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Biomedical subjects

G Wohlleben

Publications and source records attributed to G Wohlleben.

12 recordsLinked to original sources
PubMed2006

Immune stimulatory strategies for the prevention and treatment of asthma.

The severity and incidence of asthma has dramatically increased in the developed nations over the last decades. Although the reason for this development is unknown, epidemiological studies and experimental data have lead to the suggestion that this phenomenon is associated with the decline of infectious diseases, which induce T helper 1 and/or T regulatory responses. Supporting this view are recent publications showing that animals can be protected from developing asthma by using different immune stimulatory strategies. One approach is based on vaccinations using live or killed bacteria or their components, CpG-ODNs or DNA vaccination, which all induce allergen-specific or unspecific Th1 responses. Th1 responses lead to the production of IFN-gamma, IL-12, IL-18 and IL-23, thereby inhibiting Th2 responses and thus the development of asthma. A further strategy both for the prevention and therapy of asthma is the induction of Tr cells. Tr cells have also been shown to suppress allergic Th2 responses, however, in contrast to Th1 cells through a cell/cell contact mediated mechanism or by the secretion of the anti-inflammatory cytokines IL-10 and/or TGF-beta. Furthermore, there is growing information on how to induce Tr cells both in animals and humans. Here we review the data showing that animals can be protected from developing asthma by immune stimulation leading to Th1 or Tr responses. Possible future human use and safety of the described strategies are also discussed.

Animals↗
PubMed2005

Vaccinations with T-helper type 1 directing adjuvants have different suppressive effects on the development of allergen-induced T-helper type 2 responses.

BACKGROUND: Allergen-induced T-helper type 2 (Th2) responses can be inhibited with Th1 directing vaccines. However, studies comparing the efficacy of the different adjuvants have not been performed in detail. OBJECTIVE: For this reason we compare the effects of live Bacillus-Calmette-Guerin(BCG), heat-killed (hk)-BCG, CpG-ODN (oligodeoxynucleotide) or PPD on the development of allergen-induced Th2 responses in mice. METHODS: Ovalbumin (OVA)-specific allergic responses were induced in C57BL/6 mice by two intraperitoneally (i.p.) applications of OVA/alum followed by the intranasal challenge with OVA. The different Th1-inducing adjuvants were applied to the mice together with OVA/alum i.p. during the OVA-sensitization period and, subsequently, different parameters of allergic immune responses were evaluated. RESULTS: All the adjuvants were effective in inhibiting the development of allergen-induced airway eosinophilia, mucous production and, with the exception of PPD, also airway hyper-reactivity, when they were applied together with OVA/alum. However, allergen-specific IgG1 and IgE serum levels were only reduced in live BCG- and PPD-treated mice. Suppression of airway eosinophilia was not observed in IFN-gamma- or IL-12-deficient mice (hk-BCG, CpG-ODN and PPD). Interestingly, live BCG was still able to suppress allergen-induced Th2 responses in the absence of either IFN-gamma or IL-12. When mice vaccinated with the different adjuvants together with OVA/alum were subjected to a second period of OVA/alum immunization, only live and hk-BCG were able to efficiently suppress the development of airway inflammation. This effect could be adoptively transferred by splenic CD4(+) T cells. CONCLUSIONS: Taken together our data suggest that live BCG>hk-BCG>CpG-ODN >PPD are effective in suppressing allergen-induced Th2 responses. The degree of suppression and the component of the Th2 response affected (airway inflammation vs. the production of allergen-specific IgE and IgG1) were dependent upon the adjuvant used and how it was applied. Our results contribute to the design of novel vaccines protecting humans from developing allergic disorders.

Adjuvants, Immunologic↗
PubMed2001

Atopic disorders: a vaccine around the corner?

The incidence and severity of atopic disorders, in particular asthma, is steadily increasing at an alarming rate. Furthermore, no primary prevention measure exists to date. However, recent results obtained from numerous animal studies suggest that primary prevention in humans might be possible in the near future. The most promising approaches include the induction of systemic or local allergen-dependent or -independent T helper 1 (Th1) immune responses, through the use of killed bacteria (or components derived from them), CpG oligodeoxynucleotides or plasmid DNA, and the induction of allergen-specific T-cell tolerance. Here, we review the data showing that animals can be protected from developing allergic Th2 responses by vaccination. Possible future use in humans and potential side-effects of the described vaccination strategies are discussed also.

Animals↗
PubMed2000

Regulation of Fas and FasL expression on rat Schwann cells.

