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D L Boros

Publications and source records attributed to D L Boros.

At least 55 records · Page 3Linked to original sources
PubMed1987

Collagen isotypes, laminin, and fibronectin in granulomas of the liver and intestines of Schistosoma mansoni-infected mice.

Patterns of fibrosis within hepatic and intestinal granulomas of Schistosoma mansoni-infected mice were analyzed by indirect immunofluorescence. Deposition of collagen isotypes, laminin, and fibronectin was evaluated semiquantitatively between 8 and 20 weeks of the infection. Liver granulomas were the largest at 8 weeks and contained low amounts of type I and higher amounts of type III collagen and fibronectin. Collagen deposition became pronounced as infection progressed. The relative amounts of type I collagen deposits rose and equalled that of type III. In the smaller immunomodulated granulomas at 20 weeks both types I and III were high, and type IV collagen deposition was observed. Fibronectin and laminin deposits were also detected. The small ileal granulomas did not change their size during the course of the infection. At 8 weeks, connective tissue matrix deposition was barely detectable within these lesions. Gradually, small deposits of types I and III appeared in equal amounts and attained highest levels by 20 weeks of the infection. Fibronectin deposits at that time were very prominent but laminin and type IV collagen were absent. Colon granulomas at 8 weeks of the infection were only somewhat smaller than those of the liver, yet contained very sparse deposits of types I and III collagen. During the ensuing weeks collagen deposits rose only slightly. By 20 weeks the granulomas diminished in size and within those lesions type III collagen was predominant. Whereas the presence of fibronectin was pronounced, type IV collagen and laminin were detectable only in trace amounts. These observations indicate the existence of important organ-related differences in the intragranulomatous deposition of connective tissue matrix.

Animals↗
PubMed1986

Regulation of granulomatous inflammation in murine schistosomiasis. III. Recruitment of antigen-specific I-J+ T suppressor cells of the granulomatous response by I-J+ soluble suppressor factor.

Down-modulation of the schistosome egg-induced granulomatous response involves various interacting subsets of T suppressor (TS) lymphocytes. In the present study the inductive phase of the process of modulation was analyzed. A soluble, I-J+ granuloma TS cell recruiting factor (Gr-TSRF) derived from spleen cells of chronically infected mice is described. This factor eluted from immunoabsorbent columns coupled with anti-I-Jk alloantisera induced the recruitment and expansion of antigen-specific I-J+ TS cells from a TS precursor cell population in the spleens of acutely infected mice. The recruited TS cells suppressed the granulomatous response of normal recipients in a 2-day adoptive transfer model. The antigenic specificity of the recruited TS cells was demonstrated by their inability to suppress KLH-induced artificial granulomatous response. This mechanism of recruitment described in the current study and illustrated by adoptive transfer experiments is likely to be active in vivo in initiating the process of spontaneous modulation. The I-J+ Gr-TSRF and the I-J+ TS cell described in this paper, together with the previously described H-2 restricted I-C+ factor and the subsets of TS cells (THs, TSe, TSpr), indicate the existence of an intricate, regulatory pathway(s) that operates during the modulation of the granulomatous response.

Animals↗
PubMed1986

Immunoregulation of granuloma formation in murine schistosomiasis mansoni.

