Biomedical subjects

S Beissert

Publications and source records attributed to S Beissert.

At least 19 recordsLinked to original sources

PubMed2006

Therapeutic modulation of cutaneous autoimmunity by regulatory T cells.

Cutaneous autoimmunity is characterized by the presence of autoantibodies and/or autoreactive T cells. Several mechanisms have been developed to avoid loss of immunotolerance to self such as activation-induced cell death, deletion, ignorance and active suppression of autoreactivity. Regulatory ('suppressor') T cells play a pivotal role in inhibiting the activation and function of effector T cells. CD4(+)CD25(+) T cells constitute a subset of regulatory T cells, which have been shown to suppress the development of organ-specific autoimmunity in mice. Recent understanding in the generation and function of human regulatory T cells indicates that these cells are involved in the appearance of inflammatory as well as bullous autoimmune dermatosis. These findings suggest that modulation of regulatory T cell numbers or function might be a promising therapeutic alternative for the treatment of such disorders. In the following, recent strategies aimed at inducing antigen-specific or non-specific regulatory T cells for the immunotherapy of ongoing cutaneous autoimmunity are presented and discussed. Hopefully, pursuing these strategies in the future will result in the initiation of randomized clinical studies analysing the usefulness of regulatory T cells for human skin diseases in great detail.

Animals↗

PubMed2006

Phototherapy: a promising treatment option for skin sclerosis in scleroderma?

In systemic sclerosis (SSc; scleroderma) fibrosis of the skin can lead to considerable morbidity. No significant improvement has been reported from studies investigating antifibrotic therapies so far. In dermatology, phototherapy with ultraviolet (UV) irradiation is successfully used for treatment of several diseases because of its anti-inflammatory as well as immunosuppressive mechanisms, and its low-risk profile. In addition, the UVA spectrum in particular exerts antifibrotic effects as it leads to reduction of procollagen synthesis and expression of collagenase-1 in vitro. Accordingly, treatment with long-wavelength UVA-1 irradiation or photochemotherapy with UVA plus the photosensitizer psoralen (PUVA) have been successfully used to reduce skin fibrosis in localized scleroderma (morphea). There are only in particular few reports on treatment of skin sclerosis in SSc, but the results are in concordance with the good experience that have been observed at our and other dermatological centres. Phototherapy is able to stop or inhibit the fibrotic processes and to induce softening of sclerotic skin, especially in limited SSc. Phototherapy thus represents a therapeutic alternative for antifibrotic treatment with a low rate of adverse effects, which should be applied before the sclerotic process has proceeded too far.

Fibrosis↗

PubMed2006

Who is really in control of skin immunity under physiological circumstances - lymphocytes, dendritic cells or keratinocytes?

Our views of the skin immunity theatre are undergoing constant change. These not only reflect paradigm shifts in general immunology and skin biology, but also have profound clinical implications, which call for strategic changes in dermatological therapy. Nowhere can this be witnessed at a greater level of instructiveness and fascination than when addressing the question posed by this new Controversies feature. Thus, after a very long period of dominance by T cells and Langerhans cells as 'lead actors' on the skin immunity stage, the lowly keratinocyte has recently made an astounding theatrical appearance as a key protagonist of the innate skin immunity system, which may control even acquired skin immune responses. Further enhancing dramatic complexity and tension, the mast cell has entered as an additional actor claiming centre stage, and the epidermal Langerhans cell has slipped in a surprise appearance as the chief agent of immunotolerance. May you, esteemed reader, enjoy the spectacle offered here by selected immunodermatology authorities who double as 'stage managers' pushing their respective favourite actors into the limelight. You get everything you may expect from a good performance - complete with the impresario's overture that lures you into the theatre and sets the stage, competing divas, recently discovered new talents and even the critic's digest while the performance is still ongoing. By the time the curtain drops, you will have reached your own, independent conclusions on how to answer the title question of this play - at least for the time being...

Dendritic Cells↗

PubMed2005

In vitro-generated regulatory T cells induced by Foxp3-retrovirus infection control murine contact allergy and systemic autoimmunity.

