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M Röllinghoff

Publications and source records attributed to M Röllinghoff.

At least 19 recordsLinked to original sources
PubMed1992

Transition from interleukin 1 beta (IL-1 beta) to IL-1 alpha production during maturation of inflammatory macrophages in vivo.

In situ production of interleukin 1 alpha (IL-1 alpha) and IL-1 beta was investigated in Peyer's patches (PP) of mice undergoing an acute bacterial infection with Yersinia enterocolitica O8. Synthesis of IL-1 beta, as determined by immunohistochemistry, was found primarily in monocytes migrating into the inflamed PP. In comparison, synthesis of IL-1 alpha was temporarily delayed by at least 24 h and was only found in mature macrophages, which did not produce detectable levels of IL-1 beta. This indicates a transition from IL-1 beta to IL-1 alpha production during maturation of monocytes into inflammatory macrophages, and further emphasizes a dichotomy between IL-1 alpha and IL-1 beta.

Animals↗
PubMed1992

Two signals are involved in polyclonal B cell stimulation by T helper type 2 cells: a role for LFA-1 molecules and interleukin 4.

T helper cell type 2 (Th2) cells when triggered by antibodies to CD3 acquire the capacity to stimulate the polyclonal proliferation of syngeneic, resting B cells. Here, we tested the ability of various monoclonal antibodies (mAb) to block the B cell proliferation-inducing potential of such activated Th2 cells. We demonstrate that anti-interleukin 4, as well as anti-LFA-1 antibodies interfere with the T-B cell interaction. In kinetic studies, anti-LFA-1 was found to be operative during the first half and anti-interleukin 4 during the second half of the 48-h culture period. This defines at least two different steps in B cell triggering by Th2 cells. In addition, the data imply that the T-B cell interaction involves an additional structure, namely an activation molecule, on the T cell surface.

Animals↗
PubMed1992

Murine epidermal Langerhans cells are potent stimulators of an antigen-specific T cell response to Leishmania major, the cause of cutaneous leishmaniasis.

Cutaneous leishmaniasis is initiated by the bite of an infected sandfly and inoculation of Leishmania major parasites into the mammalian skin. Macrophages are known to play a central role in the course of infection because they are the prime host cells and function as antigen-presenting cells (APC) for induction of the cell-mediated immune response. However, in addition to macrophages in the dermis, the skin contains epidermal Langerhans cells (LC) which can present antigen (Ag) to T cells. Therefore, using a murine model of cutaneous leishmaniasis, we analyzed the ability of epidermal cells to induce a T cell response to L.major. The results demonstrated that freshly isolated LC, but not cultured LC, are highly active in presenting L.major Ag in vitro to T cells from primed mice and to a L.major-specific T cell clone. Furthermore, freshly isolated LC had the ability to retain L.major Ag in immunogenic form for at least 2 days. Their efficiency was much greater than that of irradiated spleen cells, a standard population of APC. LC stimulated both T cell proliferation and production of the lymphokines interleukin (IL)-2 and IL-4. The response was Ag specific and could be induced by lysate of L.major parasites and by live organisms. The data suggest that epidermal LC are important APC in cutaneous leishmaniasis. They may perform a critical function by capturing L.major Ag in the skin and presenting it either to quiescent T cells circulating through the draining lymph node or locally to T effector cells infiltrating the cutaneous lesion.

Animals↗
PubMed1992

Immunoblotting as a valuable tool to differentiate human visceral leishmaniasis from lymphoproliferative disorders and other clinically similar diseases.

Diseases presenting with splenomegaly, fever and pancytopenia require intensive differential diagnostic considerations. These diseases include lymphoproliferative and autoimmune diseases, but also chronic infections like mansonian schistosomiasis or visceral leishmaniasis (kala-azar). Diagnosis for the latter is usually performed by testing for the presence of antileishmanial antibodies using the immunofluorescence test (IFT) or the enzyme-linked immunosorbent assay (ELISA) technique. Here, we report on patients who displayed positive antileishmanial antibody titres in the IFT and/or ELISA, but did not develop kala-azar and were eventually diagnosed as having one of the non-kala-azar diseases listed above. These false-positive sera proved to be seronegative when tested on a Leishmania immunoblot. Our studies lead us to recommend the immunoblot technique as a confirmatory test in cases with doubtful IFT or ELISA antibody titres.

Animals↗
PubMed1992

[Persistence and transient conjunctival pathogen colonization before planned intraocular interventions].