Schistosomiasis mansoni is a chronic, T lymphocyte-mediated granulomatous disease that affects mainly the liver and intestines of the infected host. The chronic inflammatory process and subsequent fibrous repair are the major factors in the pathology of the disease. In the murine model of schistosomiasis at the onset of the chronic stage of the infection, the granulomatous response undergoes spontaneous modulation with concomitant alleviation of the pathologic disturbance. Analysis of the process of modulation revealed that it results from the interaction between inflammatory and regulatory subpopulations of T lymphocytes. At the acute phase of the infection, the granulomatous response is initiated and maintained by inflammatory TDH cells that release lymphokines which mobilize and recruit the macrophages, eosinophils, etc. for the generation of the lesion. Already at this stage, while the inflammatory influence prevails, a low number of suppressor T lymphocytes are present. With the progress of the infection, the overheated inflammatory response is curbed by regulatory processes. At least two, but perhaps more, T suppressor lymphocytes are involved in the maintenance of the modulation of the granulomatous response. Modulation is an active process that needs constant maintenance, probably by recruitment of fresh suppressor cells. Removal of the suppressor population causes an immediate elevation of the granulomatous response. During modulation, T suppressor lymphocytes either abrogate or greatly diminish inflammatory lymphokine production. This in turn may be the cause for decreased cell recruitment and diminution in newly formed granuloma size. Apparently a total abrogation of the granulomatous response is not desirable because released egg antigens can be harmful to liver parenchyma cells. This has been demonstrated both in thymus-deprived and in nude, infected mice. Thus, a smaller inflammatory response has the double advantage of not only being less destructive, but also shielding the underlying tissue from damage by parasite products. The various subpopulations of T lymphocytes communicate with one another by means of soluble suppressor factors that arise from the suppressor T cells. The factors may have different functions. One factor may regulate lymphokine production whereas another may recruit fresh suppressor cells from a pool of precursors. The factors act in an antigen-specific manner. Tentatively, one may assume that these factors are composed of two units: one is the I subregion membrane marker and the other is the specific recognition receptor. The nature of this receptor is still unclear, but it may be an anti-idiotypic determinant.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Anti-L3T4 antibody treatment suppresses hepatic granuloma formation and abrogates antigen-induced interleukin-2 production in Schistosoma mansoni infection.

In murine schistosomiasis mansoni, granulomatous inflammation is an immune response that involves egg antigen presentation to T cells in the context of class II major histocompatibility complex determinants and subsequent inflammatory lymphokine production by delayed-hypersensitivity (TDH) lymphocytes. In the present study, monoclonal antibodies directed against L3T4, I-A, and Lyt-2 molecules were injected intraperitoneally into S. mansoni-infected mice to study the role of these membrane antigens in the process of granuloma formation. A dramatic suppression of the hepatic granuloma size and antigen-induced interleukin-2 (IL-2) production by spleen cells was seen in mice that received anti-L3T4 monoclonal antibody treatment. The total number of cells, especially the L3T4+ T cells, was greatly diminished in the spleens. Furthermore, histopathological study of the granulomas in stained liver sections demonstrated the paucity of eosinophils and macrophages, absence of epithelioid cells and multinucleated giant cells, and minimal collagen deposition within the lesions. Damaged hepatocytes were also seen surrounding these ill-formed granulomas. In contrast, anti-I-A monoclonal antibody treatment partially suppressed IL-2 production, although granuloma size and cellular composition remained the same. Mice that received anti-Lyt-2 monoclonal antibody did not show any changes in either IL-2 production or hepatic granulomatous inflammation. The data presented in this paper indicate a crucial role for L3T4 molecules present on a subset of class II major histocompatibility complex-restricted TDH cells in IL-2 production and the generation of the granulomatous response.

Animals↗
PubMed1986

Modulation of murine schistosomiasis by exogenously administered prostaglandins.

The effect of parenteral administration of prostaglandins, 15-(s)-15-methyl PGE1 (M-PGE) and PGF2 alpha (PGF) on the pathophysiologic manifestations of active murine Schistosoma mansoni infection was examined. Both M-PGE and PGF resulted in a nearly 50% suppression of granuloma size following a 7-day course of treatment. M-PGE and PGF appeared to act by different mechanisms. The former caused a broad-spectrum immunosuppression manifested as reduced splenomegaly, B-cell proliferation, and antigen-specific interleukin-2 (IL-2) production as well as decreased granuloma macrophage Ia antigen expression, superoxide anion (O2-) production, and interleukin-1 (IL-1) production. In contrast, PGF did not ameliorate splenomegaly, but caused increases in splenic asialo-GM1 (natural killer cells) and L3T4 (helper) positive T cells. Prostaglandin F also reduced IL-2 production, but to a lesser extent that M-PGE. Although PGF caused reduced granuloma macrophage Ia expression and O2- production, it did not suppress IL-1 production. Overall, these data show that PGs can significantly modulate immunopathologic events in chronic granulomatous disease states.