Regulatory T cells are promising candidates for the modulation of inflammation and autoimmunity. To generate regulatory T cells in vitro, we have infected naïve CD4+CD25- T cells with a retrovirus encoding the transcription factor Foxp3. Foxp3-infected T cells are similar to naturally occurring regulatory T cells as evidenced by surface marker expression and function. To investigate the effects of Foxp3-infected T cells on contact hypersensitivity (CHS) responses, sensitized mice were injected with Foxp3- or control virus-infected T cells. Only injection of Foxp3-infected T cells into sensitized mice significantly inhibited CHS compared to controls, indicating that Foxp3-infected T cells are suppressive in vivo. These findings prompted treatment of autoimmune-prone CD40L transgenic (tg) mice, which develop a severe systemic autoimmune disease including autoreactive T cells and autoantibodies, with Foxp3-infected T cells. Interestingly, injections of Foxp3-infected T cells into CD40L tg mice inhibited the ongoing development of autoimmune dermatitis and activation of cytotoxic CD8+ T cells. Strikingly, treatment with Foxp3-infected T cells reduced serum concentrations of antinuclear antibodies in CD40L tg mice, which was paralleled with reduced renal immunoglobulin depositions and increased kidney function. Together, these findings indicate that newly in vitro-generated regulatory T cells can be successfully used to treat inflammatory and ongoing autoimmune disorders.

Animals↗

PubMed2001

IL-12 prevents the inhibitory effects of cis-urocanic acid on tumor antigen presentation by Langerhans cells: implications for photocarcinogenesis.

UV radiation induces skin cancer primarily by its DNA-damaging properties, but also by its capacity to suppress the immune system. The photoisomer of urocanic acid (UCA), cis-UCA, is an important mediator of UV-induced immunosuppression and is involved in the inhibition of tumor immunity. The immunomodulatory cytokine IL-12 is known to counteract many of the immunosuppressive effects of UV radiation, including UV-induced immune tolerance. In this study, we addressed whether IL-12 also reverts the immunosuppressive activities of cis-UCA. Cis-UCA inhibits the ability of Langerhans cells to present tumor Ags for primary and secondary tumor immune responses. IL-12 treatment completely prevented the suppression by cis-UCA. IL-12 also protected mice from cis-UCA-induced suppression of contact hypersensitivity responses. To study the effects of cis-UCA on Ag-processing and Ag-presenting function in vitro, Langerhans cells were treated with UCA isomers and incubated with OVA or OVA peptide(323-339) before exposure to OVA-specific transgenic T cells. Cis-, but not trans-UCA suppressed Ag presentation, which was completely reversed upon addition of IL-12. Since these findings suggest that cis-UCA may play an important role in photocarcinogenesis by inhibiting a tumor immune response, mice were chronically UVB irradiated to induce skin cancer. Whereas all mice in the control groups developed tumors, mice treated with a mAb with specificity for cis-UCA showed a significantly reduced tumor incidence. These data strongly indicate the importance of cis-UCA during photocarcinogenesis and support the concept of counteracting cis-UCA as an alternative strategy to prevent UV-induced skin cancer, possibly via the application of IL-12.

Animals↗

PubMed2001

Overexpression of CD40 ligand in murine epidermis results in chronic skin inflammation and systemic autoimmunity.

CD40-CD40 ligand (L) interactions play a pivotal role in immune-mediated inflammatory responses via the activation of antigen-presenting cells (APCs). To investigate the effects of continuous activation of resident tissue APCs, in this case the Langerhans cells (LCs) of the skin, CD40L expression was targeted to the basal keratinocytes of the epidermis of mice using the keratin-14 promoter. Approximately 80% of the transgenic (Tg) mice spontaneously developed dermatitis on the ears, face, tail, and/or paws. Compared with littermates, Tgs had a >90% decrease in epidermal LCs yet increased numbers within the dermis suggestive of enhanced emigration of CD40-activated LCs. Tgs also displayed massive regional lymphadenopathy with increased numbers of dendritic cells and B cells. Moreover, a decrease in IgM and an increase in IgG1/IgG2a/IgG2b/IgE serum concentrations was detectable. Screening for autoantibodies revealed the presence of antinuclear antibodies and anti-dsDNA antibodies implicative of systemic autoimmunity. Accordingly, renal Ig deposits, proteinuria, and lung fibrosis were observed. Adoptive transfer of T cells from Tgs to nonTg recipients evoked the development of skin lesions similar to those found in the Tgs. Dermatitis also developed in B cell-deficient CD40L Tg mice. These findings suggest that in situ activation of LCs by CD40L in the skin not only leads to chronic inflammatory dermatitis but also to systemic mixed-connective-tissue-like autoimmune disorders, possibly by breaking immune tolerance against the skin.

Animals↗

PubMed2001

Targeted expression of bcl-2 to murine basal epidermal keratinocytes results in paradoxical retardation of ultraviolet- and chemical-induced tumorigenesis.

