Biomedical subjects

H U Beuscher

Publications and source records attributed to H U Beuscher.

At least 19 recordsLinked to original sources

PubMed2002

Anti-inflammatory effect of low-dose X-irradiation and the involvement of a TGF-beta1-induced down-regulation of leukocyte/endothelial cell adhesion.

PURPOSE: Low-dose radiotherapy (LD-RT) is known to exert an anti-inflammatory effect, but the underlying radiobiological and immunological mechanisms remain elusive. In recent studies, we observed a reduced adhesion of peripheral blood mononuclear cells (PBMC) to endothelial cells (EC) after LD-RT (0.3-0.7 Gy). This shows that this treatment affects the initial steps of the inflammatory response. To explore the role of inflammatory mediators in this process, we investigated the expression of Transforming growth factor beta(1) (TGF-beta(1)) and Interleukin 6 (IL-6) after LD-RT. MATERIALS AND METHODS: EC were grown to subconfluence and irradiated with single-dose LD-RT. Twenty-hours after irradiation, EC were treated with IL-1beta for 4 h and then incubated with peripheral blood mononuclear cells (PBMC). Adherent PBMC were counted when using light microscopy. Expression of the cytokines TGF-beta(1) and IL-6 was measured by ELISA, and mRNA levels were analysed by the RNAse-protection assay (RPA). Surface expression of E-selectin was quantified by flow cytometry. RESULTS: A relative minimum of adhesion was observed after LD-RT between 0.3 and 0.7 Gy. This was paralleled by an expression maximum of TGF-beta(1) and IL-6, as shown by protein and mRNA levels, respectively. Neutralization of TGF-beta(1) by monoclonal antibodies, but not of IL-6, increased PBMC adhesion to EC nearly to control levels. In addition, fluorescence activated cell sorter (FACS) analysis of irradiated EC demonstrated a down-regulation of E-selectin in the same dose range. CONCLUSION: Low-dose X-irradiation between 0.3 and 0.7 Gy induced a relative maximum of TGF-beta(1) production by stimulated EC. This results in a down-regulation of leukocyte/PBMC adhesion and may contribute to the anti-inflammatory effect of LD-RT.

Animals↗

PubMed2001

Constitutive expression of macrophage-inflammatory protein 2 (MIP-2) mRNA in bone marrow gives rise to peripheral neutrophils with preformed MIP-2 protein.

Macrophage-inflammatory protein 2 (MIP-2) is a major CXC chemokine involved in the migration of polymorphonuclear neutrophils (PMNs) to sites of inflammation. Although cell culture experiments have identified different cell types that can produce MIP-2, the cellular sources in vivo are not clearly defined. By using immunohistochemical staining and analysis of chemokine mRNA expression, the present study aimed to localize cells producing MIP-2 in tissues of normal mice and mice challenged with Yersinia enterocolitica. The results showed a constitutive expression of MIP-2 mRNA in bone marrow (BM) of normal mice, but not in other organs such as spleen, lung, or liver. MIP-2 protein was found in all organs tested but it was exclusively associated with PMNs that stained positive with the cell surface marker Gr-1. Bacterial infection caused a 5-fold increase in the number of MIP-2-positive PMNs recruited to spleens concomitant with a strong increase of splenic MIP-2 mRNA. This correlated well with a 3-fold loss of MIP-2-producing cells in BM. Because MIP-2 mRNA expression in PMNs was increased after stimulation with TNF, the results indicate that newly recruited PMNs can supplement their MIP-2 content through TNF-stimulated transcription. Together, the data imply a constitutive production of MIP-2 by a subset of PMNs in BM and argue for the possibility of a rapid mobilization of MIP-2 through its storage in circulating PMNs.

Animals↗

PubMed1999

Human anti-FcepsilonRIalpha autoantibodies isolated from healthy donors cross-react with tetanus toxoid.