Animals↗
PubMed1985

Collagenase, elastase, and nonspecific protease production by vigorous or immunomodulated liver granulomas and granuloma macrophages/eosinophils of S mansoni-infected mice.

Schistosomiasis mansoni is characterized by granulomatous inflammations, deposition of collagen, and irreversible liver fibrosis. In chronic infections fibrosis is cumulative, while collagen synthesis and degradation are diminished. In the present study, we compared collagenase, elastase, and nonspecific neutral protease (NP) activities in isolated vigorous (8-week infection) and immunomodulated (18-20-week infection) liver granulomas. Enzyme activity was localized in the adherent macrophage (greater than 90% purity) and nonadherent eosinophil-rich (greater than 70% purity) cell fractions of the disaggregated granulomas. Collagenase levels were approximately two times higher in granuloma extracts and explant culture supernates of the vigorous as compared with the immunoregulated lesions. However, macrophages and eosinophil-rich cells derived from either type of granuloma secreted similar enzyme levels. Elastase and NP levels in granuloma extracts and secretions of adherent macrophage and eosinophil-rich cell populations were the same in vigorous or immunomodulated lesions but were significantly greater in vigorous granuloma culture supernates. In addition to active collagenase, trypsin activatable latent collagenase was also present in both types of granuloma extracts, explants and eosinophil-rich cell culture supernates. Latent elastase was also detected in granuloma extracts or explant supernates but was absent from secretions of granuloma cells. These results suggest that the presence of active neutral proteases within granulomas may play an important role in the regulation of tissue repair and remodeling during the fibrotic process.

Animals↗
PubMed1984

Schistosome egg antigen(s) presentation and regulatory activity by macrophages isolated from vigorous or immunomodulated liver granulomas of Schistosoma mansoni-infected mice.

Previously, it was shown that macrophages isolated from liver granulomas of Schistosoma mansoni-infected mice constituted about 30% of the granuloma cell population, were highly activated, and more than 50% displayed H-2 I region-associated antigens. Moreover, the degree of macrophage maturation/activation correlated with the intensity of the granulomatous response. Thus, inflammatory macrophages from the vigorous granulomas of acutely infected mice (VigGrM phi) displayed greater phagocytic and tumoricidal activity than did M phi from the T suppressor cell-modulated granulomas (ModGrM phi) of chronically infected animals. No difference was seen, however, in the percentage of Ia-bearing M phi isolated from vigorous or modulated liver granulomas. Presently, accessory activity of GrM phi was assayed by reconstitution of the proliferative responses of M phi-depleted lymphocytes. Both VigGrM phi and ModGrM phi were able to reconstitute the Con-A induced proliferation of normal thymoctyes. Moreover, both types of GrM phi could reconstitute parasite egg antigen-specific proliferation of the mesenteric lymph node cells from acutely infected mice. Reconstitution was dependent on M phi that displayed I-A and I-E subregion-encoded determinants. In higher doses the activated VigGrM phi were more suppressive toward lymphocytic proliferation than were the less activated ModGrM phi. Apparently, the degree of M phi suppressor activity was in direct relationship to the state of M phi maturation/activation. These data indicate that the inflammatory M phi of the schistosome granuloma may be involved in the focal immune accessory/regulatory events that occur within these T cell-mediated lesions.

Animals↗
PubMed1983

Regulation of granulomatous inflammation in murine schistosomiasis. II. T suppressor cell-derived, I-C subregion-encoded soluble suppressor factor mediates regulation of lymphokine production.

