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T M Doherty

Publications and source records attributed to T M Doherty.

50 records · Page 3Linked to original sources
PubMed1995

T-cell regulation of macrophage function.

Macrophage function has long been known to be controlled by activated T cells. As the cytokines that control macrophage activation are defined, it is becoming apparent that macrophage 'activation' is more subtle than previously appreciated. Moreover, recent work has shown the dependence of T-cell development on macrophages, from the costimulation of T cells by macrophage surface molecules such as the B7 family, to the modulation by monokines of T-cell phenotype and growth, including IL-1, IL-10, IL-12 and IL-15. Combinations of cytokines and costimulators have revealed some of the processes by which an apparently dichotomous T-cell response can regulate the subtle diversity of the immune response.

Cell Communication↗
PubMed1995

Modulation of specific T cell responses by concurrent infection with Leishmania major and LP-BM5 murine leukemia viruses.

C57BL/6 mice infected with a murine leukemia virus (MuLV) mixture designated LP-BM5 develop an immunodeficiency syndrome termed MAIDS, characterized by a variety of T and B cell abnormalities, including elevated levels of IgE, suggesting that IL-4 expression is increased in these animals. It has been suggested that the immunodeficiency associated with MAIDS is caused by a conversion of immune responses normally characterized by Th1 development towards a Th2-dominated response. Mice of the same strain, infected with Leishmania major, mount a protective Th1 response with the induction of high levels of IFN-gamma and undetectable IL-4. We therefore infected mice with L. major at differing time points before and after virus infection and assessed the effects on T cell responsiveness, cytokine production and survival to L. major, as well as the effect on MAIDS-associated pathology. We have also immunized C57BL/6 mice with trinitrophenol-keyhole limpet haemocyanin (TNP-KLH), which leads to a predominantly Th2 response, and compared the effects of MAIDS on the response to TNP-KLH with the effect of MAIDS on L. major infection. Our results show that significant immunodeficiency with regard to infection by L. major is only apparent after 8 weeks of LP-BM5 MuLV infection, by which time T and B cell defects are well advanced. Further, we have found that the strongly polarized Th1 response stimulated by L. major infection can modulate the effect of MAIDS on T cells, leading to the survival of antigen-specific T cells. Our results suggest that the impairment of immune responses to either TNP-KLH or L. major is due not to an alteration of the balance of Th1/Th2 subsets but to a general loss of reactivity in antigen-specific CD4+ cells. However, prior activation of Th1 but not Th2 cells can inhibit the development of lymphoproliferation and immunodeficiency caused by MAIDS.

Animals↗
PubMed1994

Coronary arterial calcification as an active process: a new perspective on an old problem.

The mechanism and purpose of coronary atherosclerotic calcification remain unknown. However, evidence reviewed here suggests that calcification is not passive precipitation or adsorption, but instead is organized and regulated. Gla containing proteins and other proteins normally associated with bone metabolism appear to play an important role in this process. A variety of studies are currently in progress in our laboratory which we hope will provide a more comprehensive understanding of processes leading to coronary calcification as well as prognostic data useful in clinical cardiologic practice. A clearer understanding of the nature and significance of coronary calcification may well pave the way toward new interventions to protect myocardium and minimize the morbidity and mortality associated with coronary artery disease.

Arteriosclerosis↗
PubMed1994

Prognostic significance of cardiac cinefluoroscopy for coronary calcific deposits in asymptomatic high risk subjects.

