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Tilo Biedermann

Publications and source records attributed to Tilo Biedermann.

14 recordsLinked to original sources
PubMed2006

IL-12 instructs skin homing of human Th2 cells.

Distinct pattern of homing receptors determines the tissue preference for T cells to exert their effector functions. This homing competence is mostly determined early during T cell activation of naive T cells. In contrast, mechanisms governing the acquisition of particular homing receptors by T cells of the memory phenotype remain enigmatic. Th2 cell-mediated allergic diseases tend to flare during infections despite that these infections prime APCs to produce the prototypic Th1 cell-differentiating cytokine IL-12. In this study, we investigate the effect of IL-12 on the regulation of cutaneous lymphocyte Ag (CLA) on differentiated Th2 cells and consequences of this expression for allergic inflammation. Upon activation with IL-12, CLA- Th2 cells rapidly up-regulated IL-12Rbeta2 chain, alpha(1-3)-fucosyltransferase VII, and CLA molecules. IL-12-mediated CLA expression on Th2 cells was functional because it mediated rolling of these Th2 cells on E-selectin in vitro and migration into human skin grafts in SCID mice. CLA induction occurred immediately after exposure to IL-12 and was independent of IFN-gamma expression. In accordance, the transcription factor mediating IFN-gamma expression, T-bet, does not directly affect CLA expression. However, CLA expression was further enhanced after IL-12 treatment of T-bet+ -transfected Th2 cells in agreement with an increased IL-12 responsiveness of these cells caused by T-bet. The finding that IL-12 conferred skin-homing potential to already differentiated Th2 cells before inducing a switch in their cytokine production profile may explain the observed exacerbation of allergic skin diseases following bacterial infections.

Adult↗
PubMed2006

Dissecting the role of infections in atopic dermatitis.

In patients with atopic dermatitis the skin is highly susceptible to infection by bacteria, fungi and viruses. Increasing knowledge about the complex immune network that regulates anti-microbial responses has helped to dissect further the role of infections in atopic dermatitis. Conserved patterns of microbes are recognized by the innate immune system, which mediates microbicidal activity, either directly or through inflammatory responses. New evidence suggests that components of the innate immune system, such as anti-microbial peptides, humoural lectins, nucleotide-binding oligomerization domain-containing (NOD) proteins, and Toll-like receptors not only protect from microbial invasion, but contribute to skin inflammation in atopic dermatitis. In addition, atopic patients tend to develop Th2-dominated immune responses that weaken anti-microbial immunity. This impairment of an appropriate anti-microbial defence compounded by amplified microbe-driven innate and adaptive immune responses leads to the vicious circle of skin inflammation. New microbial management in atopic dermatitis will foster a well-balanced microbial flora, which establishes natural defence mechanisms to maintain immuno-surveillance of the skin. In addition to anti-microbial therapies, other innate immune stimuli may suppress pro-inflammatory signals and help to break the vicious circle of cutaneous inflammation. To elucidate further these different interactions of the skin immune system and microbes in atopic dermatitis, clinical studies and further efforts in basic research are needed.

Animals↗
PubMed2005

CCL18 is expressed in atopic dermatitis and mediates skin homing of human memory T cells.

CCL18 is a human chemokine secreted by monocytes and dendritic cells. The receptor for CCL18 is not yet known and the functions of this chemokine on immune cells are not fully elucidated. In this study, we describe that CCL18 is present in skin biopsies of atopic dermatitis (AD) patients but not in normal or psoriatic skin. CCL18 was specifically expressed by APCs in the dermis and by Langerhans and inflammatory dendritic epidermal cells in the epidermis. In addition, the serum levels of CCL18 and the percentages of CCL18-producing monocyte/macrophages and dendritic cells were significantly increased in AD patients compared with healthy controls. Furthermore, we demonstrate that CCL18 binds to CLA(+) T cells in peripheral blood of AD patients and healthy individuals and induces migration of AD-derived memory T cells in vitro and in human skin-transplanted SCID mice. These findings highlight a unique role of CCL18 in AD and reveal a novel function of this chemokine mediating skin homing of a subpopulation of human memory T cells.

