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W Solbach

Publications and source records attributed to W Solbach.

At least 55 records · Page 3Linked to original sources
PubMed1996

B-cell outgrowth and ligand-specific production of IL-10 correlate with Th2 dominance in certain parasitic diseases.

In many parasitic infections, dominant T helper cell (Th) type-2 CD4+ T cell responses exacerbate the disease. We have previously demonstrated that lacto-N-fucopentaose-III (LNFPIII), a sugar found on soluble egg antigens (SEA) of Schistosoma mansoni, stimulates splenic B cells from parasite-infected mice to proliferate and produce IL-10, a cytokine that promotes the generation of Th2 immune responses. In the present study, we extend our observations on ligand-specific activation of IL-10 producing B cells to leishmaniasis and lymphatic filariasis. We report here that infection with Leishmania major increases the splenic B220+ B cell subset in BALB/c mice, but not BALB/c. xid (lacking B-1 cells and carrying defective B-2 cells). In addition, these B cells secrete large amounts of IL-10 in vitro in response to stimulation with soluble leishmanial extract (LSE), LNFPIII, or SO4-Lewis(x). We also observed that injection of LSE increased the level of peritoneal exudate (PeC) B-1 cells (CD5+B220+) in BALB/c mice, but not C57BL/6, as compared to buffer-injected controls. Further, LSE elicited PeC B cells secreted IL-10 in response to LSE as well as to the sugars tested. A similar differential secretion of IL-10 by splenic B cells from BALB/c and BALB/c.xid was seen after S. mansoni infection. Likewise, injection of soluble microfilarial extract (MFX) resulted in an increase in percentage of PeC B-1 cells in BALB/c mice, but not C57BL/6, and these cells secreted IL-10 in response to stimulation with MFX or phosphorylcholine (PC). Collectively, these results suggest a correlation between expansion of ligand-specific IL-10 producing B and B-1 cells with dominance of Th2-type T cells in mice with the susceptible phenotype for these diseases.

Animals↗
PubMed1996

Invasion, control and persistence of Leishmania parasites.

Significant advances in research on the immunopathogenesis of leishmaniasis include the discovery of novel putative evasion and survival strategies of Leishmania parasites, a more detailed understanding of the function and regulation of interleukin-12, definition of molecules involved in cognate interaction between macrophages and T cells and new ideas concerning the mechanisms of host resistance and susceptibility. The use of transgenic mice for (re)probing certain immunological aspects of leishmaniasis has yielded not only predictable and confirmatory but also unexpected and pioneering results which require critical appreciation.

Animals↗
PubMed1996

Co-transfer of B cells converts resistance into susceptibility in T cell-reconstituted, Leishmania major-resistant C.B-17 scid mice by a non-cognate mechanism.

Resistance to infection of mice with Leishmania major parasites is dependent on the production of IFN-gamma by CD4+ T helper cells. C.B-17 scid mice, lacking both T and B cells, succumb very quickly to the infection, but develop resistance if reconstituted with appropriate numbers of T cells from BALB/c mice. In this model, we studied the role of B cells with regard to their ability to influence disease outcome and to function as antigen-presenting cells for T cells. For this purpose, we reconstituted scid mice (H-2d) with either T cells or with T and B cells obtained from (BALB/c x BALB.B)F1 mice (H-2d x b), and infected them with L. major parasites 1 day after reconstitution. Mice reconstituted with T cells alone cured the disease, whereas additional B cell reconstitution led to susceptibility. Healing was associated with a predominant Th1-type response. In all mice, L. major-specific T cell proliferation was restricted to the MHC phenotype of the recipient (H-2d) but not to that of the donor (H-2d x b), indicating that there was no detectable contribution of donor B cells in the priming of a T cell response. Furthermore, B cells, when purified from infected BALB/c mice, were unable to stimulate a L. major-specific CD4+ T cell clone (L1/1) without addition of exogenous antigen, in contrast to macrophages from the same animal. These data suggest that B cells, in vivo, do not carry L. major antigen in a form capable of activating specific CD4+ T cells. Therefore, B cells promote disease by means other than cognate interaction with CD4+ T cells.

