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Biomedical subjects

E de Heer

Publications and source records attributed to E de Heer.

At least 73 records · Page 4Linked to original sources
PubMed1993

Effect of chronic graft-versus-host disease on the intestine in adult BDF1 mice.

This study was performed to characterize the intestinal lesions in chronic graft-versus-host disease (GVHD) in mice and to determine a possible role of intestinal intraepithelial lymphocytes (ilEL) in the development of these lesions. Chronic GVHD was induced by transfer of DBA/2 lymphocytes into non-irradiated (C57BL/10 x DBA/2)F1 (BDF1) recipients. There was mild to moderate mucosal oedema with multifocal mixed inflammatory cell infiltrations in the small intestine. The caecum was more severely affected with severe oedema, progressive loss of crypts and severe distortion of the mucosal architecture. The total number of ilEL did not change during the development of chronic GVHD, but there were alterations in the composition of the ilEL population. An increase of CD3+, Thy-1+ cells was accompanied by an increase of TCR alpha beta + cells and a decrease of TCR gamma delta + cells. There was no evidence of infiltration of donor lymphocytes into the intestinal epithelium as determined by the H2K haplotype of the ilEL. These lesions differ from previously described models of chronic GVHD, induced by DBA/2 donor lymphocytes in BDF1 recipients. We suggest that the haemopoietic organs that are used as the source of donor lymphocytes determine the outcome of the GVHD. Modulation of the composition of the donor lymphocyte population may be useful in the establishment of relevant animal models of human enteropathy.

Animals↗
PubMed1992

Immunomodulation of streptococcal cell wall-induced arthritis. Identification of inflammatory cells and regulatory T cell subsets by mercuric chloride and in vivo CD8 depletion.

Streptococcal cell wall (SCW)-induced arthritis is a chronic, erosive polyarthritis which can be induced in susceptible Lewis rats by one intraperitoneal injection of a sterile, aqueous suspension of SCW. The chronic phase of the disease is dependent on T cells. Mercuric chloride is an immunomodulating agent, causing autoimmunity in BN rats, but an OX8+ cell-mediated immunosuppression in Lewis rats. Therefore, we investigated the effect of mercuric chloride, whether or not combined with in vivo OX8 depletion, on SCW-induced arthritis in Lewis rats. We show that (a) depletion of OX8+ cells leads to a more chronic arthritis with a more rapid onset, (b) treatment with mercuric chloride induces a rapidly developing disease which is not chronic, and (c) treatment with mercuric chloride and OX8+ cell depletion induces an arthritis with a very rapid onset and enhanced chronicity. Together with histological data this suggests an important role for OX8+ T cells in controlling both the acute and chronic phase of the disease. In addition, mercuric chloride seems to induce an early activation of T cells resulting in an enhanced onset of disease, which is controlled later by enhanced activation of OX8+ cells.

Adjuvants, Immunologic↗
PubMed1992

Antigenic specificities of glomerular-bound autoantibodies in membranous glomerulopathy induced by mercuric chloride.

The present study describes the development of membranous glomerulopathy (MGP) with high proteinuria in DZB rats exposed to mercuric chloride (HgCl2). IgG1 and IgG2a antibodies, eluted from glomeruli with subepithelial immune deposits, bind to the interface of the GBM and epithelial cells. High reactivity to GBM was demonstrated by ELISA and Western blotting, which could be absorbed for 30% by laminin or laminin-associated extracellular matrix components. No reactivity was found with type IV collagen, fibronectin, heparan sulfate proteoglycans, or tubular brush border antigens. Absorption to GBM removed the reactivity to renal antigens. Passively transferred eluted antibodies bind in a predominantly linear pattern along the GBM, causing focal ultrastructural transformations of the podocytes. These results suggest that this type of HgCl2-induced MGP, associated with epithelial cell injury and proteinuria, is caused by autoantibodies to basement membrane components which are located at the epithelial cell-basement membrane interface and may be involved in cell-matrix binding.