The risk of a postoperative endophthalmitis is influenced by the presence of a significant bacterial colonisation of the conjunctiva before intraocular surgery. Between February and August 1990 we performed conjunctival smears in 481 patients 1) on the eve of the operation and 2) just before planned intraocular surgery, to evaluate a persistent or transient microbial colonisation of the conjunctiva. 352 patients showed insignificant ("negative") and 129 patients a significant ("positive") bacterial growth in the first conjunctival smear. 96% of the patients (n = 336) had a negative result in both smears. 30% of the patients (n = 37) with a positive conjunctival smear showed a persisting bacterial colonisation, whereas 70% of the patients (n = 92) had a transient colonisation of the conjunctiva with a negative second smear. As a persisting microbial colonisation of the conjunctiva may be an important factor for the development of postoperative endophthalmitis, we recommend prophylactic conjunctival smears before surgery to diminish the risk of intraocular infections after surgery.

Bacteria↗
PubMed1992

[The role of interleukin 1 in infection and sepsis].

Interleukin(IL-)-1 is the prototype of a proinflammatory cytokine, produced in response to infection and other forms of trauma. At low concentrations IL-1 brings about increases in a number of defense mechanisms, particularly immunologic and inflammatory responses. However, over- or continued production of IL-1, as seen for example during septic infection, significantly contributes to pathological reactions such as hemodynamic shock. Thus, it is not surprising that IL-1 activities are tightly regulated, most notably at the levels of transcription and secretion. Additional regulation is provided by the action of a protein, that blocks the binding of IL-1 to its receptors. This protein, termed IL-1-receptor antagonist (IL-1ra) has been cloned recently, and may provide the possibility of specific therapeutic measures.

Animals↗
PubMed1991

Formation of intrachain disulfide bonds gives rise to two different forms of the murine IL-1 beta precursor.

IL-1 beta is an inflammatory cytokine produced by activated macrophages. Secretion of IL-1 beta comprises a biologic inactive precursor (molecular mass = 31 kDa) and a bioactive low molecular mass peptide (17 to 20 kDa). The questions of where IL-1 beta processing takes place and what is its relationship to secretion remain to be analyzed. Here we report the novel finding that lysates of murine macrophages contain two forms, with molecular masses of 31 and 35 kDa, of the IL-1 beta precursor that can be distinguished by their different electrophoretic mobilities under nonreducing conditions. The more rapid migration of the 31-kDa polypeptide was due to a disulfide-mediated protein folding, as concluded from the following evidence. The native 31-kDa polypeptide could be unfolded to a 35-kDa polypeptide by reduction, and it spontaneously refolded to the 31-kDa polypeptide when the reducing agent was removed. Refolding of the reduced 31-kDa polypeptide was blocked in the presence of iodoacetamide, indicating that alkylation of the protein prevented the re-oxidation of disulfides. Culture supernatants contained predominantly the 31-kDa polypeptide and the mature IL-1 beta with a low m.w. of 20,000. Little or no 35-kDa IL-1 beta was detected extracellularly. These data indicate that murine macrophages contain two populations of the IL-1 beta precursor, one of which can undergo a disulfide-mediated protein folding; they also suggest that oxidation of -SH groups may be critical for the proteolytic processing of the IL-1 beta precursor.

Alkylation↗
PubMed1991

Cytokine interactions in experimental cutaneous leishmaniasis. Interleukin 4 synergizes with interferon-gamma to activate murine macrophages for killing of Leishmania major amastigotes.

We investigated the effect of recombinant murine interleukin 4 (IL 4) in the absence or presence of recombinant murine interferon-gamma (IFN-gamma) on adherent bone-marrow macrophages (M phi), peritoneal exudate and resident peritoneal M phi from susceptible BALB/c M phi, which were pulse-infected with Leishmania major amastigotes (AM), IL 4 (5-100 U/ml) failed to activate any of these M phi populations for killing of intracellular AM. However, in the presence of low concentrations of IFN-gamma (10-20 U/ml), which alone caused only a slight or intermediate reduction of the number of intracellular parasites. IL 4 led to a dramatic increase of the parasite elimination by all M phi populations. In the case of resident peritoneal M phi, the synergism of IFN-gamma and IL 4 required the incubation of the M phi with both cytokines or with IFN-gamma alone for at least 10 h prior to infection; adding both cytokines after infection of the M phi did not cause a significant reduction of the intracellular parasite burden. The synergistic effect of IL 4 and IFN-gamma was completely abrogated in the presence of anti-IL 4 antibodies. Furthermore, there was no significant difference between M phi derived from either susceptible BALB/c or from resistant C57BL/6 mice. Evidence is presented that the synergistic action of IL 4 and IFN-gamma occurs via an L-arginine-dependent killing pathway. From these data we conclude that IL 4 provides a strong stimulus for the killing of intracellular L. major AM provided low concentrations of IFN-gamma are present. Also, IFN-gamma is apparently an important priming signal for the activation of resident M phi to eliminate intracellular AM.