Natural antibodies (Ab) reacting with self antigens have been shown to be present in all individuals. These autoantibodies (auto-Ab) can be either pathogenic or non-pathogenic. Auto-Ab reacting with the alpha-subunit of the high-affinity receptor for IgE (FcepsilonRIalpha) have been implicated in the pathogenesis of a subset of patients with chronic idiopathic urticaria (CIU). Intravenous immunoglobulin (IVIg) preparations have been used with variable clinical benefit in the treatment of these patients. Here we show that anti-FcepsilonRIalpha auto-Ab are present in a therapeutic IVIg preparation as well as in atopic and chronic urticaria patients and healthy individuals. We affinity-purified the anti-FcepsilonRIalpha Ab from an IVIg preparation using recombinant FcepsilonRIalpha. Interestingly, these anti-FcepsilonRIalpha auto-Ab showed no evidence of histamine release but strongly cross-reacted with an external antigen, tetanus toxoid (TTd) with a higher affinity for TTd than for the FcepsilonRIalpha. Since the cross-reacting Ab are non-anaphylactogenic, there is no evidence that TTd immunization may contribute to the pathogenesis of CIU. However, our results may indicate that the anti-FcepsilonRIalpha auto-Ab belong to the natural Ab and serve as the parental Ab for some anti-TTd Ab.

Animals↗

PubMed1999

Analysis of the Yersinia enterocolitica 0:8 V antigen for cross protectivity.

The plasmid encoded V antigen (Vag) of pathogenic Yersinia spp. is a major virulence factor as well as a protective immunogen. Recently, two main types of Vag, represented by either Yersinia enterocolitica 0:8 or Yersinia pseudotuberculosis, have been identified and it has been suggested, that antibodies generated against one type are unable to protect against Yersinia spp. carrying the other type. By using a recombinant Vag (rVagHis) of the Y. enterocolitica 0:8 type we show here, that actively immunized mice were completely protected against challenge with both, Y. enterocolitica 0:8 and Y. pseudotuberculosis serotype III. In addition, passive protection was possible with polyclonal rabbit anti-rVagHisIgG. However, while a single antibody dose (200 microgramg) was sufficient to protect against challenge with Y. enterocolitica 0:8, repetitive injections at intervals of 2 to 3 days were needed to protect against challenge with Y. pseudotuberculosis III. The apparent difference in protection correlated with a rapid disappearance of anti-rVagHisIgG from the circulation by days 3 to 4. The data therefore indicate, that expression of distinct types of Vag by Yersinia spp. does not necessarily exclude immunoprotection in mice immunized with the other type of Vag. It rather appears, that differences in immunoprotection between Yersinia species relate to the amount of cross-protective antibody. Finally, as revealed by the lack of complement-mediated killing and the lack of immunostaining of Yersiniae with anti-rVagHisantibodies, evidence is provided to indicate that immunoprotection does not occur via opsonisation or complement lysis.

Animals↗

PubMed1998

Costimulation via TCR and IL-1 receptor reveals a novel IL-1alpha-mediated autocrine pathway of Th2 cell proliferation.

Previous studies have shown that triggering of Th2 cells via the TCR is sufficient for production of IL-4 but not for proliferation of these cells. Proliferation of Th2 cells occurs only in the additional presence of a costimulatory signal delivered by IL-1. For the majority of Th2 cell clones, this type of proliferation was found to be independent of IL-4. Here, we further investigated the mechanism of IL-4-independent proliferation. We demonstrate that, after costimulation via TCR and IL-1R, but not via either receptor alone, Th2 cells are triggered to produce cell-associated IL-1alpha, as detected at the level of function, protein, and mRNA expression. In the presence of the TCR signal, autocrine IL-1alpha is then able to costimulate IL-4-independent proliferation of Th2 cells and to further enhance its own production. Thus, our results point to a novel, IL-4-independent, self-amplifying autocrine pathway of Th2 cell proliferation that requires a signal via the TCR and a costimulatory signal via IL-1R. This pathway may explain frustrating results in experimental models that attempted to treat established Th2-mediated diseases in vivo with IL-4-neutralizing agents alone.

Animals↗

PubMed1997

Tumor necrosis factor-alpha expression induced by anti-YopB antibodies coincides with protection against Yersinia enterocolitica infection in mice.