In the present study, we extended the analysis of the regulation of inflammatory lymphokine production in mice with schistosomiasis mansoni. Splenic lymphocytes of chronically infected mice were briefly pulsed in vitro by soluble egg antigens, washed, and then cultured overnight. The supernatant culture fluid added to cultures of splenic cells of acutely infected or peritoneal lymphocytes of antigen-sensitized mice inhibited the production of migration inhibition factor (MIF). Elaboration of MIF suppressor factor (MIF-SF) required the Lyt-1-,2+,3+ subset of T lymphocytes. MIF-SF acted only on egg antigen-primed cells and required H-2 compatibility with the target cell for its suppressive effect. Further analysis with recombinant strains revealed that the factor interacted with I-AB or I-C subregion-compatible target cells. Experiments using immunoadsorbent columns with bound anti-I subregion alloantisera indicated that MIF-SF contained I-C subregion-encoded determinants. Extrapolation of this in vitro model to in vivo conditions would indicate that the granulomatous response is modulated by I region-derived suppressor factor(s) that regulate lymphokine production by TDH effector cells.

Animals↗
PubMed1983

Schistosoma mansoni: schistosomulicidal activity of macrophages isolated from liver granulomas of infected mice.

Mice infected with Schistosoma mansoni develop T cell-mediated granulomatous reactions around disseminated parasite eggs. In this study, granuloma-derived leucocytes have been examined for schistosomulicidal capacity by the use of in vitro cytotoxicity assays. Adherent macrophages, that were shown by electron microscopy to exhibit no gross morphological abnormalities, were unable to mediate significant mortality in the absence of serum factors. When cocultured with immune serum and complement, however, these cells killed +/- 26% of the larvae at a cell:target ratio of 5000:1. In contrast, granuloma-derived cell populations that were enriched for eosinophils (50-70% eosinophil content) showed only minimal cytotoxic potential. This may be related to observed structural changes in the eosinophil lysosomal granules, or perhaps to blocking of the cell-surface receptors by immune complexes. It is concluded that granuloma macrophages, activated by egg antigen-sensitised T lymphocytes, may serve as effector cells in immunity to schistosomules.

Animals↗
PubMed1983

Production of superoxide anion, prostaglandins, and hydroxyeicosatetraenoic acids by macrophages from hypersensitivity-type (Schistosoma mansoni egg) and foreign body-type granulomas.

Macrophages isolated from hypersensitivity (Schistosoma mansoni egg) and foreign body- (Sephadex bead) type granulomas were evaluated with regard to superoxide anion (O2-) production and arachidonic acid metabolism. Granuloma macrophages from schistosome-infected mice were examined during both the acute and modulated phases of the disease. In addition, the populations were characterized phenotypically by measurement of Ia antigen expression. Based on differences in the parameters studied at least three different macrophage populations could be identified in acute, modulated, and foreign body-type lesions, respectively. Macrophages from acute lesions (8-week granuloma macrophages) produced significant amounts of O2-, prostaglandins, and monohydroxyeicosatetraenoic acids without the addition of an exogenous stimulus. These cells also showed a high degree of Ia expression. In contrast, macrophages from modulated (20-week granuloma macrophages) and foreign body (foreign body granuloma macrophages) lesions required stimulation with phorbol ester to evoke significant O2- production and minimally metabolized arachidonic acid. However, 20-week and foreign body granuloma macrophages could be distinguished by their high and low degrees of Ia expression, respectively. The role of lymphokines and other intercellular signals in determining macrophage activation states within granulomas is discussed.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1983

Accessory cell function of liver granuloma macrophages of Schistosoma mansoni-infected mice.

In murine schistosomiasis mansoni, the inflammatory macrophage comprises 30% of the granuloma which forms around parasite eggs in the tissue. These granuloma macrophages (GR-Mphi) displayed dense Fc and C3 receptors, and about 50% expressed H-2I region-encoded determinants (Ia antigens). These GR-Mphi were able to effectively reconstitute the burro erythrocyte-specific immunoglobulin M and G antibody response of primed macrophage-depleted spleen cells. However, in contrast to splenic macrophages, GR-Mphi gave only minimal reconstitution of the primary immunoglobulin M response. The reconstitution of the T-cell proliferative response to L-glutamic60-L-alanine30-L-tyrosine10, an antigen under Ir gene control, was also observed when GR-Mphi were added to purified lymph node T-cells. The addition of a monoclonal antibody recognizing a determinant on the Ia complex effectively blocked L-glutamic60-L-alanine30-L-tyrosine10 presentation by GR-Mphi. These studies demonstrated that inflammatory GR-Mphi could function as antigen-presenting cells and that this accessory function was mediated by H-2I region gene products.