Animals↗
PubMed1991

Cytokine interactions in experimental cutaneous leishmaniasis. II. Endogenous tumor necrosis factor-alpha production by macrophages is induced by the synergistic action of interferon (IFN)-gamma and interleukin (IL) 4 and accounts for the antiparasitic effect mediated by IFN-gamma and IL 4.

Tumor necrosis factor-alpha (TNF-alpha) strongly activates murine peritoneal macrophages (M phi) for killing of amastigotes from Leishmania major in the presence of low amounts of interferon-gamma (IFN-gamma). Recently, we found that IFN-gamma and interleukin 4 (IL 4) also synergistically enhance the antileishmanial potential of M phi. In this report, evidence is provided that the synergism of IFN-gamma and IL 4 is based on the ability of the lymphokines to induce the endogenous production of TNF-alpha. First, both IFN-gamma and IL 4 as single agents and in combination were potent inducers of TNF-alpha production by M phi infected with L. major amastigotes. Second, the synergistic effect of IFN-gamma and IL 4 on parasite killing by M phi strongly correlated with their synergistic effect on the release of TNF-alpha. Third, the IFN-gamma/IL 4-mediated parasite elimination was completely abrogated not only in the presence of antibodies to IFN-gamma and IL 4, but also with an antibody specific for TNF-alpha. Consistent with the conclusion that endogenously produced TNF-alpha accounts for the synergism of IL 4 with IFN-gamma is the finding that N omega-monomethyl-L-arginine, an inhibitor of the L-arginine-dependent generation of microbicidal nitrogen intermediates, totally blocked the M phi activation induced by IFN-gamma combined with IL 4 as well as by IFN-gamma combined with TNF-alpha. These results underline the complex interplay of cytokines derived from lymphocytes and M phi and the role of TNF-alpha as pivotal factor for the induction of antileishmanial effector functions.

Animals↗
PubMed1991

Lymphocytes play the music but the macrophage calls the tune.

Researchers interested in immunological aspects of bacterial, fungal, protozoan and helminthic infection are too often kept apart by artificial subject boundaries. These barriers were temporarily breached by a recent workshop* in which the complex interplay between microbes and their mammalian hosts were examined from a global viewpoint. The role of T-cell subsets and their products came under close scrutiny but the most forceful image was that of the macrophage. As host for infective agents, as modulator of specific immune activity and as ultimate mediator of the host response, the macrophage plays a virtuoso's role in the host-parasite drama.

Animals↗
PubMed1991

Interferon-gamma inhibits the efficacy of interleukin 1 to generate a Th2-cell biased immune response induced by Leishmania major.

Splenic adherent cells from L. major-infected resistant and susceptible mice were restimulated in vitro and analyzed for the expression of IL-1 activity. Three weeks or later after infection, cells from parasite infected susceptible BALB/c mice produced substantially more IL-1 activity than those from non-infected controls or from L. major-infected resistant C57BL/6 animals. More than 95% of the IL-1 bioactivity was mediated by IL-1 alpha, as determined by blocking experiments with an anti-IL-1 alpha antiserum. The strain-specific differences in IL-1 production correlated with different accumulation of IL-1 producing adherent cells in the spleens of infected animals, but also with different IL-1 producing capacity on a per cell basis. When adherent cells were mixed with syngeneic IFN-gamma producing CD4+ T lymphocytes from L. major-infected C57BL mice or from animals that had been pretreated with anti-CD4 monoclonal antibody prior to infection, the level of detectable IL-1 decreased depending on the number of T cells added. This inhibition could be blocked completely with an anti-IFN-gamma antibody. No such effect was seen, when CD4+ cells were used that were derived from parasite-infected BALB/c mice and did not produce IFN-gamma. In contrast to L. major, L. donovani antigen not only failed to induce IL-1 production, but also dose-dependently suppressed the IL-1 activity elaborated by L. major antigen. We conclude from these data that IFN-gamma effectively inhibits the efficacy to IL-1 to generate to Th2-cell biased immune response induced by L. major. A T cell independent and as yet unknown mechanism to inhibit the IL-1 response is used by L. donovani.

Animals↗
PubMed1991

Expression of T-cell-associated serine proteinase 1 during murine Leishmania major infection correlates with susceptibility to disease.

