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E Gleichmann

Publications and source records attributed to E Gleichmann.

At least 55 records · Page 3Linked to original sources
PubMed1994

Proliferation inhibition and CD4/CD8 thymocyte subset skewing by in vivo exposure of C57BL/6 mice to Ah receptor-binding 3,3',4,4'-tetrachlorobiphenyl.

3,3',4,4'-Tetrachlorobiphenyl (TCB) and other Ah receptor-binding xenobiotics lead to thymus atrophy and immunosuppression, the former possibly causing the latter. In order to better understand the TCB-induced events in the murine thymus, we analyzed the effects of TCB on the proliferation capacity and maturation kinetics of different thymocyte subsets in 2-week-old C57BL/6 mice (i.e. of the Ahb-1 'dioxin-sensitive' genotype). Mice were injected with a single dose of TCB, and the development of thymocytes was followed up for 10 days using flow cytometric surface marker analysis combined with measurement of DNA content by 7-amino-actinomycin D staining. Already 2 days after exposure to TCB, fewer of the more immature thymocytes (CD4-CD8-, CD4-CD8+ alpha beta TCR-) were proliferating than in thymi from control animals. Eventually this led to a severe decrease in thymus cellularity. Moreover, a shift towards the CD4-CD8+ mature subpopulation was observed. The effects were reversible, and proliferation and CD4/CD8 subset distribution returned to normal levels within the observation period. The results are in good agreement with the data obtained previously in vitro with fetal thymus organ cultures.

Animals↗
PubMed1993

T lymphocytes ignore procainamide, but respond to its reactive metabolites in peritoneal cells: demonstration by the adoptive transfer popliteal lymph node assay.

The drug procainamide (PA) is notorious for causing drug-induced systemic lupus erythematosus (SLE) in humans. Indirect evidence suggests that metabolism of PA to a reactive intermediate metabolite is involved in the pathogenesis of drug-induced SLE in that N-hydroxylation of the arylamine group of PA favors this condition, whereas N-acetylation prevents it. If this is correct, one would expect hydroxylamine-PA (HAPA) to be immunogenic, whereas N-acetyl-PA (N-ac-PA) should be nonimmunogenic. This hypothesis was confirmed by means of the popliteal lymph node assay (PLNA) in mice: injection of PA and N-ac-PA failed to induce a reaction in the direct PLNA, whereas HAPA induced a vigorous reaction. Using the adoptive transfer PLNA, splenic T cells of mice that had received three injections of HAPA were shown to be specifically sensitized to this metabolite, but not to PA or N-ac-PA. In this system, an anamnestic T cell response could also be elicited when homogenized peritoneal cells of mice that had been treated with PA for 4 months were used as the challenging antigen, indicating that the peritoneal cells of PA-treated animals contained or had been exposed to the reactive intermediate metabolite HAPA. Whereas in slow acetylator mice this 4-month PA treatment sufficed to generate HAPA in peritoneal cells, fast acetylators required additional stimulation of their oxidative metabolism in order to produce enough HAPA detectable by sensitized T cells. These findings clearly support the concept that reactive intermediate metabolites, such as HAPA, are generated by the oxidative metabolism of phagocytic cells and are immunogenic for T cells.

Acecainide↗
PubMed1993

Murine systemic autoimmune disease induced by mercuric chloride (HgCl2): Hg-specific helper T-cells react to antigen stored in macrophages.

