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Biomedical subjects

J M Mansfield

Publications and source records attributed to J M Mansfield.

At least 37 records · Page 2Linked to original sources
PubMed1986

Trypanosoma brucei rhodesiense infection in mice prevents virus-induced diabetes: possible role of interferon and immunological mechanisms.

B10.BR, DBA/2, and BALB/c by J mice were infected with Trypanosoma brucei rhodesiense (Lou Tat clone 1). Subsequent infection with the D variant of encephalomyocarditis virus (EMC-D) resulted in no diabetes or encephalitis, even in the susceptible DBA/2 and BALB/c by J strains. Low levels of circulating interferon (IFN) were detected in trypanosome-infected mice at the time of EMC-D infection. All strains were severely immunosuppressed as a result of trypanosome infection, as evidenced by decreased virus-specific neutralizing antibody titers, compared to virus-infected controls. We attempted to simulate some aspects of T.b. rhodesiense infection in B10.BR mice by pretreating mice with cyclophosphamide and IFN prior to EMC-D infection. Immunosuppression by cyclophosphamide greatly enhanced the pathogenesis of EMC-D, while IFN protected against the diabetogenic effect of this virus. Our results indicate that: (i) T.b. rhodesiense infection inhibited EMC-D-induced diabetes, (ii) this inhibition was not due solely to the immunosuppression generated by the trypanosome infection, and (iii) IFN generated by the trypanosome infection could play some protective role in the inhibition of EMC-D-induced diabetes by trypanosome infection.

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PubMed1985

Genetics of resistance to the African trypanosomes. V. Qualitative and quantitative differences in interferon production among susceptible and resistant mouse strains.

The induction of interferon (IFN) was examined in different inbred mouse strains infected with Trypanosoma brucei rhodesiense. Relatively susceptible C3HeB/FeJ mice that do not exhibit variant-specific immunity or control parasitemia did not exhibit detectable IFN throughout the infection. Relatively resistant B10.BR mice that exhibit variant-specific immunity and control the first peak of parasitemia exhibited detectable IFN at two intervals. The appearance of IFN in B10.BR serum first coincided with the onset of the parasitemia 4 days after infection and then disappeared; this IFN peak was predominantly IFN-alpha/beta. The second time of appearance coincided with high titers of antibody and remission of the parasitemia. This IFN was predominantly IFN-gamma. Intermediately susceptible CBA/J mice also exhibited two detectable peaks of IFN; the first IFN-alpha/beta peak coincided with the onset of the parasitemia as in B10.BR mice. The second peak of IFN in the serum of CBA mice, however, was delayed in appearance and lower in concentration compared with B10.BR mice. This peak was characterized as being predominantly IFN alpha/beta. BALB/c mice (also intermediately susceptible) did not exhibit a first peak of IFN-alpha/beta production, but the second peak of IFN-alpha/beta production was similar to that seen in CBA mice. In contrast to infected mice, IFN was induced in both susceptible (C3H) and resistant (B10.BR) mice after immunization with glutaraldehyde-fixed trypanosomes or after chemotherapy of infection. We conclude that both the levels of IFN as well as the type of IFN induced during infection with T. b. rhodesiense depend upon the genetic background of the mouse strain infected. The induction of IFN-gamma in mice of the C57BL background may be linked functionally to more effective parasite control and to the presence of an effective immune response to T. b. rhodesiense.

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PubMed1984

Lymphocyte function in experimental African trypanosomiasis. VII. Loss of antigen-nonspecific suppressor-T-cell activity.

The extent of immunosuppression occurring in mice infected with the pathogenic African trypanosomes was studied. Spleen cells from Trypanosoma rhodesiense-infected C57BL/6J mice were tested for antigen-nonspecific suppressor-T-cell (Ts) activity after concanavalin A (Con A) treatment in vitro. After exposure to Con A, control and infected mouse spleen cells were added to responder spleen cell cultures stimulated with sheep erythrocytes (SRBC). Assays for the resultant plaque-forming cell responses to SRBC revealed that antigen-nonspecific Ts activity was lost during the first week of infection. Changes in infected mouse T-cell subpopulations, including a terminal loss of Lyt 2.2+ cells, accompanied but did not precede the demonstrable loss of Ts function. Splenic suppressor macrophages which arise during infections with T. rhodesiense also did not seem to be associated with the loss of antigen-nonspecific Ts activity. It is concluded that the generalized immunosuppression associated with experimental African trypanosomiasis extends to the mitogen-induced Ts population.

