PubMed Health⌕ Search

Biomedical subjects

W Solbach

Publications and source records attributed to W Solbach.

At least 73 records · Page 4Linked to original sources
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

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↗
PubMed1990

Tumor necrosis factor-alpha in combination with interferon-gamma, but not with interleukin 4 activates murine macrophages for elimination of Leishmania major amastigotes.

We have previously shown that during an infection with Leishmania major, susceptible BALB/c mice, as opposed to mice of a resistant strain (C57BL/6), are primed by lipopolysaccharide for the production of high levels of tumor necrosis factor-alpha (TNF-alpha) which is known to be a potent macrophage (M phi) stimulator in other parasitic diseases. In the present study we investigated whether TNF-alpha activates M phi for killing of L. major parasites. In the absence of interferon-gamma (IFN-gamma) or lipopolysaccharide, TNF-alpha (0.025-25,000 U/ml) failed to activate peritoneal exudate M phi from BALB/c mice for killing of L. major amastigotes. In the presence of suboptimal doses of IFN-gamma (5 or 10 U/ml), however, TNF-alpha mediated a rapid elimination of intracellular parasites, which was highly significant compared to IFN-gamma alone. The combination of TNF with interleukin 4, in contrast, was inactive in this respect and allowed survival of intracellular parasites. From these data we conclude that the presence of IFN-gamma is crucial for TNF-alpha-mediated killing of L. major parasites by M phi. Disease progression in susceptible mice therefore seems to be a consequence of a deficiency of IFN-gamma and a predominance of interleukin 4 rather than the result of an excess amount of TNF-alpha.

Animals↗
PubMed1990

Immunization of susceptible hosts with a soluble antigen fraction from Leishmania major leads to aggravation of murine leishmaniasis mediated by CD4+ T cells.

This study was performed in order to define Leishmania major antigens that function as disease-modulating immunogens in susceptible BALB/c mice. A soluble leishmanial antigen preparation (S-SLA) derived from highly infective stationary-phase L. major parasites was fractionated by preparative gel electrophoresis. In vitro, the low molecular mass fraction (less than 31 kDa) of S-SLA fraction D (FR D) was found to be a potent stimulator of L. major-specific Th1 and Th2 helper cell clones. In vivo, immunization with FR D induced a Th2-biased immune response in BALB/c mice as determined by the numbers of splenic CD4+ cells secreting interleukin 4 and interferon-gamma according to limiting dilution analyses. In addition, FR D caused significant disease exacerbation in parasite-infected susceptible mice as assessed by the local lesion development and the numbers of parasites in lymph nodes and spleen. This effect was observed after local subcutaneous application of FR D as well as after systemic immunization (intrasplenic or intraperitoneal). Transfer experiments revealed, that the disease-aggravating effect of FR D was mediated by CD4+ T cells. From these results it is concluded that leishmanial protein preparations exist that not only fail to induce protective anitparasitic immunity, but can mediate disease exacerbation, independently of the primary application site of the immunogen. The existence of such structures may serve the parasite as a means to evade the host's immune attack and may also have implications for the development of vaccines.

Animals↗
PubMed1990

Evasion strategies of Leishmania parasites.

Leishmania have long been known to clinicians and parasitologists as the causative agents of a variety of acute or chronic, cutaneous or visceral diseases in mammalian hosts. More recently, these protozoan parasites have evoked the interest of immunologists, as Leishmania infections are an excellent model for studying T-cell dominated antiparasite immune responses. In this review, Christian Bogdan, Martin Röllinghoff and Werner Solbach discuss the multiple interactions of Leishmania with components of the host immune system that illustrate the variety of highly elaborate evasion strategies developed by this parasite.

Journal Article↗
PubMed1990

Production of tumour necrosis factor during murine cutaneous leishmaniasis.