Animals↗
PubMed1995

Early parasite containment is decisive for resistance to Leishmania major infection.

We investigated the early spread of Leishmania major in various mouse strains. In BALB/c mice, which are extremely vulnerable to L. major infection, the parasites disseminated within 10-24 h from the site of subcutaneous footpad infection in to the popliteal lymph node, spleen, lung, liver and bone marrow. Application of recombinant (r)IL-12 prior to infection prevented the early dissemination of parasites into visceral organs and the animals healed the infection. In three mouse strains tested, C57BL/6, CBA/J and C3H/HeJ, which are all resistant to L. major infection, the parasites remained localized in the footpad and in the draining LN for 3 days without evidence of dissemination. In C57BL/6 mice, depletion of NK1.1+ cells or neutralization of interferon (IFN)-gamma prior to infection led to rapid parasite spreading with kinetics similar to those seen in susceptible animals. Depletion of either CD4+ or CD8+ T cells in vivo prior to infection did not alter the kinetics of dissemination in any mouse strain tested. Experiments with severe-combined immunodeficient mice provided further evidence that parasite containment depends on natural killer cells and IFN-gamma, but is independent of T cells. The finding that all resistant mouse strains restrict the spread of the parasites within the first 24 h after infection strongly suggests that early parasite containment is closely associated with a resistant phenotype. The data show that local restriction of parasites in the pre-T cell phase of the infection is mediated by the innate immune system and suggest that this function plays an important role in the development of a protective T cell response.

Animals↗
PubMed1995

Leishmania major infection: the overture.

Local infection of mice with Leishmania major results in either healing or death depending on the preferential action of Th1 or Th2 T helper cells, respectively. Although the parasite-induced T-cell responses and their consequences for the disease are well understood, relatively little is known about the initial events that kindle the adaptive immune response. Werner Salbach and Tamás Laskay here discuss how differences in parasites spreading from the site of infection to different immune organs during the first 10-24 hours and, in consequence, the 'where and when' of the first encounter of Leishmania with the cells of the immune system may well be the starting point for the development of resistance or susceptibility.

Journal Article↗
PubMed1995

Protective effect of leflunomide on the natural course of Leishmania major-induced disease in genetically susceptible BALB/c mice.

Leflunomide has been reported as an immunomodulating agent which acts on a variety of cells including T- and B-lymphocytes. CD4+ T-lymphocytes are essential for the type of disease that develops after infection with the protozoan parasite Leishmania major. A variety of immunological interventions has been shown to modulate disease development. Therefore, the effect of leflunomide on the development of parasite-induced lesions and the ensuing immune response was investigated in genetically susceptible BALB/c mice. Oral feeding for 7 to 10 days of leflunomide (30 mg/kg per day) beginning 2 days prior to or at the day of infection led to the development of a stable resistant phenotype, i.e. to long-lasting (> 13 months) regression of the lesions and clinical cure. Starting leflunomide treatment 3 days after infection was ineffective. The main bioactive metabolite, 1726 B, did not inhibit viability or growth of L. major promastigotes and amastigotes in vitro. Quantitative analysis of CD4+ and CD8+ cells in spleens and lymph nodes of parasite-infected animals treated with leflunomide for 5 days showed no significant effect. In vitro, 1726 B dose-dependently inhibited growth of stimulated T-cells, which could not be restored by saturating amounts of exogenous IL-2 and IL-4. No effect was observed on the killing function of activated macrophages. Taken together, the data indicate that leflunomide is a potent prophylactic agent to prevent an otherwise lethal infection of BALB/c mice.

Animals↗
PubMed1995

Effect of IL-7 treatment on Leishmania major-infected BALB.Xid mice: enhanced lymphopoiesis with sustained lack of B1 cells and clinical aggravation of disease.