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PubMed1984

Genetics of resistance to the African trypanosomes. IV. Resistance of radiation chimeras to Trypanosoma rhodesiense infection.

The cellular bases of resistance to the African trypanosomes were examined in inbred mice. As part of these studies, reciprocal bone marrow cell transplants were performed between H-2 compatible mice which differ in relative resistance to Trypanosoma brucei rhodesiense infection. Survival times, parasitemias and IgM antibody responses to the surface antigen of the infecting variant type were measured in these semiallogeneic bone marrow chimeras. Relatively resistant C57BL/10 mice, intermediate A.By mice, and least resistant C3H.SW mice that were reconstituted after lethal irradiation with syngeneic bone marrow cells displayed resistance and immunity characteristic of the homologous donor strain. When C57BL/10 mice were reconstituted with C3H.SW mouse bone marrow cells they retained the ability to produce antibodies to trypanosome surface antigen but the antibody titers were significantly reduced. Control of parasitemia and mean survival time were reduced in these chimeras, but differed significantly from C3H.SW mice. A.By mice that received cells from C57BL/10 donors exhibited antibody responses and survival times similar to the C57BL/10 mice. Survival times of A.By mice given syngeneic cells or C3H.SW cells were the same, but the antibody responses of A.By mice given C3H.SW cells were lower than those of A.By mice given syngeneic cells. C3H.SW mice reconstituted with C57BL/10 bone marrow cells were capable of making antibodies and controlling parasitemia, in marked contrast to the absence of such responses in C3H.SW mice reconstituted with syngeneic cells. Survival times, however, were indistinguishable from those of C3H.SW mice given syngeneic cells. Thus, resistance to T. b. rhodesiense was shown for the first time to depend on donor bone marrow derived cells as well as upon radiation-resistant cells/factors associated with host genetic background. Also, parasite-specific IgM antibody responses seem to be regulated by a mechanism which does not depend on bone marrow derived cells alone, and the presence of such immune responses is not linked to survival time.

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PubMed1984

Lymphocyte function in experimental African trypanosomiasis. VIII. Loss of suppressor T cell function in lymph nodes.

The immunosuppression that occurs in mice experimentally infected with African trypanosomiasis has been examined further. In the present study we have examined lymph node cells from Trypanosoma rhodesiense-infected C57Bl/6J mice for the ability to produce mitogen induced antigen-nonspecific suppressor T cells (Ts). Inguinal, mesenteric, and brachial lymph node cells were harvested from uninfected control mice and from mice at different periods of infection. These cells were cultured with or without concanavalin A (Con A) for 48 hr to induce Ts activity. After stimulation, the control and infected lymph node cells were passed over Sephadex G-10 columns to remove suppressor macrophages that arise during the infection from Con A-induced Ts. The column passed cells were then added to normal mouse responder spleen cells in a primary in vitro antibody response culture system with sheep erythrocytes (SRBC) as antigen. The resultant plaque-forming cell responses to SRBC indicated that Ts function was not induced in infected lymph node cell populations. However, early in the infection, a stimulatory signal was provided by both the untreated and Con A-treated infected lymph node cells, which was lost in the terminal stage. Determinations of T cell subpopulations revealed that the infected Lyt 2.2-bearing subpopulation was not significantly altered from normal controls. We conclude that T. rhodesense infected mice fail to mount normal lymph node cell antigen nonspecific Ts responses and that this loss of activity may be due to an intrinsic dysfunction in the suppressor T cell population.

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PubMed1984

Morphological changes in Trypanosoma brucei rhodesiense following inhibition of polyamine biosynthesis in vivo.

The effect of alpha-difluoromethylornithine (DFMO) treatment on the morphology of African trypanosomes was investigated. For this purpose inbred mice were immunosuppressed and infected with a clone of the protozoan blood parasite Trypanosoma brucei rhodesiense. The mice were then treated with DFMO, an irreversible inhibitor of ornithine decarboxylase, which inhibits polyamine synthesis. DFMO treatment in the absence of host immunity resulted in arrest of cytokinesis of the trypanosomes and many binucleated cells could be seen in blood smears. If mice were infected with a highly virulent trypanosome clone (ETat 1.10), which does not normally transform from long slender (LS) to short stumpy (SS) forms, DFMO treatment caused SS transformation to occur on days 3-4. This morphological SS transformation was substantiated by the presence of diaphorase activity and nuclear and mitochondrial changes. The results suggest a possible involvement of polyamines in the transformation from LS to SS forms.