We have assessed the role of tumour necrosis factor-alpha (TNF) during cutaneous leishmaniasis and demonstrated that significant levels of TNF were released by spleen cells from infected mice after in vitro restimulation with Leishmania major promastigotes. Spleen cells from both genetically resistant and genetically susceptible mice were equally capable of producing TNF. After challenge with bacterial endotoxin, TNF activity could also be demonstrated in the serum of L. major-infected mice and the titres correlated with the course of cutaneous disease in susceptible and resistant mice. TNF did not exert a direct leishmanicidal effect in vitro. Furthermore, our study indicated that macrophages are the source of L. major-induced TNF activity and that its elicitation is dependent on the presence of T cells. These findings suggest that TNF acts in concert with other cytokines produced during L. major infection and that its role depends on the composition of T cell subsets and cytokines present.

Animals↗
PubMed1989

Coexistence of antigen-specific TH1 and TH2 cells in genetically susceptible BALB/c mice infected with Leishmania major.

CD4-positive T cell clones with specificity for the protozoan parasite Leishmania major (L. major) of both the protective TH1 and the disease-exacerbating TH2 subtype were isolated from a diseased L. major-infected mouse of the susceptible BALB/c strain. In addition, TH2 cells were isolated from the lesion-draining lymph nodes of an animal clinically healed nine months after sublethal irradiation and subsequent infection. Our data support the notion that the differential outcome of the disease in non-irradiated versus irradiated BALB/c mice reflects the regulation of the two CD4+ T cell subsets. These data also argue against the possibilities that: 1) TH2 cells and their precursors are totally eliminated by irradiation and that 2) TH2 cells are capable of completely hindering the expansion of TH1 cells in diseased animals.

Animals↗
PubMed1989

[Parasitic evasion mechanisms: Leishmania as an example].

Leishmania display a variety of mechanisms for effective evasion of the humoral and cellular immune responses of the host which are strongly associated with the expression of two major surface glycoconjugates, gp63 and lipophosphoglycan. The parasites are poor activators of the alternative complement pathway thus avoiding their own extracellular lysis. Complement bound on the surface of promastigotes promotes the uptake of leishmania by macrophages which function as "safe targets" as long as they are not activated by T lymphocytes. This is due to the fact that intracellular parasites are able to 1. decrease the oxidative burst; 2. scavenge toxic oxygen metabolites; 3. inhibit degradative lysosomal enzymes; 4. exploit the acidic milieu of lysosomes for their own metabolism. Finally, leishmania have been shown to evade the host's cellular immune response by down-regulating T cell-activating processes and by initiating the expansion of T cell subpopulations which promote their own survival.

Animals↗
PubMed1989

Cyclosporin A enhances elimination of intracellular L. major parasites by murine macrophages.

In this study we analyzed the influence of cyclosporin A (CyA) on the process of phagocytosis of L. major promastigotes and amastigotes by inflammatory peritoneal macrophages (MP) from BALB/c mice. Our data clearly demonstrate that CyA profoundly enhanced the degradation by peritoneal MP of both intracellular L. major promastigotes and amastigotes. This effect was T cell-independent and specifically associated with CyA, since the similarly structured cyclosporin F (CyF) was ineffective. CyA did not alter the replication and infectivity of extracellular parasites. From these results we conclude that the inhibition of intracellular parasite replication in the presence of CyA substantially contributes to the previously described suppressive effect of CyA on the development of L. major-induced lesions in BALB/c mice.

Animals↗
PubMed1988

Application of recombinant granulocyte-macrophage colony-stimulating factor has a detrimental effect in experimental murine leishmaniasis.

The purpose of this study was to evaluate the effect of recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) on BALB/c mice infected s.c. with the intracellular pathogen Leishmania major. Daily i.p. application of 1 microgram rGM-CSF for 21 days following the infection led to an aggravated course of the disease in most animals. In no case was a therapeutic effect observed. In vitro analysis revealed that the parasite burden was approx. 2- to 7-fold higher in the infected lesions, in the lymph nodes draining the infection and in the spleens of rGM-CSF-treated animals than in tissues from nontreated mice. L. major-infected macrophages obtained from chronically infected mice proliferated in the presence of rGM-CSF in vitro without gaining antiparasitic effector function. However, antiparasitic effector function increased and macrophage growth was inhibited in the presence of recombinant interferon-gamma (IFN-gamma). These data indicate that rGM-CSF-induced macrophage proliferation alone is not sufficient to overcome infections with intracellular pathogens like L. major, since simultaneous activation of macrophages by IFN-gamma is required.