The adoptive transfer popliteal lymph node assay (PLNA) was used to demonstrate Hg-specific T-cell responses of mice that were continuously treated with HgCl2 by a regimen known to induce a systemic autoimmune disease in H-2s (murine histocompatibility complex, haplotype s) mice, but not H-2d mice. We found that spleen cells of B10.S and A.SW donors (both H-2s) responded anamnestically to HgCl2 by inducing a significant increase in cellularity in the draining PLN of the recipient: In contrast, spleen cells of HgCl2-treated DBA/2 (H-2d) donors failed to induce an increase in PLN cellularity, and spleen cells of B10.D2/n (H-2d) donors induced no changes or even diminished PLN cellularity upon re-encounter with HgCl2. Kinetic studies showed that spleen cells of B10.S donors were stimulatory from day 3 until day 14 of donor HgCl2 treatment and, when purified splenic T-cells were tested, still on day 28, the last point in time tested. The Hg-specific T-cells prepared from HgCl2-treated B10.S mice not only induced an increased cellularity, but also B-cell activation to antibody secretion in the draining PLN of the recipient. Moreover, the Hg-specific donor T-cells transferred could specifically be restimulated by killed peritoneal cells obtained from the same donors or from syngeneic donors previously treated with HgCl2. Interestingly, when killed peritoneal cells were injected as antigen the amount of Hg required for T-cell restimulation was only 1/40 of that required when free HgCl2 was used. Taken together, these results show that an HgCl2 treatment schedule designed to induce systemic autoimmune disease primes Hg-specific T-helper (Th) cells and generates immunogenic material in peritoneal cells to which the T-cells react. The possible contribution to the pathogenesis of HgCl2-induced auto-immune disease of these Hg-specific T-cells and the autoreactive T-cells reported in the literature is discussed.

Animals↗
PubMed1993

MHC control of IL-4-dependent enhancement of B cell Ia expression and Ig class switching in mice treated with mercuric chloride.

Systemic treatment of susceptible mouse strains with HgCl2 is known to induce elevated serum concentrations of IgG1, IgG2A, and IgE, formation of antinuclear (ANA) and antinucleolar autoantibodies (ANolA), and immune glomerulonephritis. The development of these HgCl2-induced immunological alterations requires CD4+ T cells. The H-2s haplotype encodes susceptibility and, as far as studied, H-2d determines resistance. For a better understanding of susceptibility and resistance to HgCl2 at the level of Th and B cells, we compared the effects of HgCl2 treatment in the H-2 congenic mouse strains B10.S (H-2s) and B10.D2/n (H-2d). We show that (1) H-2s but not H-2d mice responded to HgCl2 treatment with massive activation of their B cells and switch to IgE, IgG1, and IgG2A; (2) both H-2s and H-2d mice responded to HgCl2 with IL-4-dependent increases in B cell Ia expression, but significantly higher levels were induced in H-2s than in H-2d mice; (3) splenic CD4+ T cells of HgCl2-treated H-2s mice showed a strong increase in IL-4 mRNA, whereas those of H-2d mice showed only a weak increase; (4) both H-2s and H-2d mice expressed enhanced splenic numbers of CD45RBlo CD4+ T cells, suggesting activation of T cells in both strains. These results indicate that the MHC, presumably by its class II loci, modulates the T cell response to the etiologic agent HgCl2, and, hence, determines which type of immune effector mechanism is activated. A possible explanation of the observed strain difference is that H-2s and H-2d mice responded to systemic treatment with HgCl2 by preferential activation of Th2 and Th1 cells, respectively.

Animals↗
PubMed1993

Adverse immune reactions to gold in rheumatoid arthritis: lack of skin reactivity.

Adverse immune reactions develop in up to 30% of patients treated with gold compounds. However, sensitization to gold(I) drugs is rarely demonstrated by in vivo or in vitro testing. Recent data from a mouse model provides evidence that gold(I) is oxidized to gold(III) before T cells are sensitized. To study the diagnostic value of skin tests, patch testing with various gold compounds - including gold(I) and gold(III) - was performed in 50 patients with rheumatoid arthritis treated with gold(I) drugs. Positive patch test reactions to either gold(I) or gold(III) compounds were not detected. In contrast, the lymphocyte transformation test (LTT) revealed a gold(III)-induced response in one of the 7 patients being tested. We conclude that patch testing fails to indicate T cell sensitization to gold(I) drugs in rheumatoid arthritis patients. The in vitro response to gold(III) obtained by LTT supports the hypothesis that biooxidation of gold(I) compounds may play a crucial role for sensitization.

Arthritis, Rheumatoid↗
PubMed1992

Protection from lethal graft-vs.-host disease by donor stem cell repopulation.

