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Andreas Thiel

Publications and source records attributed to Andreas Thiel.

At least 19 recordsLinked to original sources
PubMed2006

Complex spike-event pattern of transient ON-OFF retinal ganglion cells.

ON-OFF transient ganglion cells of the turtle retina show distinct spike-event patterns in response to abrupt intensity changes, such as during saccadic eye movements. These patterns consist of two main spike events, with the latency of each event showing a systematic dependency on stimulus contrast. Whereas the latency of the first event decreases monotonically with increasing contrast, as expected, the second event shows the shortest latency for intermediate contrasts and a longer latency for high and low contrasts. These spike-event patterns improve the discrimination of different light-intensity transitions based on ensemble responses of the ON-OFF transient ganglion cell subpopulation. Although the discrimination results are far better than chance using either spike counts or latencies of the first spikes, they are further improved by using properties of the second spike event. The best classification results are obtained when spike rates and latencies of both events are considered in combination. Thus spike counts and temporal structure of retinal ganglion cells carry complementary information about the stimulus condition, and thus spike-event patterns could be an important aspect of retinal coding. To investigate the origin of the spike-event patterns in retinal ganglion cells, two computational models of retinal processing are compared. A linear-nonlinear model consisting of separate filters for on and off response components fails to reproduce the spike-event patterns. A more complex cascade filter model, however, accurately predicts the timing of the spike events by using a combination of gain control loop and spike rate adaptation.

Algorithms↗
PubMed2006

Multidirectional interactions are bridging human NK cells with plasmacytoid and monocyte-derived dendritic cells during innate immune responses.

During innate immune responses, natural killer (NK) cells may interact with both plasmacytoid dendritic cells (pDCs) and monocyte-derived dendritic cells (MDDCs). We show that freshly isolated NK cells promote the release by pDCs of IFN-alpha, in a CpG-dependent manner, whereas they induce IL-6 production in a CpG-independent manner. In turn pDC-derived IFN-alpha up-regulates NK-mediated killing, whereas IL-6 could promote B-cell differentiation. We also show that exposure to exogenous IL-12 or coculture with maturing MDDCs up-regulates the NK-cell-dependent IFN-alpha production by pDCs. On the other hand, NK cells cocultured with pDCs acquire the ability to kill immature MDDCs, thus favoring their editing process. Finally, we show that activated NK cells are unable to lyse pDCs because these cells display an intrinsic resistance to lysis. The exposure of pDCs to IL-3 increased their susceptibility to NK-cell cytotoxicity resulting from a de novo expression of ligands for activating NK-cell receptors, such as the DNAM-1 ligand nectin-2. Thus, different cell-to-cell interactions and various cytokines appear to control a multidirectional network between NK cells, MDDCs, and pDCs that is likely to play an important role during the early phase of innate immune responses to viral infections and to tumors.

Antigens, Differentiation, T-Lymphocyte↗
PubMed2006

The temporal structure of transient ON/OFF ganglion cell responses and its relation to intra-retinal processing.

A subpopulation of transient ON/OFF ganglion cells in the turtle retina transmits changes in stimulus intensity as series of distinct spike events. The temporal structure of these event sequences depends systematically on the stimulus and thus carries information about the preceding intensity change. To study the spike events' intra-retinal origins, we performed extracellular ganglion cell recordings and simultaneous intracellular recordings from horizontal and amacrine cells. Based on these data, we developed a computational retina model, reproducing spike event patterns with realistic intensity dependence under various experimental conditions. The model's main features are negative feedback from sustained amacrine onto bipolar cells, and a two-step cascade of ganglion cell suppression via a slow and a fast transient amacrine cell. Pharmacologically blocking glycinergic transmission results in disappearance of the spike event sequence, an effect predicted by the model if a single connection, namely suppression of the fast by the slow transient amacrine cell, is weakened. We suggest that the slow transient amacrine cell is glycinergic, whereas the other types release GABA. Thus, the interplay of amacrine cell mediated inhibition is likely to induce distinct temporal structure in ganglion cell responses, forming the basis for a temporal code.

Action Potentials↗
PubMed2006

Test-retest reliability of the Eating Disorder Inventory 2.