Animals↗
PubMed1987

Kinetics of cell-mediated immunity developing during the course of Leishmania major infection in 'healer' and 'non-healer' mice: progressive impairment of response to and generation of interleukin-2.

Leishmania major (L. major)-infected mice of 'non-healer' (BALB/c) and 'healer' (C57BL/6) mouse-strain origin were studied with regard to the kinetics of cell-mediated immunity developing during the course of the disease. Cells obtained from lymph nodes draining L. major-infected footpads were comparatively analysed for their representation in the respective L3T4+, Lyt-2+ and sIg+ lymphocyte subsets; they were studied for their capacity to release interleukin-2 and to proliferate in response to L. major antigen and concanavalin A, including the determination of the frequencies of T cells proliferating antigen-specifically with or without an exogenous source of IL-2. The data obtained indicate L. major infection-induced long-lasting alterations in the cellular composition of the lymph node in both 'healer' and 'non-healer' mice. Moreover, they suggest that the inability of 'non-healer' mice to recover from L. major infection is associated with a progressive impairment of their lymph node T cells to release interleukin-2 in the culture supernatant and to respond to this lymphokine in vitro.

Animals↗
PubMed1986

Suppressive effect of cyclosporin A on the development of Leishmania tropica-induced lesions in genetically susceptible BALB/c mice.

The effect of cyclosporin A (CyA) application on the development of cutaneous lesions was analyzed in genetically susceptible BALB/c mice infected s.c. with Leishmania tropica promastigotes. Daily i.p. injections of CyA, beginning 2 days before or at the day of the infection, dose dependently inhibited the development of parasite-induced lesions; no effect on the lesions was observed, however, if CyA application was started 14 days after the infection. Cessation of CyA administration after having successfully suppressed the cutaneous lesions for a period of 42 days, resulted in the development of lesions within 3 days. CyA had no inhibitory effect on lesions developing in L. tropica infected hypothymic BALB/c nu/nu mice. CyA or CyA-containing mouse serum did not directly affect the viability and the growth rate of L. tropica promastigotes, suggesting that the effect of the agent was imposed on the cells participating in the formation of the cutaneous lesions. Quantitative analysis of the cell distribution in the spleens of infected mice revealed that CyA markedly suppressed the infection-associated numerical increase of splenocytes. Within the Thy-1+ lymphocyte compartment, CyA had its most pronounced effect on the Lyt-1+ T lymphocyte subset. Early in the disease, the frequency of splenic cells proliferating in response to L. tropica antigen in vitro was clearly inhibited by CyA; in the later stages of the infection, however, this effect could not be observed, indicating the presence of L. tropica-inducible T cells being relatively resistant to CyA. Taken together, our findings indicate that CyA reversibly inhibits or delays the parasite-induced expansion of Lyt-1+ splenic T lymphocytes, and thus suppresses the biological function of those T cells that are instrumental for the formation of cutaneous lesions in L. tropica-infected BALB/c mice.

Animals↗
PubMed1985

On the partial suppression of IL-2 receptor expression and the prevention of lectin-induced lymphoblast formation by cyclosporine A.

The effect of cyclosporine A (CyA) on the expression of the Tac-antigen (IL-2 receptor) on PHA-activated PBMNC was analysed by immunofluorescence. In the initial experiments we determined the number of Tac(+) cells, disregarding cell size; we found that CyA did not affect the number of cells expressing the Tac antigen after lectin stimulation (Fig. 1, Table 1). When we found that comparable numbers of Tac(+)-lymphocytes absorbed less IL-2 when grown in CyA as compared to solvent controls, we analysed in more detail the correlation between Tac-antigen expression and cell size of cell populations grown in CyA. It was found that CyA prevented a majority of PHA-activated PBMNC to undergo blastogenesis despite having expressed the IL-2 receptor. A minority of the cells, however, were refractory to the CyA-mediated suppression of blast formation. Studies analysing the Tac antigen expression semiquantitatively showed that CyA reduced the intensity of Tac antigen expression on cells of all sizes.

Cyclosporins↗