The antiapoptotic protein bcl-2 is found up-regulated in a number of malignant and premalignant skin conditions of keratinocyte origin, but in normal skin, it is expressed at low levels only in interfollicular epidermis. To investigate whether unregulated bcl-2 expression could affect the incidence of epidermal tumors, we have generated a mouse line that over-expresses human bcl-2 in the basal layer of epidermis under the control of the human keratin 14 promoter. These mice were subjected to both UVB photocarcinogenesis and classical two-stage chemical carcinogenesis. Although transgenic bcl-2 in these mice reduces the formation of sunburn cells after short-term UVB irradiation, chronically UVB irradiated K14/bcl-2 mice were protected against tumor development, because transgenic mice developed tumors much later and at a significantly lower frequency than controls. Immunohistochemical analyses of the UVB-induced tumors revealed no significant differences in the degree of inflammatory cell infiltrates. When either K14/bcl-2 mice or F(1) progeny of matings with mice expressing an activated Ha-ras oncogene (K14/bcl-2/ras) were treated with 9,10-dimethyl-1,2-benzanthracene/phorbol 12-myristate 13-acetate, the latency of first papilloma appearance was the same in transgenic mice and controls, but further papillomas developed more slowly in the mutant mice. Moreover, the K14/bcl-2/ras mice developed far fewer albeit larger tumors/mouse than did the ras/+ controls. The rate of conversion to malignant carcinomas, the carcinoma grade, and the frequency of lymph node metastases were not significantly different between mutants and controls. We conclude that, despite its antiapoptotic function, bcl-2, overexpressed in basal epidermal keratinocytes, exerts a paradoxical retardation on the development of skin tumors induced by chemical carcinogens and particularly by UVB.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2000

Mycophenolate mofetil impairs the maturation and function of murine dendritic cells.

The immunosuppressive drug, mycophenolate mofetil (MMF), has been successfully introduced in allogeneic transplantation medicine and, more recently, in the treatment of autoimmune skin disorders. MMF inhibits lymphocyte proliferation via a blockade of the enzyme inosine 5'-monophosphate dehydrogenase, an enzyme on which lymphocytes solely depend to generate the purines necessary for DNA/RNA synthesis. To investigate the effects of MMF on cutaneous immune responses, a murine model of contact hypersensitivity (CHS) was used, with oxazolone or trinitrochlorobenzene as a contact allergen. Compared with the respective vehicle, i.p. applied MMF significantly inhibited the elicitation and, surprisingly, the induction of CHS responses. This prompted further studies into the effects of MMF on Ag presentation. Bone marrow-derived dendritic cells (DC) were cultured with GM-CSF and IL-4 in the presence of MMF and were tested for their Ag-presenting capacity. Sensitization and elicitation of CHS and delayed-type hypersensitivity responses by s. c. injected haptenated DC were reduced upon preincubation of DC with MMF. CHS responses were not impaired upon resensitization, indicating that MMF does not induce hapten-specific immunotolerance. In addition, MMF decreased the ability of DC to stimulate allogeneic T cells in MLR assays. Accordingly, flow cytometric analyses revealed a dose-dependent reduction of the expression of CD40, CD80, CD86, I-A, and ICAM-1 on DC with a concurrent reduction of IL-12 production. These data suggest that MMF, in addition to affecting T lymphocytes, directly affects APC, resulting in an impairment of immune responses. They furthermore point to a possible role of inosine 5'-monophosphate dehydrogenase in the maturation of DC.

Animals↗

PubMed2000

Evidence for functional relevance of CTLA-4 in ultraviolet-radiation-induced tolerance.

Hapten sensitization through UV-exposed skin induces hapten-specific tolerance that can be adoptively transferred by injecting T lymphocytes into naive recipients. The exact phenotype of T cells responsible for inhibiting the immune response and their mode of action remain unclear. Evidence exists that CTLA-4 negatively regulates T cell activation. We addressed whether CTLA-4 is involved in the transfer of UV-induced tolerance. Injection of lymph node cells from mice that were sensitized with dinitrofluorobenzene (DNFB) through UV-irradiated skin inhibited induction of contact hypersensitivity against DNFB in the recipient animals. When CTLA-4+ cells were depleted, transfer of suppression was lost. Likewise, significantly fewer lymphocytes enriched for CTLA-4+ cells were necessary to transfer suppression than unfractionated cells. Expression of CTLA-4 appears to be functionally relevant, since in vivo injection of a blocking anti-CTLA-4 Ab was able to break UV-induced tolerance and inhibited transfer of suppression. Upon stimulation with dendritic cells in the presence of the water-soluble DNFB analogue, DNBS, CTLA-4+ T cells from DNFB-tolerized mice secreted high levels of IL-10, TGF-beta, and IFN-gamma; low levels of IL-2; and no IL-4, resembling the cytokine pattern of T regulatory 1 cells. Ab blocking of CTLA-4 resulted in inhibition of IL-10 release. Accordingly, transfer of tolerance was not observed when recipients were treated with an anti-IL-10 Ab. Hence we propose that T cells, possibly of the T regulatory 1 type, transfer UV-mediated suppression through the release of IL-10. Activation of CTLA-4 appears to be important in this process.