Animals↗
PubMed1991

Induction of lymphokine-activated killer activity in rat splenocyte cultures: the importance of 2-mercaptoethanol and indomethacin.

The role of 2-mercaptoethanol and indomethacin in the induction of lymphokine-activated killer (LAK) activity by interleukin-2 (IL-2) in rat splenocyte cultures was investigated. Spleens from 4-month-old male rats of five different strains were tested. Splenocytes were cultured for 3-5 days in the presence of IL-2 (1000 U/ml) and LAK activity was assessed by 4-h 51Cr release assays with P815 and YAC-1 cells as targets. LAK activity could be induced by IL-2 in splenocytes from all rat strains, but only when 2-mercaptoethanol was present in the culture medium. Optimal LAK activity was induced when the 2-mercaptoethanol concentration in splenocyte cultures was at least 5 microM. Different rat strains showed differences in levels of in vitro induction of LAK activity. In the presence of 2-mercaptoethanol the level of LAK activity induced by IL-2 was high in BN and Lewis rats, intermediate in Wistar and Wag rats, and low in DZB rats. In the absence of 2-mercaptoethanol no or minimal LAK activity was induced. Furthermore we observed that addition of 50 microns indomethacin to the culture medium in the presence of 2-mercaptoethanol augmented the induction of LAK activity to some extent. In the absence of 2-mercaptoethanol, addition of indomethacin resulted only in low levels or no induction of LAK activity. We conclude that for optimal induction of LAK activity by IL-2 in rat splenocyte cultures 2-mercaptoethanol is essential, while indomethacin can only marginally further improve this induction.

Animals↗
PubMed1991

Glomeruli synthesize nitrite in active Heymann nephritis; the source is infiltrating macrophages.

Glomeruli synthesize nitrite (NO2-) in experimental nephrotoxic nephritis, a model of glomerulonephritis where infiltrating macrophages are pathogenic. NO2- synthesis was studied in active Heymann nephritis (AHN), a model of membranous glomerulonephritis in which macrophages have not been implicated. Active Heymann nephritis (AHN) was induced with purified renal tubular epithelial antigen and adjuvants. Glomeruli isolated at seven to eight weeks after induction (proteinuria 183 +/- 28 mg/24 hr, N = 6; adjuvant controls, 1.2 +/- 0.8 mg/24 hr, N = 6) produced NO2- in culture spontaneously (7.1 +/- 1.4, adjuvant controls 2.1 +/- 0.9 nmol/2000 g/48 hours; P = 0.021) and in increased amount following LPS stimulation (12.1 +/- 2.8, controls 4.2 +/- 1.6 nmol/2000 g/48 hours; P = 0.047). Synthesis was inhibited by L-NMMA, a competitive inhibitor of NO synthase. Enzymic digestion of glomeruli plus staining with mouse anti-rat macrophage monoclonal antibody ED1 showed macrophage infiltration (32 +/- 6, adjuvant controls 14 +/- 2 macrophages/glomerulus; P = 0.002). Whole body irradiation (XR) suppressed NO2- production (LPS stimulated: 1.0 +/- 0.4, N = 5; non-XR controls 7.2 +/- 4.6 nmol/2000 g/48 hours; N = 5, P = 0.016) and macrophage infiltration (1.1 +/- 0.5; non-XR controls 30 +/- 12 macrophages/glomerulus; P = 0.008) but had no effect on proteinuria. Irradiation with renal shielding confirmed the close correlation between glomerular NO2- synthesis and glomerular macrophage numbers (rs = 0.837, P less than 0.001). These results show that macrophages infiltrate glomeruli in AHN; they are the source of NO2- in this model. Neither macrophages nor NO2- are the cause of proteinuria.

Animals↗
PubMed1991

Renal immunopathology in murine host-versus-graft disease.