OBJECTIVE: This study reports on findings concerning the test-retest reliability of the Eating Disorder Inventory 2 (EDI-2). METHODS: Three hundred twenty-seven female inpatients who met the DSM-IV criteria for eating disorders (anorexia nervosa, bulimia nervosa, or eating disorders not otherwise specified) and 209 inpatients with a diagnosis of depression, obsessive-compulsive disorder, anxiety disorder, or somatoform disorder took part in the study. The EDI-2 was administered to the patients at the beginning of inpatient therapy and a second time 7 days later. RESULTS: All 11 EDI-2 subscales showed significant test-retest correlations ranging from .81 to .89 in the eating disorder group and from .75 to .94 in the group with other diagnoses. DISCUSSION: The test-retest reliabilities for the EDI-2 subscales are relatively high, indicating a good and acceptable stability over time. These results provide further evidence that the EDI-2 is an instrument with good reliability for the assessment of eating disorder symptoms.

Adult↗
PubMed2005

Direct access to CD4+ T cells specific for defined antigens according to CD154 expression.

The direct assessment of T helper (T(H))-cell responses specific for antigens is essential to evaluate pathogenic and protective immunity. Presently, analysis and isolation of antigen-specific T(H) cells is restricted to cells that produce cytokines, or can be performed only with a rare selection of specific peptide major histocompatibility complex class II (MHC II) multimers. Here we report a new method that enables the assessment and isolation of T(H) cells specific for a defined antigen according to CD154 expression induced after stimulation in vitro. We show that antigen-induced CD154 expression is highly sensitive and specific for human and mouse antigen-specific T(H) cells. Moreover, the isolation of antigen-specific CD154(+) T(H) cells necessitates only surface staining with antibodies, thereby enabling the fast generation of antigen-specific T(H) cell lines. Our approach allows assessment of T(H) cells with a defined specificity for the combined quantitative and qualitative analysis of T(H)-cell immunity as well as for the isolation of specific T(H) cells for targeted cellular immunotherapies.

Animals↗
PubMed2005

Distributed delays stabilize ecological feedback systems.

We consider the effect of distributed delays in predator-prey models and ecological food webs. Whereas the occurrence of delays in population dynamics is usually regarded a destabilizing factor leading to the extinction of species, we here demonstrate complementarily that delay distributions yield larger stability regimes than single delays. Food webs with distributed delays closely resemble nondelayed systems in terms of ecological stability measures. Thus, we state that dependence of dynamics on multiple instances in the past is an important, but so far underestimated, factor for stability in dynamical systems.

Animals↗
PubMed2005

HLA-B27-restricted CD8+ T cell response to cartilage-derived self peptides in ankylosing spondylitis.

OBJECTIVE: Several hypotheses have been proposed to explain the strong association between HLA-B27 and ankylosing spondylitis (AS). Among these, the arthritogenic peptide theory proposes that certain B27 subtype alleles bind specific arthritogenic peptide(s) due to their unique amino acid anchor residues. Cartilage antigens have been discussed as candidate targets for the immune response in AS. The recognition of HLA-B27-peptide complexes by self-reactive CD8+ T cells might contribute to joint-specific tissue damage. Therefore, we investigated the presence of autoreactive CD8+ T cells specific for cartilage-derived peptides in patients with AS. METHODS: An HLA-B27-binding prediction program and a proteasome-cutting prediction program for the human 20S proteasome were used to screen 18 human cartilage proteins for potentially immunogenic nonamer peptides. The peptides identified were used to stimulate peripheral blood mononuclear cells from 20 HLA-B27-positive patients with AS and synovial fluid (SF) mononuclear cells from 7 HLA-B27-positive patients with AS. Activation of T cells was measured by antigen-specific intracellular cytokine staining and quantified by flow cytometry. RESULTS: From the screening analysis, we identified 121 nonamer peptides. Of these, 1 peptide derived from type II collagen and 1 from type VI collagen were stimulatory for peripheral blood CD8+ T cells in only 1 of 20 patients. However, in 4 of 7 SF samples the same type VI collagen-derived nonamer peptide stimulated SF CD8+ T cells, but none of the other peptides was stimulatory. This CD8+ T cell response could be blocked by an anti-HLA-B27 antibody, confirming an HLA-B27-restricted immune response. CONCLUSION: Our findings suggest that cartilage-directed cellular autoimmunity might play an important role in joint-specific tissue damage in patients with AS. Future research is necessary to determine whether the identified peptide is of pathogenetic relevance.

Adult↗
PubMed2005

Activation of human NK cells by plasmacytoid dendritic cells and its modulation by CD4+ T helper cells and CD4+ CD25hi T regulatory cells.