OBJECTIVES: This research investigated the prognostic significance of radiographically detectable coronary calcific deposits. BACKGROUND: Coronary calcific deposits are almost always associated with coronary atherosclerosis. We investigated the association between fluoroscopically determined coronary calcium and coronary heart disease end points at 1 year of follow-up. METHODS: This prospective population-based cohort study was conducted in the suburbs of Los Angeles. Fourteen hundred sixty-one asymptomatic adults with an estimated > or = 10% risk of having a coronary heart disease event within 8 years underwent cardiac cinefluoroscopy for assessment of coronary calcium at initiation of the study. Clinical status including angina, documented myocardial infarction, myocardial revascularization and death from coronary heart disease were determined after 1 year. RESULTS: The prevalence of calcific deposits was high (47%). A follow-up examination at 1 year was successfully completed in 99.9% of subjects. Six subjects (0.4%) had died from coronary heart disease and 9 (0.6%) had had a nonfatal myocardial infarction. Thirty-seven subjects (2.5%) reported angina pectoris, and 13 (0.9%) had undergone myocardial revascularization. Fifty-three subjects had at least one event during the 1-year period. Radiographically detectable calcium was associated with the presence of at least one of these end points, with a risk ratio of 2.7 (confidence limits 1.4, 4.6). The presence of coronary calcium was an independent predictor of at least one end point when controlling for age, gender and risk factors. However, three deaths due to coronary heart disease and two nonfatal myocardial infarctions occurred in subjects without detectable coronary calcium. CONCLUSIONS: The presence of coronary calcific deposits incurs an increased risk of coronary heart disease events in asymptomatic high risk subjects at 1 year. This increased risk is independent of that incurred by standard risk factors.

Aged↗
PubMed1994

Reversal of T cell unresponsiveness by augmentation of antigen presenting cell function.

We have previously described epitopes of the 18 kDa protein of Mycobacterium leprae which stimulate T and B cell responses in different strains of mice. A series of overlapping 20-mer peptides that span the 18 kDa protein were used as immunogens to examine T and B cell recognition of different epitopes. Strain-specific variation in the epitopes which induce the strongest responses was affected by genes linked to the H-2 complex and the T cell responses revealed by re-challenge with antigen were at least partially controlled by factors other than T cell specificity. We have examined the responses to one such antigen, peptide 1-20, which contains strongly immunogenic epitopes for T and B cells. T cells from draining lymph nodes of peptide 1-20 immunized B10.BR, but not BALB/c mice, proliferated in vitro in response to rechallenge with peptide 1-20 or whole protein. Immunization with the same peptide also induced specific antibody only in B10.BR mice. However, immunization of BALB/c mice results in 'silent' priming of T cells since these can be induced to respond in vitro to this antigen when cultured with activated macrophages as antigen presenting cells (APC). The failure of APC from mBALB/c mice primed with peptide 1-20 to stimulate CD4+ proliferation when re-challenged in vitro and the failure to elicit antibody responses to peptide 1-20 are presumably due to the same defect in antigen-presenting cell function, since presentation of peptide 1-20 by activated macrophages is sufficient to restore both responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Modulation of murine macrophage function by IL-13.

Activated macrophages are important effector cells for immune response to many parasites and immune responses are strongly modulated in part by the effect of Th cell-derived cytokines on macrophages. Th1-derived cytokines such as IFN-gamma are strong stimulators of macrophage activation, while cytokines produced by Th2 cells, including IL-4 and IL-10, have been shown under some conditions to inhibit macrophage activities associated with inflammatory responses. IL-13, a recently described cytokine produced by Th2 cells, is also capable of down-modulating macrophage activity in a manner similar to that previously described for IL-4. Treatment of activated macrophages with IL-13 reduces the production of inflammatory monokines in response to IFN-gamma or LPS, both potent stimulators of these factors. In addition, IL-13 decreases the production of nitric oxide by activated macrophages. Nitric oxide has been implicated in both macrophage cytotoxicity and macrophage-associated immunosuppression. The suppression of nitric oxide by IL-13 leads to a decrease in parasiticidal activity by activated macrophages. However, our data indicate that IL-13 has pleiotropic effects, while the inflammatory potential of activated macrophages is significantly reduced, the potential of other macrophage subsets is unimpaired. These data indicate that IL-13 could be a potent modulator of immune responses in vivo, with effects that may embrace both macrophage suppressive and macrophage potentiating functions.

