of central nervous system (CNS) infection at which a mAb specific for the reoviral cell attachment protein sigma 1 (sigma 1mAbG5) acts to protect mice against lethal disease. sigma 1mAbG5 administered either before or at the time of footpad inoculation with reovirus T3D prevented entry of T3D into the CNS. sigma 1mAbG5 also inhibited the spread of reovirus T3C9 from the gastrointestinal tract to the CNS after peroral inoculation with T3C9. These effects occurred in the absence of a significant effect of sigma 1mAbG5 on primary replication in skeletal muscle (T3D) or the gastrointestinal tract (T3C9). sigma 1mAbG5 administered after T3D had reached the spinal cord inhibited subsequent spread of infectious virus from spinal cord to brain. Even after direct intracerebral inoculation of T3D, sigma 1mAbG5 prevented both growth in the brain and spread of infectious virus from brain to eye, spinal cord, and muscle. Treatment with sigma 1mAbG5 after intracerebral inoculation with T3D prevented neuronal necrosis and resulted in a delayed and topographically restricted inflammatory response. We detected no antibody-resistant T3D variants in vivo after treatment with sigma 1mAbG5. We conclude that systemic IgG does not play a significant role at the primary site of infection with reoviruses, while it clearly acts to prevent infection of the CNS and extension of infection with the CNS. Further study will be directed to defining what components of the immune system do act at primary sites of infection, and to defining the mechanisms by which antibody acts at defined stages in pathogenesis.

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PubMed1988

Antibody protects against lethal infection with the neurally spreading reovirus type 3 (Dearing).

The mammalian reoviruses have provided a valuable model for studying the pathogenesis of viral infections of the central nervous system (CNS). We have used this model to study the effect of antibody on disease produced by the neurally spreading reovirus type 3 (Dearing) (T3). Polyclonal and monoclonal antibodies protect mice from fatal infection with T3 after either footpad or intracerebral virus challenge. Protection occurs with monoclonal antibodies directed against the viral cell attachment protein sigma 1, and with polyclonal antisera without T3 sigma 1 binding activity. In vivo protection occurs with both neutralizing and nonneutralizing monoclonal antibodies. Antibody-mediated protection does not require serum complement and, under specific circumstances, can occur via Fc-independent mechanisms. Antibody can protect mice when transferred up to 5 days after intracerebral challenge and up to 7 days after footpad challenge, times when high titers of virus are present in the CNS. Thus, antibody mediated protection against this neurally spreading virus does not require neutralizing antibody or serum complement and occurs even in the face of established CNS infection.

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PubMed1986

In vivo and in vitro expression of macrophage membrane interleukin 1 in response to soluble and particulate stimuli.

We examined the expression of a membrane form of interleukin 1 (IL 1) by macrophages. Murine peritoneal macrophages fixed immediately after harvesting, in suspension, did not show membrane IL 1. Membrane IL 1 was expressed after a 3-hr culture on plastic dishes. These findings allowed us to examine some conditions in vivo that may trigger the expression of this protein; that is, by fixing the macrophages in suspension we could determine if a given stimulus had an effect. We found that membrane IL 1 was expressed briefly after administration of live or dead Listeria monocytogenes or endotoxin. Serum proteins were ineffective. At the time of maximal activation of macrophages by live Listeria, membrane IL 1 was not expressed. Analysis of in vitro conditions indicated that expression of membrane IL 1 and Ia molecules could be dissociated. In culture, recombinant interferon-gamma induced Ia but no membrane IL 1. Uptake of dead Listeria organisms had no effect on Ia but triggered membrane IL 1. The stimulation of membrane IL 1 was not caused by phagocytosis per se: latex particles were ineffective. Opsonized red cells stimulated membrane IL 1 on macrophages that were activated in vivo by inflammatory stimuli.

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PubMed1985

Suppression of immune response to Listeria monocytogenes: mechanism(s) of immune complex suppression.