The Xid immunodeficiency was characterized by a total lack of B1 cells and reduced numbers and functions of B2 cells. In BALB.Xid mice, this defect results in an reduced susceptibility against infections with parasites such as Trypanosoma cruzi and Leishmania major. Since IL-7 acts on the B cell compartment by stimulation of pre-B cell proliferation, we analyzed the effect of recombinant IL-7 on L. major infection in BALB.Xid mice. After application of a single dose of IL-7 simultaneously with the infection, the clinical course in BALB.Xid mice was markedly aggravated, resembling that of normal BALB/c mice. IL-7-induced disease promotion was accompanied by an up to 100-fold higher parasite load in several tissues of these mice. When cytokine production of purified, L. major-specific CD4+ T cells from lesion-draining lymph nodes was examined, the IFN-gamma production seen in untreated BALB.Xid mice was suppressed in IL-7-treated animals. One of the major effects of IL-7 treatment in the lymphoid organs of BALB.Xid mice was the increase of the total number of B220, sIgM and MHC II-positive cells. These cells belonged to the B2 subset, since cells expressing surface molecules characteristic for B1 cells (Mac-1 and Ly-1) remained absent in spleens, lymph nodes and the peritoneum. In conclusion, selective up-regulation of B2 cells by IL-7 in the absence of B1 cells is associated with disease aggravation in L. major-infected BALB.Xid mice.

Animals↗
PubMed1994

Leishmania major parasites share an epitope with the murine CD3-T cell receptor complex.

After immunization of BALB/c mice with a low molecular mass fraction (FrD; < or = 31 kDa) isolated from a soluble extract of Leishmania major promastigotes, a panel of monoclonal antibodies (mAb) was obtained. One of these antibodies (mAb 9C) recognized a cytosol-associated antigen from L. major of approximately 21 kDa as shown by Western blot and immunoprecipitation. In addition, mAb 9C reacted with surface structures of murine splenic T cells and T cell clones. Reactivity was confined to murine cells, but was not strain restricted. Immunoprecipitation studies and surface-labeling experiments with CD4+ T cell clones and the T cell receptor (TCR)-CD3-T cell line TG40 transfected with V alpha/beta chains from human TCR and concomitant co-expression of murine CD3 suggested that mAb 9C binds to an epitope located within the murine CD3-TCR complex. In addition, mAb 9C induced strong T cell proliferation. We conclude that L. major parasites share an epitope with the murine CD3-TCR complex which is functionally important for T cell activation.

Animals↗
PubMed1994

The Xid defect determines an improved clinical course of murine leishmaniasis in susceptible mice.

The course of Leishmania major infection in B cell-defective BALB.Xid mice was investigated. Infected BALB.Xid mice showed a significantly slower lesion development compared with BALB/c controls accompanied by a 10- to 30-fold lower parasite burden in lymphatic organs. The B cell immune response, as quantified by anti-leishmanial antibody production and B cell numbers in lymphatic organs, remained significantly lower in BALB.Xid mice as compared with BALB/c control mice. In accordance with disease development, CD4+ T cells from lymph nodes of infected BALB.Xid mice produced 6- to 10-fold more IFN-gamma than the respective T cells of BALB/c mice, when stimulated with leishmanial antigen in vitro. B cells from lymph nodes and the peritoneal cavities of BALB/c mice could be induced to produce 3- to 8-fold more IL-10 than the respective cells from B cell-defective BALB.Xid mice. The data thus indicate that the Xid mutation allows for the development of Th1 cells which confer resistance to infection with L. major. Moreover, the data suggest that B cells contribute to susceptibility to L. major infection in BALB/c mice by skewing the Th cell network towards a Th2 phenotype. Since the difference in B cell-derived IL-10 production between BALB/c and BALB.Xid mice was more prominent in peritoneal B cells, the data support the notion that the skewing of the T cell response may be predominantly mediated by the B1 cell subset.

Animals↗
PubMed1993

Natural killer cells participate in the early defense against Leishmania major infection in mice.