BALB/c mice neonatally injected with 1 x 10(8) (A/J x BALB/c)F1 hybrid spleen cells develop polyclonal B cell activation and autoimmune features as a consequence of a host-versus-graft (HVG) reaction. In this study, we first analyzed the time-course development of the renal lesions in HVG mice. From week 2 to week 6, linear deposits of IgG were observed by immunofluorescence along the glomerular capillary walls. From week 8 to week 12, the immunofluorescence pattern of IgG changed from linear to granular, and by immunoelectron microscopy, the IgG deposits were located on the epithelial side of the glomerular basement membrane (GBM). In addition, focal glomerulosclerosis complicated this membranous glomerulopathy in about 50% of the 12-week-old HVG mice and albuminuria was increased in most of them. Circulating antibodies to antigens of the GBM (laminin, type IV collagen) and of the renal tubular epithelial (RTE) cells (dipeptidyl peptidase IV, gp330) were already detected at week 2 and were still present at week 12. Immunoglobulins eluted from isolated glomeruli contained antibodies directed against type IV collagen, laminin, and to a lesser degree against gp330. F1 donor B cells were involved in the production of nephritogenic antibodies as indicated by (a) the presence of A/J allotypic determinants on serum anti-laminin antibodies and (b) the abrogation of the in vitro production of anti-GBM, anti-laminin and anti-RTE antibodies when spleen cells from HVG mice were depleted of F1 donor B cells. Finally, mixed lymphocyte culture experiments established that T cells from HVG mice stimulate normal B cells from F1 donor hybrids to produce anti-GBM, anti-laminin, anti-type IV collagen, anti-RTE, anti-gp330 and anti-dipeptidyl peptidase IV antibodies. We conclude that mice neonatally injected with semi-allogeneic spleen cells develop a glomerulonephritis characterized by the transition from a linear to a granular IF pattern, and that the production of nephritogenic antibodies results from the activation of donor B cells by host helper T cells.

Animals↗
PubMed1990

Immunological factors responsible for pathogenetic cell degeneration in pregnancy.

The placenta has an important role as an immunological barrier during pregnancy. When the placental barrier is disrupted, materno-embryonic transfusion takes place. Several clinical reports relate congenital malformations or abortion to intrauterine bleeding or transplacental transfusion. In an earlier experiment, pathogenetic cell degeneration was induced using an in vitro whole rat embryo culture. Transplacental transfusion was simulated by intracardiac injection of an allogeneic rat-antirat serum directed against the blood group antigens. The present study examines the morphological and immunological effects on the development of rat embryos 9 to 10 days old (stages 8-10 somites) of the separate administration of primary allogeneic antisera, obtained 10-17 days after immunization, and secondary allogeneic antisera, obtained after booster immunization on day 45-52. Rat-antirat alloantibodies were directed against the blood group antigens. Transplacental transfusion was simulated by the embryonic intracardiac microinjection of approximately 0.5 microliters serum enriched with either primary or secondary obtained allogeneic antibodies. After 48 hours' incubation, the embryos were examined microscopically, and it appeared that the secondary antisera, which had hemolytic activity, was more potent (P less than 0.005) in the induction of pathogenetic cell degeneration. It is well known that IgG antibodies display hemolytic activity. This finding was confirmed by direct immunofluorescence performed on rat embryos 2, 4, and 6 hours after injection, where incubation with rabbit-antirat anti-IgG antibodies gave a strong reaction. The hypothesis discussed is whether or not pathogenetic cell degeneration subsequent to transplacental transfusion of maternal antibodies can be initiated by similar immunological events.

Animals↗
PubMed1990

Transplacental induction of membranous nephropathy in a neonate.

We report a case of renal failure in a newborn infant due to membranous glomerulonephritis. The patient was anuric in the first 3 weeks of life, after which renal function recovered. The serum of the mother contained IgG antibodies which reacted with tubular brush borders and glomeruli of adult and fetal human kidneys. Reactivity with renal epithelium from human kidneys was detected. We suggest that a transplacental, passive Heymann nephritis-like mechanism was the pathogenesis of the neonate's symptoms, although the antigen(s) involved was shown not to be gp 330 or any of the renal antigens known to be involved in experimental nephropathies.