We have investigated possible mechanisms underlying immune complex suppression of resistance to Listeria monocytogenes. Inhibition of resistance was found when immune complexes were formed in vivo in immune mice or in nonimmune mice adoptively transferred with specific antibody. Suppression was also found when nonimmune mice were injected with immune complexes preformed in vitro. We investigated the role of complement by decomplementing mice with cobra venom factor purified by high-pressure liquid chromatography. Complete depletion of serum C3 did not eliminate immune complex suppression of resistance to L. monocytogenes, suggesting that complement activation is not required for immune complex suppression. Infection-induced changes in the surface phenotype and functional properties of macrophages from normal and immune complex-suppressed mice were also investigated. Macrophage expression of both H-2K and Ia molecules increased during the response of normal mice to L. monocytogenes. However, these changes were not found in immune complex-suppressed mice. In contrast, membrane interleukin 1 expression was increased in macrophages from suppressed mice compared with macrophages from normal mice. Macrophages from L. monocytogenes-infected normal and immune complex-suppressed mice expressed cytotoxicity against tumor cells in vitro. We conclude that immune complexes do not inhibit resistance to L. monocytogenes by activation of complement or decreasing macrophage cytotoxic activity. Rather, defects in Ia expression by macrophages from suppressed mice might be one component responsible for immune complex suppression of resistance to L. monocytogenes.

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PubMed1985

Immune complex effects on murine macrophages. II. Immune complex effects on activated macrophages cytotoxicity, membrane IL 1, and antigen presentation.

We investigated the effects of immune complexes on macrophage functions in vitro. Immune complexes inhibit lymphokine induction of both I-Ak expression and cytotoxic activity by fetal calf serum elicited macrophages during long-term (7 days) culture. In addition, induction of antigen presentation was significantly inhibited by immune complexes. Expression of membrane interleukin 1 (IL-1) (a membrane-bound bound form of the T cell mitogen required for antigen presentation by fixed cells) was minimally inhibited by immune complexes. Therefore, inhibition of antigen presentation was primarily due to effects on Ia expression rather than membrane IL 1 expression. The inhibitory effect of immune complexes was not found during short-term culture (4 to 48 hr) when activated macrophages (bearing high levels of Ia) from mice infected with Listeria monocytogenes were examined. Immune complexes maintained or even increased levels of both I-Ak and cytotoxicity in activated macrophages. The implications of these findings for immune complex modulation of the immune response are discussed.

Animals↗
PubMed1985

Immune complex effects on murine macrophages. I. Immune complexes suppress interferon-gamma induction of Ia expression.

We have studied the effects of immune complexes on the expression of macrophage surface proteins in vitro. Increased expression of the H-2 molecules I-A, I-E, and K on the macrophage membrane was induced by in vitro culture with crude lymphokine or interferon-gamma. Expression of all three of the molecules was additionally increased by stimulating the cultures with heat-killed Listeria monocytogenes. Addition of soluble immune complexes to the cultures did not have any effect on macrophage expression of these proteins. However, significant inhibition of lymphokine or interferon-gamma induction of I-A, I-E, and H-2K was observed when macrophages were cultured on plates to which immune complexes had been bound. This inhibition was dose dependent, required an immunoglobulin (Ig) molecule with an intact Fc portion, did not require the presence of T cells, and occurred in the presence of indomethacin. Complexes containing IgG1, IgG2a, IgG2b, and IgE, but not IgM or IgA, antibodies mediated the inhibitory effect.

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PubMed1984

Suppression of the immune response to Listeria monocytogenes. I. Immune complexes inhibit resistance.

Murine infection with the facultative intracellular pathogen Listeria monocytogenes was studied as a model of cell-mediated immunity. Overwhelming lethal infection with Listeria developed when mice were given a secondary challenge with a protein antigen at the same time as Listeria infection. Three days after infection, mice immunized with ovalbumin and then challenged with Listeria and ovalbumin had up to 2.1(10)6 times as many viable Listeria organisms in their spleens as mice challenged only with Listeria. The suppressive effect of secondary challenge with a protein antigen was found to be antigen-specific, transient, and not dependent on route of challenge with either Listeria or ovalbumin. Secondary challenge with a protein antigen suppressed both the primary and the secondary responses to Listeria. Immune serum, or affinity-purified antibody, was found to transfer the suppressive effect to nonimmune mice. These findings demonstrate that acute formation of immune complexes causes a transient state of high susceptibility to infection with an intracellular pathogen. Possible mechanisms for, and implications of, these findings are discussed.

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