Animals↗
PubMed1993

Leishmania antigens presented by GM-CSF-derived macrophages protect susceptible mice against challenge with Leishmania major.

Leishmania major, a causative agent of leishmaniasis, in humans is also capable of infecting mice. Several strains of mice, including the BALB/c strain, are unable to mount appropriate T cell responses to the parasite and develop a fatal, disseminated infection. We present evidence that injection of granulocyte-macrophage-CSF derived bone marrow macrophages (GMM phi), previously incubated with L. major antigens, into BALB/c mice before infection, induced a Th1-dominated response and subsequent healing. Injection of BALB/c mice with GMM phi pulsed with irrelevant Ag, or other macrophages pulsed with L. major Ag, failed to protect against L. major challenge. Protection induced by L. major Ag-bearing GMM phi correlated with the induction of a Th1-like response with the production of high levels of IFN-gamma, delayed-type hypersensitivity reactivity and long-lived resistance to reinfection. GMM phi-T cell interaction, rather than parasite killing by GMM phi, appeared to be a crucial step and there was a strong correlation between ability to function as APC in vitro and induction of protective immunity in vivo. These data suggest that presentation of Ag by a population of L. major Ag-bearing GMM phi can activate Th1 cells in BALB/c mice, leading to a protective immune response to parasite invasion. This implies that the nature of the APC population which presents Ag may influence the response to that Ag in vivo.

Animals↗
PubMed1993

Differential effect of IL-10 on dendritic cell-induced T cell proliferation and IFN-gamma production.

IL-10 has previously been shown to inhibit cytokine production by Th1 cells by blocking macrophage accessory cell function. In this study we demonstrate that dendritic cell-induced Th1 proliferation was unaffected by IL-10, whereas macrophage-stimulated proliferation was inhibited in the same system. In contrast dendritic cell induced IFN-gamma production by the Th1 clones was down-regulated by IL-10. Inasmuch as dendritic cells have been shown to be potent APC for T cells in primary responses we determined the effect of IL-10 on dendritic cell-induced proliferation and IFN-gamma production by CD4+ and CD8+ T cells. Dendritic cells were effective at stimulating both proliferation and IFN-gamma secretion of CD4+ or CD8+ T cells in a primary allogeneic mixed leukocyte response. In contrast, IL-10 markedly inhibited dendritic cell driven IFN-gamma production by purified CD4+ and CD8+ T cells. Down-regulation of dendritic cell-induced IFN-gamma production suggests a role for IL-10 in inhibiting the initiation of cell-mediated immune responses.

Animals↗
PubMed1993

Identification of T cell stimulatory epitopes from the 18 kDa protein of Mycobacterium leprae.

We have used different mouse strains to examine in vivo and in vitro responses to the 18 kDa protein of Mycobacterium leprae, which appears to be strongly immunogenic in both mice and humans. B and T cell stimulatory epitopes recognised by different strains of mice have been mapped using overlapping peptides that span the entire 18 kDa protein. Previous work established that immunization of mice with the 18 kDa protein results in specific antibody production to common B cell epitopes and immunization of mice with peptides containing these B cell epitopes resulted in the induction of specific IgG to only a limited subset of epitopes in each strain. Now we report that T cells purified from mice immunized with peptides that stimulate antibody production, proliferate in vitro when rechallenged. The proliferating T cells produce levels of IL-2 and IFN-gamma, that indicate antigen-specific T helper type 1 cells are present in significant numbers. Thus, a comparison of in vivo and in vitro data suggests that T cells bearing the phenotype associated with potentially protective cell-mediated responses can be primed in vivo by epitopes on small peptides. Since T cells from both strains of mice are capable of responding to the immunogenic synthetic peptides in vitro, but give different responses to the same peptides in vivo, factors other than epitope structure appear to influence T cell subset activation. This may have important implications for diseases such as leprosy where a polarized T cell response appears to develop and for the development of synthetic subunit vaccines.