Plasmacytoid dendritic cells (pDC) represent a specialized cell population that produce type I interferon (IFN) in response to virus. Although type I IFN is a natural killer (NK) cell modulator, a direct role for pDC in coordinating NK cell functions has not yet been elucidated in detail, especially in humans. Here we report that human pDC, following engagement of Toll-like receptor (TLR) 9, not only activate autologous NK cells, as indicated by the induction of CD69 expression, but also enhance their effector functions, especially cytotoxicity. Moreover, they can induce selective proliferation of CD56bright CD16- NK cells. This activity can be strongly augmented by the addition of autologous CD4+ CD25- T helper cells in an IL-2-dependent fashion. Strikingly, CD4+ CD25hi T regulatory (Treg) cells completely abrogate this IL-2-dependent proliferation of NK cells, while they are not able to influence NK cell activation or proliferation solely induced by pDC. Our data show that TLR9-engaged pDC represent a critical stimulus for human NK cells and that CD4+ Th cells and CD4+ CD25hi Treg cells play an important role in modulating human NK cell responses.

Adult↗
PubMed2005

Post-thymic in vivo proliferation of naive CD4+ T cells constrains the TCR repertoire in healthy human adults.

In spite of thymic involution early in life, the numbers of naive CD4(+) T cells only slowly decline in ageing humans implying peripheral post-thymic naive CD4(+) T cell expansion. This proliferation may compensate for continuous activation and death of naive CD4(+) T cells but may also have negative consequences for protective immunity. Here we show that naive CD4(+) T cells that have proliferated in the periphery are characterized by a highly restricted oligoclonal TCR repertoire. Additionally these cells, which constitute the majority of naive CD4(+) T cells in the elderly, display signatures of recent TCR engagement. Our results demonstrate for the first time that peripheral post-thymic proliferation of naive CD4(+) T cells in healthy human individuals causes a significant contraction of the peripheral TCR repertoire. This age-dependent deterioration of CD4(+) T cell immunity could entail ageing-associated autoimmunity, increased susceptibility to infection or cancer and decreased efficiency of vaccination.

Adult↗
PubMed2005

CD31+ naïve Th cells are stable during six months following kidney transplantation: implications for post-transplant thymic function.

Little is known about thymus function in transplant patients. Until recently, the phenotype of T cells that recently emigrated the thymus was unknown. Now it has been demonstrated that CD4(+) recent thymus emigrants coexpress CD31 and CD45RA. Here, we investigated whether uremia and immunosuppression influence CD31(+) CD45RA(+) Th cells before and after kidney transplantation, respectively. Forty-eight renal transplant patients were included receiving either standard triple/quadruple (n = 35) immunosuppression, OKT-3 induction (n = 7) or FTY-720 (n = 6), respectively. Peripheral CD31(+) CD45RA(+) Th cells were quantified flowcytometrically before and at week 1, 4, 12 and 24 post-transplantation. Thirty-nine healthy adults served as controls. CD31(+) CD45RA(+) Th cells correlated inversely with age in patients and controls and were comparable in patients before transplantation and age-matched controls. Importantly, CD31(+) CD45RA(+) Th cell frequencies remained stable during 6 months post-transplantation. In conclusion, CD31(+) CD45RA(+) Th cells are not significantly altered by uremia before and during 6 months of immunosuppressive therapy after kidney transplantation. Implications for thymus function are discussed.

Aging↗
PubMed2004

Use of HLA-B27 tetramers to identify low-frequency antigen-specific T cells in Chlamydia-triggered reactive arthritis.