Animals↗
PubMed1983

Induction of collagen synthesis in cultured human fibroblasts by live Schistosoma mansoni eggs and soluble egg antigens (SEA).

There is a dearth of knowledge on the tissue fibrosis that contributes to the pathology of schistosomiasis mansoni. The present study was designed to test the direct effect of live schistosome eggs and soluble egg antigens (SEA) on cultured normal human fibroblasts. Coincubation for 3 days of fibroblast monolayers with 100-500 live eggs/ml medium or equivalent amounts of SEA caused enhanced incorporation of labelled proline. The newly synthesized polypeptides were sensitive to purified collagenase enzyme activity. Collagen synthesis was also verified by measuring increased hydroxyproline content in fibroblasts. Whereas low numbers of eggs stimulated fibroblast activity, 500 eggs/ml medium caused a disarray in the arrangement of cells, with cytoplasmic granulation, cell detachment and death. These results indicate that fibroblast stimulation and collagen synthesis may also be triggered by the direct action of egg secretions on tissue fibroblasts.

Animals↗
PubMed1983

Organ-dependent differences in composition and function observed in hepatic and intestinal granulomas isolated from mice with Schistosomiasis mansoni.

In murine schistosomiasis mansoni, eggs deposited in the liver and intestines induce a cell-mediated granulomatous reaction. Previous studies have shown that maximal granuloma size differs in the liver and various segments of the gastrointestinal tract. The objective of this investigation was to isolate intestinal granulomas and to determine whether organ-dependent differences in cell composition and granuloma function exist. Intestinal granulomas representative of those in tissue were isolated by a combination of chemical and mechanical techniques. When dissociated by collagenase, these lesions yielded a viable heterogeneous population of inflammatory cells. Granulomas from the liver, colon, and ileum showed differences in cellular composition. Liver lesions contained the largest number of T and B lymphocytes, eosinophils, and mast cells whereas ileal granulomas comprised mostly macrophages. Immunofluorescence studies on frozen tissue sections revealed that T and B lymphocytes also displayed different patterns of distribution within granulomas from different tissues. In contrast to isolated cultured liver granulomas that produced MIF-like substances, isolated colonic and ileal granulomas had weak or no MIF activity. It thus appears that granuloma formation in various organs is influenced by local factors that could affect the ultimate resolution of the lesions.

Animals↗
PubMed1983

Modulation of granulomatous hypersensitivity. V. Participation of histamine receptor positive and negative lymphocytes in the granulomatous response of Schistosoma mansoni-infected mice.

The possible role of histamine and histamine-receptored inflammatory cells in the granulomatous response of Schistosoma mansoni-infected mice was examined. Special staining revealed the presence of numerous mast cells, many partially degranulated within the liver granulomas. Treatment of infected mice with cimetidine (an H2 receptor antagonist) enhanced, and diphenyhydramine (an H1 receptor antagonist) decreased the granulomatous response. Fluorescein-labeled histamine-rabbit serum albumin conjugate (H-FRSA) and unlabeled conjugate (H-RSA)-coated culture plates were used to identify and isolate cells with histamine receptors. A large proportion of granuloma macrophages, lymphocytes, eosinophils, neutrophils, and splenic lymphocytes had histamine receptors. Elution of adherent cells from H-RSA-coated culture plates with H1 or H2 receptor antagonists suggested that receptors on granuloma cells were predominately H1 with some granuloma lymphocytes bearing H2-type receptors. Splenic lymphocytes from infected mice were functionally divided according to the presence or absence of histamine receptors on their cell surface. Receptor-negative lymphocytes appeared to mediate SEA-stimulated MIF production (TDH cells) and participated in the adoptive transfer of suppression of granulomas (TH cells). Whereas, TS cells appeared to have histamine receptors. Based on these data, it is inferred that lymphocytes that regulate lymphokine production (TS cells) within the granuloma may be triggered via their histamine receptors to exert suppressive activity.