Adult↗
PubMed1988

Glomerular capillary wall charge and antibody binding in passive Heymann nephritis.

The interaction between nephritogenic antibodies and antigens in the glomerular capillary wall is influenced by physicochemical determinants such as the electrical charge. We studied the effect of neutralization of a negative glomerular capillary wall (GCW) charge by polyethyleneimine (PEI) on the binding of anti-renal tubular epithelium (RTE) IgG in passive Heymann nephritis. For these studies, glomerular binding of intravenously administered radiolabeled anti-RTE IgG was determined in Wistar rats preinjected 30 minutes earlier with either 0.2 ml 0.05% PEI (molecular weight 40,000 kd) or 0.2 ml saline solution; control rats received 0.025 mg radiolabeled nonimmune rabbit IgG (NRIgG) after PEl or saline solution. Glomerulus-bound antibody was measured in saline solution-perfused isolated glomeruli 1 hour after this injection. Intravenously administered radiolabeled anti-RTE IgG binding was found to be significantly increased in rats pretreated with PEI compared with those given saline solution. Intravenously administered radiolabeled NRIgG with or without pretreatment with PEl did not bind to the GCW. Administration of PEl had no effect on blood pressure, glomerular filtration rate, or renal plasma flow during antibody administration, which means that hemodynamic changes could not have been responsible for the observed differences in antibody binding. We conclude that binding of PEI to the GCW enhances fixation of anti-RTE IgG, probably because of neutralization of charged sites of the GCW leading to greater accessibility of intrinsic antigens present in the GCW to anti-RTE antibody.

Animals↗
PubMed1986

Reestablishment of self tolerance by suppressor T-cells after active Heymann's nephritis.

Adoptive transfer experiments were performed to obtain evidence that the down-regulation of the autoimmune response in rats with active Heymann's nephritis (HN) is due to suppressor T cells. Late in the course of HN antigen-specific OX8+ suppressor T cells were found in the spleen, but never in the draining lymph nodes. These cells were shown to suppress the autoimmune response when transferred to naive recipients that were subsequently challenged. By mixing B cells or helper T cells from rats with HN with suppressor T cells from high-dose tolerant rats we showed that OX8+ suppressor T cells appeared to have a direct suppressive effect on autoreactive B cells. A profound suppressive effect on helper T cells appeared after 10 weeks. Possible mechanisms to account for the failure of Lewis rats to maintain self tolerance are discussed.

Animals↗
PubMed1985

The autoimmune response in active Heymann's nephritis in Lewis rats is regulated by T-lymphocyte subsets.

In this study the cellular events which are responsible for the induction and suppression of active Heymann's nephritis (HN) in Lewis rats were investigated. Using an enzyme-linked short-term culture assay specific autoantibody production in vitro by lymphoid cells directed against the nephritogenic renal tubular epithelial glycoprotein (RTE-Gp) was measured. By this method it was shown that only the lymph nodes that drain the site of immunization contained autoreactive B cells. Pretreatment with cyclosporine A (Cy-A) or with multiple injections of high doses of antigen in Freund's incomplete adjuvant markedly inhibited the development of disease to a subsequent nephritogenic challenge. In challenged high-dose-tolerant (HDT) rats the autoimmune response was only 5-10% of immunized nontolerant rats. This tolerance could not be transferred by lymphoid cells from Cy-A-treated rats, but could be transferred by lymphoid cells derived from the thymus or spleen of HDT rats. Thus a suppressor cell of thymic origin may be responsible for HDT. Transfer of affinity column-fractionated splenic T cells from HDT rats demonstrated that OX8- helper and OX8+ suppressor T cells are involved in the induction and suppression, respectively, of the autoimmune response in this experimental nephropathy.

Animals↗
PubMed1985

Possible involvement of terminal complement complex in active Heymann nephritis.