The expression of T-cell-associated serine proteinase 1 (MTSP-1) in vivo during Leishmania major infection was analyzed in genetically resistant C57BL/6 mice and in genetically susceptible BALB/c mice. Using a monoclonal antibody as well as an RNA probe specific for MTSP-1 to stain tissue sections, we found T cells expressing MTSP-1 in skin lesions and spleens of mice of both strains. In skin lesions, MTSP-1-positive T cells could be detected as early as 3 days after infection. Most importantly, the frequency of T cells expressing MTSP-1 was significantly higher in susceptible BALB/c mice than in resistant C57BL/6 mice. These findings suggest that MTSP-1 is associated with disease-promoting T cells and that it may be an effector molecule involved in the pathogenesis of cutaneous leishmaniasis.

Animals↗
PubMed1991

Cytokine interactions in experimental cutaneous leishmaniasis.

Destruction of intracellularly living Leishmania major amastigotes is achieved by activated macrophages. In this report, we have investigated the contribution of IL-4, TNF-alpha and IFN-gamma to the induction of antileishmanial macrophage activation. It was found that as single lymphokine only IFN-gamma led to amastigote elimination by peritoneal exudate macrophages. Neither IL-4 nor TNF-alpha or the combination of both cytokines led to antimicrobial activation. When the macrophages were incubated with concentrations of IFN-gamma that by themselves were insufficient for maximum cell activation, it was found that both IL-4 and TNF-alpha very effectively synergized with IFN-gamma for induction of antiparasitic activity. The activation which was achieved when IFN-gamma was combined with IL-4 could be blocked not only with antibodies to either of the lymphokines, but also with an antiserum specific for TNF-alpha, suggesting the involvement of endogenously generated TNF-alpha in this synergism. Any of the synergistic activities observed presumably lead to the activation of the L-arginine dependent pathway used by the cell for the production of nitrogen oxides as effector molecules for parasite killing since NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of this pathway, completely blocked the killing of intracellular parasites. We conclude that macrophage activation for antiparasitic activity is directed by a complex network of cytokine-interactions, in which IL-4 and TNF-alpha very effectively synergize positively with low levels of IFN-gamma.

Animals↗
PubMed1991

T-cell reactivity to purified lipophosphoglycan from Leishmania major: a model for analysis of the cellular immune response to microbial carbohydrates.

The major macromolecule on the surface of Leishmania major promastigotes is a lipophosphoglycan (LPG). This glycoconjugate plays a key role in determining infectivity and survival of parasites in the mammalian host cell. In addition, L. major LPG is able to induce a host-protective immune response. In this article, we summarise the evidence for recognition of highly purified LPG by T cells and we discuss the potential mechanisms of T-cell stimulation by this non-protein antigen.

Animals↗
PubMed1991

Polyclonal B-cell stimulation by T-cells in a parasitic disease.

Polyclonal B-cell stimulation resulting in B-cell proliferation and antibody production occurs in many infectious diseases. Here, we review our data showing that CD4-positive T-cells are instrumental for such polyclonal B-cell stimulation in a chronic parasitic infection, namely murine cutaneous leishmaniasis. The mechanism used by the T-cells involves a membrane interaction between B-cells and activated T-cells which can take place in the absence of antigen, as well as the action of lymphokines such as IL-4. The membrane interaction does not seem to involve the CD4 molecule on T-cells and MHC class II molecules on B-cells, as it is the case in cognate interaction during antigen-specific stimulation of B-cells by CD4 positive T-helper cells. Whether or not adhesion molecules, e.g. of the integrin family, play a role in the triggering process, is currently under investigation.

Animals↗
PubMed1990

Different response of TH1 cells for stimulation with anti-CD3 antibodies.

In this report, evidence is provided for a further subdivision of CD4+ T helper cell lines. The earlier definition of the TH1 and TH2 subtypes was confirmed by their differential response to interleukin (IL) 1. An additional subdivision of the TH1 subset was revealed when TH1 cell lines were costimulated with anti-CD3 antibodies and IL2. The IL2-induced proliferation of three of the resulting TH1 lines was blocked by anti-CD3 antibodies. By contrast, no such block was observed in a fourth TH1 cell line. In all four lines anti-CD3 triggering caused production of IL2. The block of proliferation was reversed neither by antigen-presenting cells nor by phorbol 12-myristate 13-acetate, a protein kinase C activator. In all TH2 cells, however, anti-CD3 triggering led to IL4 production, but had only marginal effects on IL2-induced cell proliferation.

Animals↗