Graft-vs.-host reaction (GVHR) induced in non-irradiated F1 mice with DBA/2J parental spleen and lymph node (LN) cells usually does not lead to acute GVH disease (GVHD). This contrasts with the GVHR induced in other parent-F1 combinations involving both major histocompatibility complex (MHC) class I and class II differences between donor and host. Most signs of acute GVHD in non-irradiated F1 mice relate to immunodeficiency following destruction of the lymphohemopoietic system of the host, which leads to wasting and death due to infections. This sequence of events is prevented when donor lymphoid cells, originating from grafted stem cells, repopulate the destroyed lymphohemopoietic system of the host. To examine whether a "silent" repopulation of the F1 host by donor stem cells might underly the absence of clinical signs of acute GVHD when GVHR is induced with DBA/2J lymphoid cells, GVHR was induced with LN cells, which do not contain stem cells. Indeed, GVHR induced in (C57BL/10 x DBA/2J)F1 (BDF1) mice with 80 x 10(6) DBA/2J LN cells led to acute GVHD. Signs of acute GVHD such as wasting and death did not occur when donor stem cells, from an inoculum of DBA/2J spleen and LN cells, were allowed to repopulate the lymphohemopoietic system of the host. The effect of donor stem cells on clinical signs of acute GVHD was more apparent when (B10.D2 x DBA/2J)F1, instead of DBA/2J, lymphoid cells were used to induce GVHR. The detection of alloreactive anti-host cytotoxic T lymphocyte (CTL) activity during acute GVHD induced with DBA/2J donor lymphoid cells supports the hypothesis that such CTL contribute to the destruction of the host immune system in acute GVHD.

Animals↗
PubMed1992

T-cell-dependent popliteal lymph node reactions to platinum compounds in mice.

The requirements for sensitization to complex salts of platinum were investigated in a mouse model by means of the popliteal lymph node (PLN) assay. A single subcutaneous injection of dissolved hexachloroplatinates without adjuvant induced a vigorous primary immune reaction in the draining PLN. Dose-dependent lymph node activation was determined by an increase in both PLN weight and cellularity. In C57BL/6 mice, peak reactions were obtained around day 6 after administration of 90-180 nmol Na2[PtCl6] or (NH4)2[PtCl6] per animal. Mice primed to [PtCl6]2- mounted an enhanced response upon local restimulation with suboptimal doses of the same but not unrelated compounds, indicating a specific secondary response. T cells were required to elicit PLN reactions to [PtCl6]2-, because athymic nude mice completely failed to respond, in contrast to their +/nu littermates. Differences between various inbred strains of mice revealed that Pt-induced PLN responses are genetically controlled. Moreover, the immunogenicity of Pt salts in mice is not confined to hexachloroplatinates, but other compounds, such as the antineoplastic agent cis-dichlorodiamine platinum, are able to induce comparable PLN reactions.

Animals↗
PubMed1991

IL-4 is required for the IgE and IgG1 increase and IgG1 autoantibody formation in mice treated with mercuric chloride.

Previous studies have established that in susceptible mouse strains, such as A.SW (H-2s), repeated injections of subtoxic doses of HgCl2 induce increased serum levels of total IgE and IgG1, high serum titers of antinuclear autoantibodies (ANo1A), and immune-complex glomerulonephritis. Moreover, it has been shown that susceptibility is determined by H-2As and that Th cells are required for the induction of these immunopathologic alterations by HgCl2. In the present study we showed that treatment in vivo with anti-IL-4 mAb completely abrogated the HgCl2-induced increase in total IgE and partially inhibited the increase in IgG1, but failed to suppress the increase in IgG2A. Furthermore, we showed that IL-4 influences the pattern of IgG subclass distribution among ANo1A of HgCl2-treated mice. Whereas treatment with anti-IL-4 mAb significantly reduced the titers of IgG1 ANolA, it increased those of IgG2A, IgG2B, and IgG3 ANolA. Thus, these results show that IL-4 contributes to the optimal formation in vivo of murine IgG1 and that it is involved in the autoantibody formation of a systemic autoimmune disease. The available evidence suggests that HgCl2 induces an increased production of IL-4 by Th2 cells. If this is correct, it implies that MHC class II alleles determine whether the preferential response to HgCl2 is made by Th1 or Th2 cells and, hence, the type of immunopathologic alterations ensuing.