We investigated whether the appearance of various complement components in renal deposits of immune complexes correlated with the development of proteinuria in rats with active Heymann nephritis. Sequential kidney biopsy specimens and serum samples were obtained from Lewis rats immunized with Fx1A in complete Freund's adjuvant. Circulating antibodies against purified auto-antigen renal tubular epithelial glycoprotein, as measured by ELISA, were found in the circulation together with a diffuse granular deposition of IgG1, IgG2a, and IgG2b in the glomeruli within 2 weeks after immunization. Biopsy specimens taken 4 weeks after immunization showed diffuse deposition of C4 and C3, which indicated that activation of complement by the classical pathway had occurred. The detection of the C5b-9 complex of complement in glomerular deposits coincided with the development of abnormal proteinuria indicating that the glomerular damage in this autoimmune disease may be caused by complement-mediated lesions in the glomerular capillary walls.

Animals↗
PubMed1984

Lymph node cells from rats with Heymann's nephritis produce in vitro autoantibodies directed against purified renal tubular antigen.

A method is described for the purification and identification of the nephritogenic glycoprotein in renal tubular epithelium (RTE-Gp) from Wistar and Lewis rats. This antigen is responsible for the induction of Heymann's nephritis (HN) in Lewis rats. RTE-Gp was detected in chromatographic fractions by an enzyme-linked immunosorbent assay using rat antibodies eluted from glomeruli of Lewis rats with active HN. In each step of the purification procedure, an absolute correlation between detection of RTE-Gp in vitro and nephritogenicity in vivo was demonstrated. Lymph node cells obtained from rats with HN produced in vitro autoantibodies in a linear dose-response fashion against both allogeneic and autologous RTE-Gp, as detected by an enzyme-linked immune protein sorbent assay. During a 2 hr incubation period, 10(6) lymph node cells produced 10-40 ng of IgG. Antibody production above background levels could be detected with an input of 10(5) lymph node cells. This study shows that the specific autoimmune response in rats with NH can be measured at the cellular level.

Animals↗
PubMed1979

Adjuvanticity of lactobacilli. I. Differential effects of viable and killed bacteria.

The adjuvanticity of Lactobacillus brevis and Lactobacillus plantarum was the subject of this study. The latter was the better adjuvant in both delayed hypersensivity and antibody formation to sheep red blood cells. Viable L. plantarum stimulated exclusively the delayed hypersensivity, where heat-killed bacteria had an adjuvant effect on antibody formation. For optimal adjuvant effects lactobacilli had to be injected in a dose of 10(8) into the same site as the antigen. Viable lactobacilli and to a lesser degree heat-killed bacteria induce hepato-splenomegaly, suggesting mediation of the adjuvant activity by the reticuloendothelial system. Granuloma formation with mainly mononuclear cell infiltrates could be observed after subcutaneous administration of viable lactobacilli whereas heat-killed lactobacilli induced granulomata containing about equal numbers of granulocytes and mononuclear cells. The possible clinical application of L. plantarium in the immunotherapy of tumours is suggested.

Adjuvants, Immunologic↗
PubMedDate not supplied

Treatment with mycophenolate mofetil attenuates the development of Heymann nephritis.

Active Heymann nephritis in the rat is a model of idiopathic membranous glomerulopathy in man. The autoimmune response is directed to gp330, a large epithelial glycoprotein that is expressed on the tubular and the glomerular epithelium. Characteristic of the disease is the presence of immune complexes and complement in the glomerulus and proteinuria. We studied the effect of a new xenobiotic immunosuppressive agent, mycophenolate mofetil, on active Heymann nephritis. Mycophenolate mofetil significantly reduced the production of autoantibodies against gp330 in rats with Heymann nephritis. Glomerular deposition of IgG was not significantly lower in the treated groups than in the untreated groups with active Heymann nephritis, as detected by immunofluorescence staining. Glomerular complement component C3, however, was significantly lower in the mycophenolate mofetil treated rats. Treatment did not completely prevent the disease, but the percentage of rats that developed proteinuria in the treated groups was significantly lower than in untreated Heymann rats. The results of this study show that mycophenolate mofetil influences the T-cell-mediated humoral autoimmune response in active Heymann nephritis and results in a decreased severity of the disease.

Animals↗