Animals↗
PubMed2005

Identification of CD13, CD107a, and CD164 as novel basophil-activation markers and dissection of two response patterns in time kinetics of IgE-dependent upregulation.

Using two-colour flow cytometry >200 antibodies submitted to the 8th International Workshop of Human Leukocyte Differentiation Antigens (HLDA8) have been analyzed for their reactivity with resting and activated CD203c+ basophils. Four antibodies either non-reactive or weakly reactive with resting basophils exhibited an increased reactivity with basophils activated by anti-IgE-mediated cross-linking of the high affinity IgE receptor (FceRI). These include antibodies against CD164 (WS-80160, clone N6B6 and WS-80162, clone 67D2), as well as two reagents with previously unknown specificities that were identified as CD13 (WS-80274, clone A8) and CD107a (WS-80280, clone E63-880). The activation patterns followed either the "CD203c-like" or "CD63-like" activation profile. The CD203c profile is characterized by a rapid and significant upregulation (of CD13, CD164, and CD203c), reaching maximum levels after 5-15 min of stimulation. The Phosphoinositide-3-kinase (PI3K)-specific inhibitor Wortmannin inhibited the upregulation of these markers whereas 12-O-tetradecanoyl-phorbol-13-acetate (TPA) induced a rapid and FceRI-independent upregulation within 1-2 min. In the CD63 profile, maximum upregulation (of CD63 and CD107a) was detected only after 20-40 min, and upregulation by TPA reached maximum levels after 60 min. In summary, our data identify CD13, CD107a, and CD164 as novel basophil-activation antigens. Based on time kinetics of upregulation, we hypothesize that molecules of the "CD203c group" and the "CD63 group" are linked to two different mechanisms of basophil activation.

Androstadienes↗
PubMed2004

Sustained T-bet expression confers polarized human TH2 cells with TH1-like cytokine production and migratory capacities.

BACKGROUND: The transcription factor T-bet mediates IFN-gamma production by T(H)1 cells and suppresses T(H)2 cytokine production when ectopically expressed in polarized murine T(H)2 cells. Thus T-bet-mediated inhibition of T(H)2 cytokine production might be beneficial for the treatment of allergic diseases like asthma or atopic dermatitis. OBJECTIVE: We sought to investigate the effects of ectopic T-bet expression in highly polarized human T(H)2 cells obtained from skin biopsy specimens of patients with atopic dermatitis. METHODS: The cytokine production of T(H)2 cells retrovirally transfected with a vector expressing human T-bet was determined by means of intracellular FACS staining and ELISA. The effects of T-bet transfection were analyzed at the mRNA level by means of real-time PCR and DNA microarrays and confirmed by using functional chemokine response assays. RESULTS: Transfection of T-bet into T(H)2 cells induced high levels of IFN-gamma and suppressed IL-5, but IL-2 and IL-4 production remained unchanged. T-bet transfection also induced IL-12Rbeta2 and CXCR3 expression on human T(H)2 cells, whereas the IL-18 receptor was only induced as a consequence of T-bet-mediated increased responsiveness to IL-12. Furthermore, sustained T-bet expression in human T(H)2 cells induced IL-2 production and decreased the secretion of IL-4. In addition, the chemokine receptor repertoire of these cells was changed toward a T(H)1-like profile. CONCLUSION: The combined switch in cytokine pattern and migratory potential of highly polarized human T(H)2 cells mediated by T-bet might provide an additional advantage for the treatment of allergic diseases.

Cell Movement↗
PubMed2004

TH1 and TH2 lymphocyte development and regulation of TH cell-mediated immune responses of the skin.

Since the first description of the subpopulations of TH1 and TH2 cells, insights into the development and control of these cells as two polarized and physiologically balanced subsets have been generated. In particular, implications of the TH1-TH2 concept for TH cell-mediated skin disorders have been discovered. This article will review the basic factors that control the development of TH1 and TH2 cells, such as the cytokines IL-12 and IL-4 and transcription factors, the possible role of costimulatory molecules, and specialized dendritic cell populations. These regulatory mechanisms will be discussed in the context of polarized TH1 or TH2 skin disorders such as psoriasis and atopic dermatitis. Also presented are the principles that govern how chemokines and chemokine receptors recruit TH1 and TH2 cells to inflammatory sites and how they amplify these polarized TH cell responses. All of these concepts, including a novel role for IL-4-inducing TH1 responses, can contribute to the design of better therapeutic strategies to modulate TH cell-mediated immune responses.