Previous studies have suggested that virulence of pathogenic Yersiniae is associated with a suppression of the local cytokine response. In this context, the plasmid-encoded 41-kDa Yersinia outer protein B (YopB) has been implicated with the lack of tumor necrosis factor-alpha (TNF-alpha) expression in Peyer's patches (PP), following oral infection of mice with the enteropathogenic Yersinia enterocolitica. The present study was performed to further evaluate the relationships between YopB-induced suppression of TNF-alpha and bacterial survival in host tissue. Results are presented to show the ability of purified YopB to suppress the release of TNF-alpha by macrophages, the effect of which was neutralized by monospecific anti-YopB antiserum. In mice orally infected with Y. enterocolitica, anti-YopB treatment on days 3 and 5 postinfection, significantly decreased the recovery of live bacteria from PP. This observation correlated with a strong increase in TNF-alpha expression, as determined by reverse transcription-polymerase chain reaction and measuring the levels of TNF activity in homogenates of PP. Moreover, treatment of mice with a combination of anti-YopB and anti-TNF-alpha antiserum, completely abrogated the beneficial effect of the anti-YopB antiserum. In controls, expression of other proinflammatory cytokines such as interleukin-1 remained unaffected by either treatment. Therefore, the results indicate that endogenous TNF-alpha is required for eradication of Y. enterocolitica from host tissue, and further imply that YopB significantly contributes to suppression of the local TNF-alpha response in PP.

Animals↗

PubMed1997

Bacterial cytokine antagonists encoded by pathogenic yersiniae.

Proinflammatory cytokines such as tumor necrosis factor alpha (TNF alpha) are important immunoregulatory mediators of the antibacterial host defense. Previous studies have suggested that virulence of pathogenic Yersiniae is associated with suppression of the local cytokine response. In this context, the plasmid-encoded 41 kDa Yersinia outer protein B (YopB) has been implicated with a lack of TNF alpha expression in Peyer's Patches (PP), following oral infection of mice with the enteropathogenic Yersinia enterocolitica. The present study was performed to further evaluate the relationships between YopB-induced suppression of TNF alpha and bacterial survival in host tissue. Results are presented to show the ability of purified YopB to suppress the release of TNF alpha by macrophages. In mice orally infected with Y. enterocolitica, anti-YopB treatment on days 3 and 5 postinfection, significantly decreased the recovery of live bacteria from PP. This observation correlated with a strong increase in TNF alpha expression, as determined by RT-PCR and measuring the levels of TNF activity in homogenates of PP. Moreover, treatment of mice with a combination of anti YopB and anti-TNF alpha antiserum, completely abrogated the beneficial effect of the anti-YopB antiserum. In controls, expression of other proinflammatory cytokines such as IL-1 remained unaffected by either treatment. Therefore, the results indicate that endogenous TNF alpha is required for eradication of Y. enterocolitica from host tissue and further imply that YopB significantly contributes to suppression of the local TNF alpha response in PP.

Animals↗

PubMed1996

Differential regulation of cytokine and cytokine receptor mRNA expression upon infection of bone marrow-derived macrophages with Listeria monocytogenes.