Animals↗
PubMed1991

Polyhalogenated dibenzo-p-dioxins and dibenzofurans and the immune system. 3. No immunosuppressive effect of 2,3,7,8-TCDD in the popliteal lymph node assay (PLNA) in rats.

We used a modified version of the popliteal lymph node assay in rats to investigate the immunosuppressive potential of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In 10 months we conducted 3 experimental series. Animals were treated with single s.c. injections of TCDD and 7 days later human red blood cells (HRBC) were injected s.c. into the right hind footpad of the rat. Another 7 days later, both popliteal lymph nodes were prepared, weighed, the cell number was counted and the quotients ("index") of these variables from the treated and the untreated side were determined. The doses applied in three experimental series were 600', 60, 6, 0.6, and 0.06 ng TCDD/kg body wt. In the first experimental series only the three highest doses were tested, in a second experimental series doses of 60, 6, 0.6, 0.006 ng TCDD/kg body wt were applied. Combining the results of these two experimental series, a statistically significant difference was found in the cell number index between the controls and the two highest doses tested (60 and 600 ng/kg body wt; p less than 0.01). This result was recently published as an abstract (Korte et al. 1990). However, with slight methodological changes in the third series of experiments (doses applied: 600, 60, 6, 0.6, and 0.06 ng TCDD/kg body wt) and using a greater number of animals we could not confirm these preliminary results. No difference was seen in the immune response to the antigen challenge in controls and in any of the treatment groups. We conclude that TCDD does not clearly influence the immune response as observed in the popliteal lymph node assay under our experimental conditions.

Animals↗
PubMed1991

TH2 cells in systemic autoimmunity: insights from allogeneic diseases and chemically-induced autoimmunity.

Systemic autoimmune diseases can be induced experimentally in rodents by graft-versus-host or host-versus-graft reactions and by chemicals such as HgCl2, gold salts and D-penicillamine. These models share several features, such as productions of anti-nuclear antibodies, immune glomerulonephritis, MHC class II hyperexpression on B cells, hyper-IgE, increased IL-4 activity and impairment of IL-2 production. This profile of cytokines suggests a central role for TH2-type cells in their pathogenesis. Here, Michel Goldman and colleagues review the data supporting this hypothesis and discuss the possible molecular bases for T-cell activation in chemically-induced systemic autoimmunity.

Animals↗
PubMed1990

Adverse immune reactions to gold. I. Chronic treatment with an Au(I) drug sensitizes mouse T cells not to Au(I), but to Au(III) and induces autoantibody formation.

Upon weekly i.m. injections of disodium gold thiomalate (Na2AuTM) 100% of A.SW mice produced IgG autoantibodies to antinuclear Ag and nucleolar Ag, respectively; about 70% of C57BL/6 mice produced IgG antinuclear Ag, whereas DBA/2 mice were resistant. Moreover, C57BL/6 mice, but not DBA/2 mice, showed increased mesangial deposits of IgG. These alterations were due not to disodium thiomalate, but to the gold ion of Na2AuTM. An assumed T cell reactivity of susceptible mouse strains to Na2AuTM was tested by means of the direct popliteal lymph node (PLN) assay. However, no distinct PLN reaction to Na2AuTM was detectable. Likewise, AuCl did not induce a PLN reaction. Both Na2AuTM and AuCl contain gold in the Au(I) state. The poor PLN responses to Au(I) contrasted with the strong PLN responses to Au(III) compounds. PLN reactions to Au(III) were dose dependent, T cell dependent, and specific. When Au(III) was reduced to Au(I) by addition of Na2TM or methionine before testing in the PLN assay its sensitizing capacity was significantly decreased. Thus, the oxidation state of gold, i.e., Au(III) vs Au(I), plays a major role for its sensitizing capacity. Therefore, we propose that the Au(I) of Na2AuTM is oxidized to Au(III) before T cells are sensitized and adverse immunologic reactions develop. Results obtained with the adoptive transfer PLN assay indicated that, indeed, repeated i.m. injections of Na2AuTM sensitized A.SW and C57BL/6 splenic T cells to Au(III).