Animals↗
PubMed1983

Modulation of granulomatous hypersensitivity. VI. T lymphocyte subsets influence mast cell density in liver granulomas of Schistosoma mansoni-infected mice.

In murine schistosomiasis mansoni, a complex series of cell-cell interactions involving T cell subclasses regulates the intensity of the inflammatory granulomatous response. Recent evidence suggests that granuloma mast cells also participate in the regulatory process by the release of histamine. The current study was performed to determine factors that affect the number of granuloma mast cells. More mast cells were detected in liver granulomas from chronically (20-wk) as opposed to acutely (8-wk) infected mice. Adoptive transfer of spleen cells from 20-wk-infected donors into acutely (6-wk) infected recipients increased granuloma mast cell density. Treatment of spleen cells with anti-Thy-1.2 or anti-Lyt-1.1 antiserum and complement, but not anti-Lyt-2.1 or normal mouse serum, abrogated adoptive transfer-induced, augmentation of granuloma mast cell density. Treatment of acutely infected animals with cyclophosphamide or cimetidine (H2 antagonist enhanced granuloma mast cell density. These data suggest that granuloma mast cell density is dependent upon subsets of T lymphocytes.

Animals↗
PubMed1982

Alteration of granuloma angiotensin I-converting enzyme activity by regulatory T lymphocytes in murine schistosomiasis.

Granulomatous inflammatory lesions in murine schistosomiasis mansoni undergo a spontaneous diminution at the chronic phase of the disease concurrent with an increase in angiotensin I-converting enzyme (ACE) activity. The objective of this investigation was to determine whether T cells influence ACE activity within the granulomas. Cyclophosphamide and cimetidine treatments of mice, which augment delayed-type hypersensitivity reactions, enhanced liver granuloma size and decreased granuloma ACE activity. The suppression of liver granuloma by the adoptive transfer of spleen cells from chronically infected, immunomodulated mice into recipients with acute infection increased ACE activity of granulomas and granuloma macrophages. The increased ACE activity was dependent upon the transfer of Thy 1.2+ splenic lymphocytes. The level of the ACE activity was proportionate to the number of administered spleen cells. Thus, the level of ACE activity within the egg-induced granuloma is dependent upon T lymphocytes present in the spleen and granulomas of infected animals.

Animals↗
PubMed1982

Atrophy of the thymic cortex in mice with granulomatous schistosomiasis mansoni.

Thymic histopathology and granulomatous hypersensitivity were examined in CBA/J mice infected with varying numbers of Schistosoma mansoni worms. At the acute phase (8 weeks) of infection, the thymi of infected mice showed depletion of cortical lymphocytes that resulted in loss of distinction in the corticomedullary region. The degree of cortical depletion correlated directly with the intensity of infection, as assessed by total egg burden of the liver. Adrenalectomy of heavily infected mice 5 to 6 weeks after infection did not alter the course of cortical lymphocyte depletion. Thymus mass was diminished by as much as 80% in heavily infected mice. However, the thymi of lightly infected mice which survived 20 weeks of infection did not differ in histology or total tissue mass from age-matched uninfected controls. Adult thymectomy at 3 weeks of infection did not abrogate the spontaneous modulation (diminution) of granuloma formation in 20-week infected mice, although spleen cells from these mice failed to adoptively transfer suppression. Heavily infected mice which did not survive beyond the acute phase (8 to 9 weeks) of infection displayed a diminished granulomatous response that was partially restored by thymectomy carried out at 5 to 6 weeks of infection. Spleen cells from heavily infected mice (8 weeks) adoptively suppressed the granulomatous response in lightly infected recipients. It is concluded that histological changes observed in the thymus concurrent with egg dissemination and granulomatous hypersensitivity correlated with T cell-mediated regulatory events.

Adrenal Glands↗