Cytokine and cytokine receptor mRNA expression was analyzed by PCR-assisted amplification of RNA extracted from bone marrow-derived macrophages (BMM phi) at different time points after infection with Listeria monocytogenes. The mRNAs for the cytokines interleukin-1 alpha (IL-1 alpha), IL-1 beta, and tumor necrosis factor alpha (TNF-alpha) were induced early after infection, whereas IL-6 mRNA appeared later and even nonhemolytic Listeria strains, which are unable to grow inside eukaryotic cells, induced the same cytokine mRNAs at levels similar to those of the wild-type strain. In most cases, the amounts of cytokines determined by various bioassays correlated with the level of mRNA induction. Inhibition of phagocytic uptake of L. monocytogenes by cytochalasin D treatment resulted in adherent bacteria which still induced the proinflammatory cytokines. In BMM phi, the level of IL-1 receptor II mRNA was unaffected, whereas mRNA expression of the two subtypes of tumor necrosis factor receptors (TNF-RI and TNF-RII) was differentially regulated upon infection: transcription of TNF-RI was reduced, and that of TNF-RII mRNA was induced. Similar to the decreased TNF-RI mRNA expression, gamma interferon receptor mRNA was downregulated in L. monocytogenes-infected BMM phi. This dose- and time-dependent induction or downregulation of cytokine receptor mRNA following L. monocytogenes infection of BMM phi was not observed upon infection of established macrophage-like cell lines J774 and P388D1. Induction of IL-6 mRNA as well as IL-1 alpha/beta and TNF-alpha mRNAs upon L. monocytogenes infection of BMM phi occurs independently of autocrine TNF-alpha signaling via TNF-RI or TNF-RII, as shown by infection of TNF-RI- and TNF-RII-deficient macrophages derived from mutant B6 x 129 mice. In contrast to gamma interferon receptor mRNA, both TNF receptor subtype mRNAs were not influenced by L. monocytogenes infection of hybrid (B6 x 129) mouse macrophages. Whereas the proinflammatory cytokine mRNAs were even induced after infection with the nonpathogenic species L. innocua, no alteration of cytokine receptor mRNA expression was observed after challenge of BMM phi with this nonpathogenic species, suggesting that the modulation of cytokine and cytokine receptor expression by L. monocytogenes could be an important way of inhibition of macrophage stimulation.

Animals↗

PubMed1995

Neutralization of endogenous IL-6 suppresses induction of IL-1 receptor antagonist.

IL-1 is a potent cytokine that promotes host defense and inflammation. These processes may be modulated by an IL-1 receptor antagonist (IL-1Ra) that binds to and blocks IL-1 receptors. The objective of this study was to define the cellular origin and regulation of IL-1Ra production during bacterial infection. Oral infection of mice with Yersinia enterocolitica resulted in expression of IL-1Ra mRNA and synthesis of IL-1Ra in Peyer's patches (PP), the local site of infection, as well as in noninfected organs such as spleens. By immunostaining, recruited circulating neutrophils were identified to be the primary source of IL-1Ra in tissues. Only approximately 20% of the IL-1Ra-staining cells were accounted for by inflammatory macrophages. Strikingly, neutralization of IL-6 by anti-IL-6 antiserum caused a suppression of both IL-1Ra mRNA in PP and synthesis of IL-1Ra in circulating neutrophils. Confirmatory evidence that IL-6 participates in the generation of IL-1Ra was obtained when rIL-6 induced, and anti-IL-6 antiserum blocked, IL-1Ra expression in cultures of macrophage and polymorphonuclear leukocytes (PMN). These findings suggest that IL-6 induced induction of IL-1Ra may provide a negative feedback loop, facilitating resolution of the inflammatory response locally and presumably at remote sites of infection.

Animals↗

PubMed1995

Bacterial evasion of host immune defense: Yersinia enterocolitica encodes a suppressor for tumor necrosis factor alpha expression.

The ability of the enteropathogenic Yersinia enterocolitica to survive and proliferate in host tissue depends on a 70-kb plasmid known to encode a number of released Yersinia outer proteins that act as virulence factors by inducing cytotoxicity and inhibiting phagocytosis. This study demonstrates that one of the Yersinia outer proteins, the 41-kDa YopB, suppresses the production of tumor necrosis factor alpha (TNF-alpha), a macrophage-derived cytokine with central roles in the regulation of immune and inflammatory responses to infection. This conclusion is based on several lines of evidence. First, in macrophage cultures, suppression of TNF-alpha mRNA expression was induced by culture supernatant (CS+) of plasmid-bearing yersiniae, the effect which was blocked by anti-YopB antiserum. Second, suppression of TNF-alpha production, but not of interleukin-1 (IL-1) and IL-6, was induced by purified YopB. Third, in Yersinia-infected mice, no increase in TNF-alpha mRNA expression was observed in Peyer's patches, the primary site of bacterial invasion, compared with IL-1 (alpha and beta) mRNA. Finally, administration of anti-YopB antiserum to mice prior to infection with Y. enterocolitica increased TNF activity levels in Peyer's patches and coincided with a reduction in bacterial growth. The results thus provide direct evidence for a secreted eubacterial virulence factor that mediates selective suppression of TNF-alpha production. Although suppression of this single cytokine response is probably not sufficient to facilitate survival of the infecting organisms, the results suggest that suppression of TNF-alpha production by YopB significantly contributes to the evasion of Y. enterocolitica from antibacterial host defense.