Animals↗
PubMed1990

Persistence of allospecific helper T cells is required for maintaining autoantibody formation in lupus-like graft-versus-host disease.

Induction of a graft-versus-host (GVH) reaction (GVHR) in non-irradiated (C57BL/10ScSn x DBA/2)F1 mice (BDF1) with DBA/2 lymphoid cells leads to chronic GVH disease (GVHD). One of the pathological alterations of this type of GVHD is hyperplasia of host B cells with production of lupus-like autoantibodies. This hyperstimulation of host B cells has previously been demonstrated to be induced by alloreactive donor T helper cells that were also proposed to maintain it. We provide three pieces of experimental evidence in support of this concept. First, treatment of mice with chronic GVHD by injection of monoclonal anti-Thy-1.2 antibodies, performed at week 6 after the injection of C57BL/6 lymphoid cells into (C57BL/6 x C57BL.bm12)F1 mice led to a significant decrease in the titre of anti-nuclear antibodies. Second, CD4+ donor T cells persisted in BDF1 mice with GVHD (GVHF1) for at least 10 weeks after the induction of GVHR; these T cells showed alloreactive helper activity against H-2b MHC determinants of the opposite parent in vitro. Third, T cells of GVHF1 mice, obtained 2 months after the induction of GVHR and transferred into normal secondary recipients, induced signs of chronic GVHD in DBF1 but not in DBA/2 mice. The combined results show that persisting donor T helper cells in GVHF1 mice retain their alloreactivity towards H-2 class II antigens for a long time after the induction of GVHR and they strongly suggest that these T cells are also the driving force behind the production of lupus-like autoantibodies at the late stage of chronic GVHD.

Animals↗
PubMed1989

Allosuppression of B cells in vitro by graft-vs.-host reaction-derived T cells is caused by cytotoxic T lymphocytes.

An acute graft-vs.-host reaction (GVHR) was induced by i.v. injection of 10(8) lymphoid cells from C57BL/10 (B10) donors (H-2b/b) into adult non-irradiated (B10 X DBA/2)F1 mice (H-2b/d). Previous experiments have established that spleen cells obtained from such GVHF1 mice suppress the primary antibody response of normal F1 spleen cells to sheep red blood cells. This type of suppression was termed "allosuppression", and it was shown to be mediated by Ly-2+ T cells of donor origin that react against H-2 antigens of the host. It was unclear, however, whether the actual mechanism of allosuppression was due to suppressive factors generated by donor T cells or whether the latter killed the F1 B cells. Here, we show that for their suppressive effect GVHF1 spleen cells need direct cell contact with F1 spleen cells; no suppressive effect was measured in a double-chamber culture system in which the GVHF1 spleen cells were separated from the responding normal F1 spleen cells by a cell-tight membrane filter. The suppressive effect only affected cells expressing the appropriate H-2 class I alloantigen; in mixed cultures of irradiated F1 spleen cells and GVHF1 spleen cells with third-party B cells the antibody response of the third-party B cells was not suppressed. GVHF1 spleen cells showed cytotoxic T lymphocyte (CTL) activity specific for the allogeneic F1 H-2 antigen. The suppressive effect of the GVHF1 spleen cells did not differ from that exerted by cloned CTL specific for MHC class I alloantigens; cloned CTL suppressed the primary antibody response of murine spleen cells without affecting the response of third-party B cells added to the cultures. The combined findings show that "allosuppression" in vitro is not due to suppression of F1B cells, but to a direct killing of these cells by alloreactive CTL.

Animals↗
PubMed1989

Immunological alterations inducible by mercury compounds. III. H-2A acts as an immune response and H-2E as an immune "suppression" locus for HgCl2-induced antinucleolar autoantibodies.