Animals↗
PubMed2003

The SCID-hu Skin mouse as a model to investigate selective chemokine mediated homing of human T-lymphocytes to the skin in vivo.

Here we report the establishment of an in vivo mouse model that allows monitoring of human T cell migration into human skin. This model is based on the use of severe combined immunodeficiency (SCID) mice transplanted with human skin (SCID-hu Skin mice). Adoptively transferred human T helper (Th)2 cells obtained from atopic dermatitis skin lesions or peripheral blood T cells selectively migrate to the human skin grafts of these SCID mice in response to defined chemokines locally injected in the human skin grafts. Homing of human T cells into the human skin on SCID-hu Skin mice is a specific process since it only occurs in response to chemokine ligands that are specific for the chemokine receptors expressed on the migrating T cells. This mechanistic model allows analysis of the relevant steps involved in human T-lymphocyte migration into inflamed skin. In addition, it is successfully used for preclinical testing of drug candidates that are highly selective for human target molecules associated with the different steps of T cell migration in an environment that resembles the physiologic or pathologic conditions occurring in man.

Animals↗
PubMed2002

Interleukin-4 therapy of psoriasis induces Th2 responses and improves human autoimmune disease.

Selective skewing of autoreactive interferon-gamma (IFN-gamma)-producing T helper cells (Th1) toward an interleukin-4 (IL-4)-producing (Th2) phenotype can in experimental animals alleviate autoimmune disease without inducing general immunosuppression. In a prospective dose escalation study, we assessed treatment with human IL-4 (rhuIL-4) in 20 patients with severe psoriasis. The therapy was well tolerated, and within six weeks all patients showed decreased clinical scores and 15 improved more than 68%. Stable reduction of clinical scores was significantly better at 0.2-0.5 microg rhuIL-4 than at < or =0.1 microg rhuIL-4 (P = 0.009). In psoriatic lesions, treatment with 0.2-0.5 microg/kg rhuIL-4 reduced the concentrations of IL-8 and IL-19, two cytokines directly involved in psoriasis; the number of chemokine receptor CCR5+ Th1 cells; and the IFN-gamma/IL-4 ratio. In the circulation, 0.2-0.5 microg/kg rhuIL-4 increased the number of IL-4+CD4+ T cells two- to three-fold. Thus, IL-4 therapy can induce Th2 differentiation in human CD4+ T cells and has promise as a potential treatment for psoriasis, a prototypic Th1-associated autoimmune disease.

Adolescent↗
PubMed2002

Targeting CLA/E-selectin interactions prevents CCR4-mediated recruitment of human Th2 memory cells to human skin in vivo.

Naive Th cells, bearing receptors for cutaneous antigens, become activated in skin-draining lymph nodes and express cutaneous lymphocyte antigen (CLA), which confers to these cells the capacity to migrate into the skin to exert their normal effector functions. In the case of atopic dermatitis (AD), allergen-specific Th2 cells generate exacerbated responses and induce skin inflammation. In such a situation, interfering with the specific mechanism of skin homing would provide a therapeutic benefit. Here we report that CLA+ Th2 memory cells, derived from skin lesions of AD patients, selectively migrate to human skin grafts transplanted onto SCID mice in response to CCR4 but not CCR3, CCR8 or CXCR3 ligands. Skin homing of human CCR4+ Th2 memory cells was Pertussis toxin sensitive and restricted to the CLA+ subset. Furthermore, treatment of these mice with anti-E-selectin monoclonal antibody was sufficient to prevent CCL22-mediated Th2 cell migration to human skin, which both, validates the model and highlights the importance of CLA/E-selectin interactions in the homing process of Th2 cells to the skin. Using this mechanistic model we demonstrate that skin homing of human Th2 memory cells can be efficiently suppressed using a low molecular weight E-selectin antagonist, which is of clinical relevance for the treatment of inflammatory skin diseases, including AD.

Adult↗