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

Transcriptional and translational regulation of IL-1 alpha and IL-1 beta account for the control of IL-1 in experimental yersiniosis.

Interleukin 1 (IL-1) gene expression was investigated in mice following oral infection with Yersinia enterocolitica 08. In Peyer's patches (PP), the primary site of bacterial invasion, induction of IL-1 alpha mRNA was delayed when compared to IL-1 beta mRNA. As shown by in situ hybridization. IL-1 alpha and IL-1 beta mRNA were found to be expressed within different cell types. These results indicate that expression of the two forms of IL-1 is regulated in a cell-specific manner at the transcriptional level. Moreover, IL-1 (alpha and beta) mRNA was increased in other organs such as spleen and lung. In spleens, IL-1 beta mRNA was found within the red pulp, and IL-1 alpha mRNA was located to the marginal zone confirming that differential expression of IL-1 alpha and IL-1 beta mRNA does not represent a tissue-specific event. However, as revealed by immunohistochemistry and measuring IL-1 activity in tissue homogenates, synthesis of IL-1 proteins was not detectable in spleens, unless mice were challenged with LPS. Because IL-1 synthesis was inducible in spleen cells following actinomycin D treatment, the results indicate that at distant sites of infection IL-1 (alpha and beta) mRNA is expressed but not translated into protein. It is concluded that cell-specific transcription of IL-1 alpha and IL-1 beta as well as dissociation between IL-1 mRNA and protein synthesis are two mechanisms effective in regulating the production of IL-1 during infection.

Animals↗

PubMed1994

Intraperitoneal injection of synthetic bacterial lipopeptides does not cause a rise in circulating inflammatory cytokines.

The production of TNF-alpha, IL-1 and IL-6 was measured in mice after i.p. injections of the synthetic bacterial lipopeptide Pam3Cys-Ala-Gly, a potent macrophage and B cell activator in vitro. Only minor amounts of IL-6 and no TNF-alpha were detectable in the serum of mice injected with 10 or 100 micrograms of Pam3Cys-Ala-Gly. Lipopeptide concentrations up to 1000 micrograms failed to induce IL-1, and TNF-alpha production and serum IL-6 levels were only slightly elevated. In contrast to Pam3Cys-Ala-Gly, i.p. injections of LPS were accompanied by high levels of the inflammatory cytokines TNF-alpha, IL-1 and IL-6 suggesting fundamental differences of the mode of action of these two substances when applied in vivo.

Amino Acid Sequence↗

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

[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

IL-1 serves as a secondary signal for IL-9 expression.

IL-9 is produced in vitro by activated CD4+ T cell lines of the Th2 subtype and by naive CD4+ T cells. Here we show that T cell lines stimulated with Con A in the presence of accessory cells (AC) such as irradiated spleen cells or bone marrow-derived macrophages produced substantially more IL-9 than T cells stimulated with Con A alone. These data suggest that AC influence the production of IL-9 through accessory signals that result in an at least 10-fold increase of IL-9 secretion by the respective T cells. Addition of IL-1 to T cells activated by Con A, PHA, or anti-CD3 antibodies revealed that this monokine was responsible for the potentiation of IL-9 production. This finding was confirmed by applying anti-IL-1 antibodies. The production of other lymphokines, namely, IL-3, IL-4, and IL-6, by activated T cells was not or only marginally enhanced in the presence of AC or IL-1, thus indicating that the synthesis of IL-9 is regulated differently from that of other Th2-derived lymphokines. Furthermore, it was demonstrated by Northern blot analysis that IL-1 increases IL-9 expression at the pretranslational level. Because IL-1 alone failed to induce the production of IL-9 by T cells, this monokine acts as a costimulator in combination with a T cell receptor-mediated signal.

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

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↗