In responder mouse strains repeated injections of subtoxic doses of HgCl2 induce formation of antinuclear autoantibodies (ANA) and antinucleolar autoantibodies (ANolA). Others have shown that responsiveness to HgCl2-induced formation of ANA and ANolA is linked to H-2. Here, we extend these studies to a variety of mouse strains not tested previously. After confirming that strain B10.S (H-2s) is a high responder we have shown that strains B10.D2 (H-2d) and B10.BR (H-2k) are nonresponders. By comparing a panel of strains carrying appropriate intra-H-2 recombinant haplotypes derived from d, k and s, we were able to map responsiveness to As. Interestingly, among four strains all of which were As, and thus responsive, only the two H-2E- ones, B10.S and B10.RSD2, were high responders whereas the two H-2E+ ones, B10.HTT and B10.S(9R), were significantly less responsive. Thus, the genetics of HgCl2-induced autoantibody formation follow the rules established for immune responses to a variety of different antigens in that expression of H-2E "suppressed" the response.

Animals↗
PubMed1989

Immunotoxicology: suppressive and stimulatory effects of drugs and environmental chemicals on the immune system. A discussion.

The fundamental characteristic of the adaptive immune system which has evolved in the vertebrates is the ability to recognise, and subsequently destroy, "foreign", and potentially harmful, antigens. The selective advantage which the immune system confers is the capacity to resist infectious, and possibly malignant, disease. It has been apparent for many years that individuals in whom immune function is impaired, due either to a congenital defect or to other factors such as treatment with certain immunosuppressive drugs, exhibit an increased susceptibility to infection and, in some cases, an elevated risk of developing at least some forms of malignancy. There is an increasing awareness from rodent studies that a variety of drugs and environmental chemicals have the potential to unintentionally impair components of the immune system. Risk assessment, based upon data from chemically induced changes in one or more parameters of immune function, is, however, dependent upon a knowledge of the functional reserve of the immune system. One of the objectives of the meeting from which this report derives was to examine what sources of information are available, and what experimental protocols can be employed, to permit accurate evaluation of immunological reserve. Although, under normal circumstances, the immune system selectively and specifically recognises foreign antigen, it is clear that the potential to recognise "self" is present and that in certain circumstances this potential is realised. Antibodies directed against normal tissue antigens have been shown to be associated with, and in some instances the presumptive cause of, "autoimmune" disease. There is a growing list of drugs and chemicals which are capable of eliciting autoantibodies and pathological autoimmune reactions. A second purpose of this meeting and of this report was to review the current state of knowledge regarding drug- and chemical-induced autoimmunity.

Adjuvants, Immunologic↗
PubMed1989

Mercuric chloride induces autoantibodies against U3 small nuclear ribonucleoprotein in susceptible mice.

Autoantibodies to nucleolar components are a common serological feature of patients suffering from scleroderma, a collagen vascular autoimmune disease. While animal models, which spontaneously develop abundant anti-nucleolar antibodies, have not yet been described, high titers of such antibodies may be induced by treating susceptible strains of mice with mercuric chloride. We have identified the nucleolar autoantigen against which the HgCl2-induced IgG autoantibodies from mice of strain B10.S are directed. It is a protein with an apparent molecular mass of 36 kDa and a pI value of approximately 8.6, which is associated with the nucleolar small nuclear RNA U3, and by these criteria must be identical with a polypeptide called fibrillarin. It is striking that scleroderma patients spontaneously produce autoantibodies against the same U3 ribonucleoprotein (RNP). The HgCl2-induced murine and the scleroderma-specific human anti-U3 RNP autoantibodies were indistinguishable in their reactivities toward fibrillarin. They further resemble each other insofar as both recognize epitopes on the 36-kDa protein, which have been highly conserved throughout evolution. Our results provide a basis to investigate at the molecular level whether similar immunoregulatory dysfunctions may lead to the preferential anti-U3 RNP autoantibody production in the animal model and in scleroderma patients.

Animals↗