Although the PNS belongs to the immune privileged sites, it can become a target of immune attacks by invading T cells, causing inflammation and destruction. Yet the PNS also has a protective potential by eliminating the inflammatory cells via apoptosis. In analogy with other immune-protected sites, participation of the apoptosis-inducing Fas/FasL molecules could play an important role. To assess the possible involvement of the Fas/FasL system in T-cell apoptosis in the PNS of the rat, we characterized Fas and FasL expression on neonatal rat Schwann cells (SC) in vitro. Cells were stimulated in vitro with interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), or a combination of both. We observed upregulation of FasL expression under the influence of IFN-gamma, while adding TNF-alpha alone to the culture medium had no effect. IFN-gamma and TNF-alpha acted synergistically, leading to an increased FasL expression that reached its maximum 70 h after cytokine exposure, as shown by FACS analysis, SDS-PAGE, and Western blot. Fas expression on untreated SC showed fluctuating levels, while addition of IFN-gamma and TNF-alpha suppressed Fas expression completely. These findings are in accord with recently published results showing Fas and FasL expression on malignant human cells, derived from brain tumors and upregulation of FasL on astrocytes after exposure to IFN-gamma and TNF-alpha. Furthermore, FasL-expressing SC could be revealed by immunostaining of sciatic nerve from Lewis rats suffering from experimental autoimmune neuritis (EAN). We suggest that Fas/FasL expression on SC may contribute to the elimination of invading autoreactive T cells in the PNS in concert with other immune defense mechanisms.

Animals↗
PubMed1999

Inhibition of T cell/B cell interaction by B-CLL cells.

The course of disease in patients suffering from chronic lymphocytic leukemia (CLL) is determined by a profound dysregulation of the immune system. The resulting immune suppression is the main cause of death in those patients. In the present study we addressed the question of whether leukemic B cells (B-CLL) are able to suppress regular T cell/B cell interaction. Activated CD4+ T cell clones induce expression of the early activation antigen CD23 on B lymphocytes in vitro. Under conditions used, this B cell activation event was dependent upon direct T cell contact. Addition of certain bystander B-CLL cells or normal B lymphocytes resulted in a cell number-dependent inhibition of B cell induction. This seems to reflect the competition of B-CLL cells for a cell contact-mediated T cell helper signal. By using CD40 ligand transfected fibroblasts as a substitute for T cell help, we show that the same B-CLL cells also suppress CD40 ligand-mediated B cell activation. B-CLL cells differ in their ability to inhibit CD40 ligand-mediated B cell activation. Some B-CLL cases (eight out of 14) are unable to compete for the T cell or CD40 ligand-mediated signal, even though they can functionally interact with CD40 ligand and thereby get activated themselves. In addition, these results indicate that the observed inhibition is not a result of cell crowding by merely reducing the chance of specific B cell/T cell interactions. Collectively, these data indicate that B-CLL cells are able to inhibit the interaction of activated T lymphocytes with normal B lymphocytes in vitro. Perturbed T cell/B cell interaction may represent an important mechanism underlying the various defects of the specific immune system observed in patients suffering from B-CLL.

Antigens, CD↗
PubMed1996

CD40, but not lipopolysaccharide and anti-IgM stimulation of primary B lymphocytes, leads to a persistent nuclear accumulation of RelB.

In this study we analyzed the effect of CD40 stimulation on the activity and nuclear appearance of Rel/nuclear factor kappaB (NF-kappaB) factors in primary murine B lymphocytes. We show that triggering of CD40 signaling pathway(s) by CD40 ligands expressed on L cells led to strong activation of an NF-kappaB-controlled beta-globin reporter gene in primary B lymphocytes from transgenic mice. Analyses of nuclear translocation of individual members of Rel proteins after CD40 induction of primary B cells showed a strong and long-lasting accumulation of RelB and, less pronounced, of c-Rel. LPS stimulation did not give rise to a persistent nuclear accumulation of RelB and c-Rel, whereas nuclear c-Rel, but not RelB, accumulated after B cell receptor stimulation. CD40 induced not only nuclear translocation but also de novo synthesis of RelB RNA and protein. S107 plasmacytoma cells, which express CD40 but are defective for the nuclear appearance of p50/p65-NF-kappaB, do not express RelB after CD40 stimulation. In S107 cells stably transfected with relB genes, stimulation of nuclear RelB translocation by CD40 was observed. These results indicate that stimulation of CD40 signaling pathways exerts a long-lasting stimulatory effect on both the transcription and nuclear translocation of RelB. Since LPS and anti-IgM were unable to activate RelB, CD40 appears to trigger a special program of gene expression involved in the proliferation and/or differentiation of B lymphocytes.