Abatacept↗

PubMed2000

UVA rush hardening for the treatment of solar urticaria.

Induction of tolerance by subsequent UV exposures is the most effective therapy for solar urticaria; however, it is time-consuming and takes a long time until protection is achieved. Three patients with solar urticaria were exposed to multiple UVA irradiations at 1-hour intervals per day. With this rush hardening regimen, protection was achieved within 3 days.

Adult↗

PubMed2000

Tumor antigen presentation by dermal antigen-presenting cells.

Several phenotypes of antigen-presenting cells are present in the dermis, where they presumably function to present encountered antigens for immune responses. This study examined the ability of dermal antigen-presenting cells to present tumor-associated antigens for the induction of in vivo antitumor immunity. Total murine dermal cells were exposed either to medium alone or to medium containing tumor-associated antigens from S1509a tumor cells. Subsequently, dermal cells were injected subcutaneously at weekly intervals into naïve mice for a total of three immunizations. One week following the final immunization, mice were challenged with living tumor cells. In these experiments, dermal cells pulsed with tumor-associated antigens induced protective immunity to tumor growth. Dermal cells exposed to tumor-associated antigens were also able to elicit delayed-type hypersensitivity after footpad injection into mice previously immunized against S1509a tumor cells. The ability to present tumor-associated antigens for both induction of antitumor immunity and elicitation of delayed-type hypersensitivity was dependent on I-A+ cells and was genetically restricted. Finally, dermal cells tended towards eliciting a greater antitumor delayed-type hypersensitivity response than epidermal cells. These results show that the murine dermis contains antigen-presenting cells capable of processing S1509a tumor antigens for the generation of protective antitumor immunity in vivo.

Animals↗

PubMed1999

Reduced ultraviolet-induced carcinogenesis in mice with a functional disruption in B7-mediated costimulation.

Immunosuppression by UV light contributes significantly to the induction of skin cancer by suppressing the cell-mediated immune responses which control the development of carcinogenesis. The B7/CD28-CTLA-4 signaling pathway provides costimulatory signals essential for Ag-specific T cell activation. To investigate the role of this pathway in photocarcinogenesis, we utilized transgenic (Tg) mice which constitutively express CTLA-4Ig, a high-affinity CD28/CTLA-4 antagonist that binds to both B7-1 and B7-2. The transgene is driven by a skin-specific promoter yielding high levels of CTLA-4Ig in the skin and serum. Chronic UV exposure of CTLA-4Ig Tg mice resulted in significantly reduced numbers of skin tumors, when compared to control mice. In addition, Tg mice were resistant to UV-induced suppression of delayed-type hypersensitivity responses to alloantigens. Most importantly, upon stimulation with mitogens and alloantigens, T cells isolated from CTLA-4Ig Tg mice produced significantly less IL-4 but more IFN-gamma compared to control T cells, suggesting an impaired Th2 response and a relative increase of Th1-type immunity. Together, these data show that overall B7 engagement directs immune responses toward the Th2 pathway. Moreover, they point out the crucial role of Th1 immune reactions in the protection against photocarcinogenesis.

Abatacept↗

PubMed1999

[Embolia cutis medicamentosa (Nicolau syndrome) after intra-articular injection].

Embolia cutis medicamentosa (Nicolau Syndrome) is a very rare complication of intramuscular injections which presents with extensive necrosis of the injected skin area. Intra-arteria and/or para-arterial injections after prior perforation of certain vessels are discussed as possible pathogenetic mechanisms. We describe the occurrence of embolia cutis medicamentosa after intra-articular injections into the knee.

Anti-Inflammatory Agents↗

PubMed1999

Mechanisms involved in ultraviolet light-induced immunosuppression.

Ultraviolet light (UV) represents one of the most relevant environmental factors influencing humans, especially with regard to its hazardous health effects, which include premature skin aging, skin cancer, and exacerbation of infectious diseases. Several of these effects are mediated by the immunosuppressive properties of UV. UV can compromise the immune system in several ways, e.g., by affecting the function of antigen-presenting cells, inducing the release of cytokines, and modulating the expression of surface molecules. Recently a link between UV-induced immunosuppression and apoptosis was recognized. In the following, the basic mechanisms underlying UV-induced immunosuppression will be discussed.