Amino Acid Sequence↗
PubMed1991

Immune responses to the 18-kDa protein of Mycobacterium leprae. Similar B cell epitopes but different T cell epitopes seen by inbred strains of mice.

Antibody responses to the 18-kDa protein of Mycobacterium leprae have been analyzed in different strains of mice. High, intermediate, and low responder strains have been identified and these response patterns show clear linkage to genes encoded in the H-2 complex. Three peptides, residues 1-50, 51-100, and 101-148 have been synthesized, as well as a series of 20-mer peptides, which span the entire 18-kDa protein. Repeated immunization of different strains of mice with the 18-kDa protein resulted in IgG responses to epitopes found on all three synthetic peptides. Immunization of BALB/cJ and B10.BR mice, two high responder strains, with 18-kDa protein resulted in high levels of IgG antibody to epitopes found on peptides 1-20, 16-35, 31-50, 46-65, and 76-95. B10.BR mice also contained IgG that bound peptide 61-80 and BALB/cJ mice produced IgG that bound peptide 91-110. Although B10.BR mice produced IgG that bound the 50-mer peptide 101-148, this IgG was not detected by binding to peptides 91-110, 106-125, 121-140, and 131-148. Immunization of B10.BR mice with individual overlapping 20-mer peptides as Ag revealed that peptides 1-20, 16-35, 31-50, and 76-95 elicited high titers of IgG that bound both the immunizing peptide as well as 18-kDa protein. As these peptides induce antibody synthesis they must contain both B cell and T cell epitopes. By contrast, immunization of BALB/cJ mice with the same 20-mer peptides, all of which contain B cell epitopes for this strain, failed to elicit IgG responses with one exception. Peptide 91-110 induced IgG that bound peptide 91-110, but not the intact 18-kDa protein. We conclude that peptides 1-20, 16-35, 31-50, and 76-95 either lack T cell epitopes for BALB/cJ mice, or activate different T cell subpopulations in the two strains. We suggest that the induction of IgG responses to small peptide Ag is an in vivo assay of the activity of Th2 cell subpopulations.

Animals↗
PubMed1991

New generation vaccines: does antibody play a directional role in antigen-processing?

Analyses of recombinant proteins isolated from genomic libraries of pathogenic organisms represent the beginning of identifying immunologically-reactive epitopes. The induction of cell-mediated and humoral immune responses to any pathogen begins with the uptake and processing of antigen by antigen-presenting cells and the display of specific epitopes to the immune system of the host. Little emphasis is placed on the molecular mechanisms underlying transport of foreign proteins into antigen-presenting cells and factors that influence degradation to the peptides which represent the epitopes that associate with newly synthesized class II molecules of the major histocompatibility complex. These cellular processes are crucial to the design of any new generation vaccine. We describe our analysis of the 18 kDa protein antigen of Mycobacterium leprae and consider a possible role for antibody in antigen-processing. In both macrophage/dendritic cells and B lymphocytes, we suggest that antibody plays a directional role in antigen uptake, subcellular compartmentalization, and antigen degradation to yield peptides. These steps will all have an impact on the construction of new generation vaccines.

Animals↗
PubMed1989

Characterization of an antibody-binding epitope from the 18-kDa protein on Mycobacterium leprae.

A murine mAb, designated L5, appears to be specific for an epitope on a protein from Mycobacterium leprae of restricted distribution within the mycobacteria. This protein, of Mr 18,000 (18 kDa) is of interest because monoclonal antibodies raised against it do not appear to cross-react with other mycobacterial pathogens. The L5 antibody-binding epitope has been mapped by two complementary methods; expression of gene fragments and synthesis of short peptides. This L5-binding region of the 18-kDa protein (amino acids 109 to 115) shows some homology to a region of the GroEL heat shock family of proteins. Characterization of this antibody-binding epitope may lead to a reagent of use in early diagnosis of infection.

Animals↗