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PubMed1984

Genetics of resistance to the African trypanosomes. III. Variant-specific antibody responses of H-2-compatible resistant and susceptible mice.

Genetically based differences in variant-specific immunity to the African trypanosomes were examined. H-2-compatible inbred mouse strains that differed in relative resistance were infected with Trypanosoma rhodesiense clone LouTat 1. Antibody responses to exposed epitopes of the LouTat 1 variant-specific surface glycoprotein (VSG) were measured. Relatively resistant B10.BR mice (H-2k) made predictable IgM antibody responses to the VSG of LouTat 1 which were associated with clearance of the LouTat 1 variant antigenic type from blood; IgG responses to LouTat 1 surface antigen appeared after clearance occurred, and were lower than peak titers of IgM. Intermediately susceptible CBA mice (H-2k) also made predictable IgM and IgG responses which followed the same pattern as the more resistant strain. Peak titers were lower for both Ig classes, however, and a delayed appearance of antibody was correlated with delayed clearance of LouTat 1. In contrast to B10.BR and CBA mice, the susceptible C3H mice (H-2k) failed to make detectable antibodies to LouTat 1 surface antigen and also failed to control the first peak of parasitemia. The absence of immunity in infected C3H mice was selective for antibody to exposed epitopes of LouTat 1 VSG because antibody was detectable to invariant VSG or internal trypanosome antigens. Also, the C3H strain was shown not to be a genetic nonresponder to LouTat 1 surface antigen because VSG-specific antibodies appeared within 1 wk after trypanocidal chemotherapy. Finally, we demonstrated that the susceptibility of C3H mice was not associated with an inability of the mononuclear phagocyte system to clear the parasites because drug cure, passive transfer of immune serum, or sensitization of trypanosomes with antibody all led to trypanosome clearance from blood by the liver. In summary, we show for the first time that major differences in variant-specific immunity occur in MHC-compatible animals after infection with the African trypanosomes.

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PubMed1983

Studies on the growth and survival of Staphylococcus aureus in corned beef.

The growth of an enterotoxin A producing strain of Staphylococcus aureus in corned beef was investigated. In the inoculated 6 lb. canned product the bacteria spread throughout the meat and attained high numbers. The rate of spread of the organisms was related to the temperature and length of storage of the cans and the numbers of bacteria inoculated. Cans which had been stored for more than four months showed high counts of the bacteria throughout the meat. It was noted that with the long term contaminated product counts of S. aureus on some selective media may give falsely low results. Numbers of S. aureus on meat inoculated by handling after removal from the can were initially extremely variable. More uniform distribution and higher counts were attained only if the meat was exposed for some hours at ambient temperature or above. The significance of the results to the investigation of outbreaks of food poisoning suspected of being associated with canned corned beef is discussed.

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PubMed1983

Lymphocyte function in experimental African trypanosomiasis. VI. Parasite-specific immunosuppression.

The ability of mice infected with African trypanosomes to produce antibodies to the surface antigen of the infecting trypanosome variant antigenic type upon primary and secondary exposure was examined. C57BL/10SnJ mice were infected initially with Trypanosoma rhodesiense clone LouTat 1.0. Surface antigen-specific antibody titers (IgM and IgG) to the infecting variant were measured throughout the course of infection; when the titers were sufficiently low, mice were reinfected with LouTat 1.0 trypanosomes and the antibody response was measured. Results demonstrate that mice in the early stage of infection exhibited transient suppression of antibody responses to LouTat 1.0 upon reexposure. In contrast, mice in the terminal phase of the disease were completely suppressed in their ability to mount a humoral response to LouTat 1.0. Trypanocidal chemotherapy of mice restored immunoresponsiveness in that treated mice responded with both IgM and IgG surface antigen-specific antibody to LouTat 1.0. The resulting antibody response, however, was more indicative of a primary humoral response to the parasites rather than a true secondary immune response.

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PubMed1983

Role of antibody in the elimination of trypanosomes after DL-alpha-difluoromethylornithine chemotherapy.