Animals↗

PubMed1999

Lipodystrophia centrifugalis abdominalis infantilis in a 4-year-old Caucasian girl: association with partial IgA deficiency and autoantibodies.

We report the third case of lipodystrophia centrifugalis abdominalis outside East Asia. A 4-year-old Caucasian girl developed an area of bluish erythema on the left side of the lower abdomen which spread centrifugally to the umbilical and inguinal areas with depression of the skin resulting from the loss of subcutaneous fat, surrounded by an erythematous border. This unusual skin disease was characterized by clinical and histological examination. Laboratory tests revealed a partial IgA deficiency, antinuclear antibodies and IgG antibodies against gliadin.

Abdomen↗

PubMed1999

Efficacy and safety of naltrexone, an oral opiate receptor antagonist, in the treatment of pruritus in internal and dermatological diseases.

BACKGROUND: The perception of pruritus is modified by endogenous opiates via central opiate receptors in a histamine-independent manner. OBJECTIVE: The aim of this pilot study was to evaluate the efficacy and safety of naltrexone, an orally active opiate antagonist, in the treatment of severe, otherwise intractable pruritus of different origin in an open-label clinical trial. METHODS: A total of 50 patients with pruritus caused by internal diseases, hydroxyethyl starch, contact with water, cutaneous lymphoma, atopic dermatitis, xerosis cutis, macular amyloidosis, psoriasis, and other skin disorders as well as with pruritus of unknown origin were randomly selected to receive naltrexone 50 mg daily. The pruritus intensity was rated by the patients before and during therapy in a visual analogue scale. RESULTS: A significant therapeutic response was achieved in 35 of the 50 patients within 1 week (confidence limits of 0.55 and 0.82 at a confidence level of 0. 95). Naltrexone was of high antipruritic effect in 9 of 17 cases of prurigo nodularis and contributed to healing of the skin lesions. Tachyphylaxis was infrequent (6/50), occurred late, and could be counterbalanced by raising the dosage in 2 patients. Adverse drug effects were restricted to the first 2 weeks of treatment and included nausea (11/50), fatigue (3/50), dizziness, heartburn, and diarrhea (1/50 each). CONCLUSION: The study suggests that oral opiate antagonists might be a well-tolerated and effective therapy for pruritic symptoms in many diseases.

Administration, Oral↗

PubMed1998

Impaired cutaneous immune responses in Thy-1-deficient mice.

Thy-1 is a cell surface glycoprotein expressed mainly on brain and lymphoid tissue. Although the functions of Thy-1 are incompletely understood, evidence exists that Thy-1 participates in T cell activation. To examine the functional role of Thy-1 in cutaneous immune responses in vivo, Thy-1 gene-targeted mice (Thy-1-/-) and wild-type mice (Thy-1+/+) were immunized with the hapten oxazolone. After challenge with oxazolone, contact hypersensitivity responses in Thy-1-/- mice were reduced by 25% compared with Thy-1+/+ mice. Likewise, irritant dermatitis induced by croton oil was also decreased. In addition, Thy-1-/- mice showed a significantly reduced delayed-type hypersensitivity response after injection of allogeneic spleen cells into the hind footpads of allosensitized animals when compared with Thy-1+/+ mice. Moreover, proliferative responses to immobilized anti-CD3 were decreased in peripheral Thy-1-/- lymphocytes; this decrease was associated with a significantly reduced intracellular Ca2+ influx and protein tyrosine phosphorylation, indicating impairment of early lymphocyte activation. In contrast, the T cell proliferation induced by mitogens was normal, suggesting that Thy-1 expression weakly contributes to TCR-mediated T cell activation. Epidermal Langerhans cells and bone marrow-derived dendritic cells from Thy-1-/- mice exhibited a normal expression of costimulatory surface molecules as well as an unaltered ability to stimulate allogeneic T cells. Taken together, these findings demonstrate that a lack of Thy-1 expression does not generally compromise the immune system; however, Thy-1 expression may be involved in the fine-tuning of T cell-mediated immune responses.

Animals↗

PubMed1998

Involvement of interleukin-3 in delayed-type hypersensitivity.

The in vivo functions of interleukin-3 (IL-3) were investigated by generating IL-3-deficient mice. Although hematopoiesis was unimpaired in homozygous mutant animals, contact hypersensitivity reactions were compromised. IL-3 was required for efficient priming of hapten-specific contact hypersensitivity responses, but was dispensable for T-cell-dependent sensitization to tumor cells. These findings reveal a critical role for IL-3 in some forms of delayed-type hypersensitivity.

Animals↗