Animals↗
PubMed1996

CD40-mediated regulation of interleukin-4 signaling pathways in B lymphocytes.

The importance of cytokines in controlling immunoglobulin isotype switching is well known. Given the defect in switching to IgG, IgA and IgE isotypes in mice and humans that carry mutations in the CD40 and CD40 ligand genes, we have investigated the role of CD40 ligation in controlling B cell responses to interleukin (IL)-4. We have found that CD40-mediated signals cause a fivefold upregulation of IL-4 receptor (IL-4R) on the B cell surface and that this is associated with a 100-1000-fold increase in the cells' responsiveness to the cytokine. While we found no evidence of increased affinity or structural change of the receptor, we do find that prestimulation of B cells with anti-CD40 antibodies brings about several changes in the IL-4 signaling pathways. Subsequent delivery of IL-4 to CD40-prestimulated cells provokes intracellular signals distinct from those induced in resting B cells in response to IL-4. While resting B cells phosphorylate Jak3 kinase shortly after IL-4 activation, cells pre-incubated with anti-CD40 exhibit active dephosphorylation of this molecule and phosphorylation of proteins of around 45 kDa upon addition of IL-4. The common gamma chain, Jak3 and Jak1 can all be immunoprecipitated in normal amounts with the IL-4R chain after CD40 prestimulation. We show that the observed dephosphorylation of Jak3 may be due to a stable association with the src-homology protein tyrosine phosphatase SH-PTP2. In contrast, the enzyme appears to be inactive and to dissociate very quickly from the signaling complex in cells that are stimulated with IL-4 alone.

Animals↗
PubMed1996

In vitro immunization of naive mouse B cells: establishment of IgM secreting hybridomas specific for souble protein or hapten from B cells cultured on CD40 ligand transfected mouse fibroblasts.

CD40 has been shown to play an important role in the regulation of B cell survival, proliferation and Ig class switching. The natural partner for CD40 is CD40 ligand, gp 39, which is transiently expressed on activated T cells. In vitro, CD40 ligation leads to polyclonal B cell proliferation and, in the presence of appropriate cytokines, to the secretion of Ig of various isotypes. In the present study we show that naive B cells cultured in vitro on CD40L-transfected mouse fibroblasts in the presence of two different soluble antigens (beta-galactosidase and phenyloxazolone coupled to ovalbumin) can be specifically immunized as shown by direct single cell Elispot assays or after establishment of B cell hybridomas. However, under the conditions of in vitro immunization used, all hybridomas analysed produced specific IgM antibodies only and we failed to detect cells that had switched to other isotypes. The data suggests that CD40 ligation can be used for efficient in vitro immunization against soluble antigens for IgM production but that CD40 signals even in conjunction with cytokines are insufficient to induce high rate switching.

Animals↗
PubMed1994

CD40 ligation in B cell activation, isotype switching and memory development.

Interaction of CD40 on B cells with its ligand on activated T helper cells is crucial for the generation of mature T-dependent antibody responses. Experimental observations suggest that CD40 ligation acts at several points in B cell differentiation; however, it is not clear whether the consequences of ligation are direct or indirect. While its role in B cell activation is clearly direct we discuss the several ways in which it might drive isotype switching, the influence that it has on the development of memory B cells and the possibility that certain types of T-dependent antibody response are CD40L-independent. Experiments in which the ligation of CD40 is blocked in vivo reveal that early CD40 signals are important for the development of memory B cells but this may only reflect the ability of 'memory precursors' generated by CD40 ligation to accept subsequent programming or survival signals.

Animals↗
PubMedDate not supplied

Inflammation versus immunoregulation: what is the key to the development of an effective antiallergy vaccine?

The incidence and severity of allergic disorders is currently increasing worldwide. The reason for this development is unclear. However, epidemiological studies and experimental data suggest that this increase may be due to a decline in infectious diseases which induce T helper type 1 (Th1) and/or T regulatory (Tr) responses. Based on these observations, antiallergy vaccines are currently being tested in animal studies aimed at inducing Th1 or Tr responses. This review focuses on novel approaches potentially leading to a vaccine protecting humans from the development of allergic disorders.

Allergens↗