The drug DL-alpha-difluoromethylornithine (DFMO), a specific inhibitor of ornithine decarboxylase, was studied as an antitrypanosomal drug. We showed that an antibody response to the surface antigen of trypanosomes was necessary for rapid elimination of parasites after DFMO treatment, as effects of drug treatment were greatly reduced in immunosuppressed mice. Efficacy of the treatment also varied with the inherent ability of different mouse strains to mount antibody responses to trypanosomal surface antigen. Further, some trypanosomes were more resistant to the combined effects of drug and host immunity, as relapses occurred with certain parasite clones.

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PubMed1983

Lymphocyte function in experimental African trypanosomiasis. V. Role of antibody and the mononuclear phagocyte system in variant-specific immunity.

The role of parasite-specific antibody and the mononuclear phagocyte system (MPS) in immunity to the African trypanosomes was examined. For this study C57BL/10SnJ mice were infected with Trypanosoma rhodesiense clone LouTat 1.0. Infected mice were injected with 75Se-labeled LouTat 1.0 trypanosomes, and clearance from the blood upon reexposure was measured throughout the course of infection. Clearance of labeled organisms occurred only on or after day 5, which was the day of natural elimination of LouTat 1.0 from the blood. Clearance was dependent on a functional immune system and correlated with the appearance of antibody to the variant-specific surface antigen (VSSA) of the trypanosomes. The ability to clear trypanosomes was transferred to normal, uninfected mice by immune serum. Both the IgM and IgG fractions of immune serum mediated the clearance, and VSSA-specific IgM fractions were as efficient in clearing LouTat 1.0 as the IgG fractions. Normal levels of complement (C3) were not required for clearance. The liver was the primary organ of clearance, and the ability of the liver to sequester radiolabeled trypanosomes was not impaired in the terminal phase of the disease or by large numbers of circulating trypanosomes present representing different variant antigenic types (VAT). We conclude that in African trypanosomiasis the MPS is not depressed in its ability to clear trypanosomes of the infecting VAT at any time during the course of infection. The observed clearance function requires parasite-specific antibody but normal levels of C3.

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PubMed1982

Effect of thymosin fraction 5 on the production of murine gamma interferon.

Mice that received one intraperitoneal injection of 120 microgram of thymosin fraction 5 just prior to induction of interferon with polyriboinosinic-polyribocytidylic acid but did not have the production of interferon affected by the thymosin treatment. An additional treatment with 120 microgram of thymosin 24 h prior to exposure to the mice to polyinosinic-polycytidylic acid also had no effect on interferon induction. However, induction of gamma (type II immune) interferon in mice by tuberculin challenge of mice previously sensitized with Mycobacterium bovis strain bacillus Calmette-Guerin was affected by treatment of the mice with thymosin fraction 5. If the mice received 120 microgram of thymosin fraction 5 intraperitoneally 24 h prior to and again immediately before tuberculin challenge, a significant decrease in gamma interferon was observed. Thymosin treatment alone did not result in induction of interferon.

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PubMed1982

Cloning of African trypanosomes in mice immunosuppressed by cyclophosphamide treatment.

The use of cyclophosphamide-treated mice for purpose of cloning the African trypanosomes was assessed. C3HeB/FeJ mice were injected with 200 mg/kg cyclophosphamide (CY) 24-72 hours prior to infection with a single trypanosome isolated from Trypanosoma rhodesiense infected blood samples. All CY-treated mice exhibited depressed parasite-exposure, which was a period of time sufficient to grow trypanosomes from a single organism to a fulminating parasitemia. Cloning efficiency was routinely 45% in these animals. Thus, our study demonstrates that CT-treated mice are a convenient and efficient vehicle for cloning African trypanosomes. Techniques which facilitate the selection of single trypanosomes from infected blood are also described in this report.

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PubMed1981

Genetics of resistance to African trypanosomes: role of the H-2 locus in determining resistance to infection with Trypanosoma rhodesiense.

Susceptibility and resistance to Trypanosoma rhodesiense infections in inbred and H-2 congenic strains of mice were studied. Mean survival times and patterns of parasitemia were examined. C3HeB/FeJ mice were highly susceptible; CBA/J, A/J, and BALB/cByJ mice displayed an intermediate level of susceptibility; whereas C57BL/10 mice were highly resistant. H-2 congenic strains with the BL/10 background resembled the BL/10 parental type, thereby suggesting that the major histocompatibility complex does not play a major role in regulating resistance and susceptibility to infection with T. rhodesiense.

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