In this study the role of natural killer (NK) cells in the course of experimental Leishmania major infection was investigated. NK cells in genetically resistant C57BL/6 mice were depleted by in vivo administration of anti-asialo-GM1 or anti-NK1.1 antibodies. A marked exacerbation of the infection was found in the NK-depleted mice within the first two weeks of infection. Both the local tissue swelling and the number of parasites in the lesions were significantly higher than in normal animals. Lymph node cells taken from infected NK-depleted mice released less interferon-gamma (IFN-gamma) when cultured in vitro. As an alternate approach we have used poly I:C treatment in order to activate NK cell activity in vivo in BALB/c mice, which are genetically susceptible to L. major infection. Poly I:C treatment led to milder symptoms and to a significantly lower parasite burden in the early course of infection. Lymph node cells from infected and poly I:C-treated BALB/c mice released higher amount of IFN-gamma in vitro than cells from control mice. These data show that NK cells are active participants in the non-specific phase of anti-leishmanial activity in the control of parasite multiplication early in the course of L. major infection in mice.

Animals↗
PubMed1993

[Tuberculosis in the otorhinolaryngologic area. A still current differential diagnosis].

Between 1986 and 1992 18 cases of tuberculosis of the cervical lymph nodes, the larynx, the middle ear, or the paranasal sinuses were diagnosed at the ENT clinic of the University of Erlangen-Nuremberg. A rare case of tuberculous infection of both the maxillary and ethmoidal sinuses and the pharyngeal tonsil is presented. All patients with involvement of the upper respiratory tract had concomitant productive pulmonary tuberculosis, whereas in tuberculous cervical lymphadenitis and otitis media the disease was regularly limited to the neck and the ear respectively. Preoperative microbiological testing pointed to a tuberculous origin in only 3 of the 18 patients, so that histological and microbiological examination of excision biopsy specimens was the most reliable test. As there was no apparent decrease in incidence over the 7 years, we conclude that tuberculosis remains an important differential diagnosis in ENT.

Adult↗
PubMed1992

[Leishmaniasis with multiple cutaneous nodules].

Six weeks after a holiday trip to Yugoslavia, a previously well 48-year-old man developed a reddish-livid, firm nodule, 0.5 cm in diameter, on the proximal joint of the right thumb. A similar nodule appeared nearby, as well as over the left patella. Eleven additional nodules occurred over the next 4 months. His general health remained good and physical examination merely noted the liver edge palpable 3 cm below the costal margin. The histology of one of the nodules showed a tuberculoid, plasma-rich inflammatory reaction reminiscent of leishmaniasis or brucellosis. No organisms were seen. Immunohistochemistry of a frozen section demonstrated Leishmania-associated antigens, and the Western-blot test was characteristic for leishmaniasis. No systemic treatment was undertaken because of likely alcoholic toxic liver damage. On local treatment with paromomycin-containing ointment the cutaneous nodules healed without scar within 3 months.

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↗
PubMed1991

T cell proliferation induced by Borrelia burgdorferi in patients with Lyme borreliosis. Autologous serum required for optimum stimulation.

The cellular immune response to Borrelia burgdorferi was studied in 24 patients with seropositive and seronegative Lyme borreliosis, 30 patients with arthritides of different origin (non-Lyme arthritides), and 20 normal blood donors. By far, the strongest T cell stimulation was induced by incubation with autologous serum; there was a significantly lower response or no response after incubation with allogeneic or heterologous sera. In patients with Lyme borreliosis, including seronegative patients, there was a strikingly elevated proliferation in response to whole B burgdorferi bacteria (mean 64,750 dpm) compared with that of normal donors (mean 19,700 dpm; P less than 0.0001) and especially that of non-Lyme arthritis patients (mean 11,600 dpm; P less than 0.0001). Levels of proliferation declined significantly in patients with Lyme borreliosis after successful antibiotic treatment. Parallel cultures using B burgdorferi and Treponema phagedenis as antigens showed that cells from patients with Lyme borreliosis responded significantly more to B burgdorferi than to T phagedenis, but this did not occur with cells from individuals with non-Lyme arthritides. There was no correlation between disease stages and proliferation values. These data indicate that lymphocyte proliferation assays may provide an important tool for the diagnosis of Lyme borreliosis, most notably in patients with arthritides and in those who are seronegative. Conversely, the lack of reactivity appears to be a strong indicator of the absence of active Lyme disease. It seems to be crucial, however, to use autologous sera in these assays.

Adolescent↗
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↗