Reports of the use of HLA-B27/peptide tetrameric complexes to study peptide-specific CD8+ T cells in HLA-B27+-related diseases are rare. To establish HLA-B27 tetramers we first compared the function of HLA-B27 tetramers with HLA-A2 tetramers by using viral epitopes. HLA-B27 and HLA-A2 tetramers loaded with immunodominant peptides from Epstein-Barr virus were generated with comparable yields and both molecules detected antigen-specific CD8+ T cells. The application of HLA-B27 tetramers in HLA-B27-related diseases was performed with nine recently described Chlamydia-derived peptides in synovial fluid and peripheral blood, to examine the CD8+ T cell response against Chlamydia trachomatis antigens in nine patients with Chlamydia-triggered reactive arthritis (Ct-ReA). Four of six HLA-B27+ Ct-ReA patients had specific synovial T cell binding to at least one HLA-B27/Chlamydia peptide tetramer. The HLA-B27/Chlamydia peptide 195 tetramer bound to synovial T cells from three of six patients and HLA-B27/Chlamydia peptide 133 tetramer to synovial T cells from two patients. However, the frequency of these cells was low (0.02-0.09%). Moreover, we demonstrate two methods to generate HLA-B27-restricted T cell lines. First, HLA-B27 tetramers and magnetic beads were used to sort antigen-specific CD8+ T cells. Second, Chlamydia-infected dendritic cells were used to stimulate CD8+ T cells ex vivo. Highly pure CD8 T cell lines could be generated ex vivo by magnetic sorting by using HLA-B27 tetramers loaded with an EBV peptide. The frequency of Chlamydia-specific, HLA-B27 tetramer-binding CD8+ T cells could be increased by stimulating CD8+ T cells ex vivo with Chlamydia-infected dendritic cells. We conclude that HLA-B27 tetramers are a useful tool for the detection and expansion of HLA-B27-restricted CD8+ T cells. T cells specific for one or more of three Chlamydia-derived peptides were found at low frequency in synovial fluid from HLA-B27+ patients with Ct-ReA. These cells can be expanded ex vivo, suggesting that they are immunologically functional.

Arthritis, Reactive↗
PubMed2004

The small subset of CD56brightCD16- natural killer cells is selectively responsible for both cell proliferation and interferon-gamma production upon interaction with dendritic cells.

The encounter of NK cells with dendritic cells (DC) undergoing maturation may result in the induction of NK cell proliferation. Whether such proliferation involves most NK cells or just a subset has yet to be determined. In the present study we analyzed the nature of such proliferating NK cells by combining carboxyfluorescein succinimidyl ester staining and double-fluorescence cytofluorimetric analysis. Freshly isolated peripheral blood NK cells cultured with LPS and immature DC underwent proliferation; however, proliferating cells were confined to a minor NK cell subset. This subset is characterized by the CD56(bright)CD16(-)NKG2A(+)KIR(-) surface phenotype (KIR, killer Ig-like receptor). This was further confirmed by the fact that, after cell sorting, only the CD56(bright) NK cells were able to proliferate in response to the DC stimulus, whereas the CD56(dull) were not. We also provide evidence that the CD56(bright) subset is the main source of IFN-gamma-producing NK cells, upon interaction with DC. The CD56(bright)CD16(-) NK cells express a panel of surface molecules including CD62L, CCR7 and CXCR3 that may allow their homing either to secondary lymphoid compartments or to inflamed tissues. This implies that, in vivo, the interactions between DC undergoing maturation and CD56(bright) NK cells may occur in different tissues and have different functional implications.

CD56 Antigen↗
PubMed2004

Stem cell transplantation for autoimmune disorders. Immune reconstitution.

Lymphocyte recovery is delayed following autologous haematopoietic stem cell transplantation (HSCT). B-cells recover before T-cells and CD8+ before CD4+ T-cells. The initial phase of T-cell recovery is dependent upon the expansion of mature host T-cells that have survived conditioning or are transferred back with the graft. This phase is therefore quicker when the graft is not CD34+ selected. Subsequently, naïve T-cells appear. Naïve CD4+ T-cell recovery is thymus dependent and starts at around 6-9 months. Naïve CD8+ recovery occurs earlier and seems less thymus dependent. Immune function recovers later than lymphocyte number, the former being dependent on a broad repertoire and diversity of effector function. We currently do not know which reconstitution markers are more likely to predict prolonged disease remission as opposed to relapse. Similarly, it is unclear whether disease-specific factors influence reconstitution. A continued, close collaboration between scientists and physicians should both improve the outcomes of HSCT and also provide important pathogenic information about the diseases under treatment.

Autoimmune Diseases↗
PubMed2004

Antigen-specific cytometry--new tools arrived!

Until recently, immunofluorescence-based cytometry and cell sorting, which have now found their place in the repertoire of state-of-the-art technologies, have mostly served to identify and assess subsets of leukocytes and thereby to evaluate rather systemic changes of the immune system. A more detailed defined evaluation of immune responses was not possible for a long time. In particular, a focus of the cytometric analysis on those lymphocytes specifically recognizing a defined antigen was hampered due to technical limitations. Yet, traditional methods for the analysis of antigen-specific lymphocytes typically relied upon measurements of proliferation or cytokine expression in bulk cultures. In recent times, this hindrance has been overcome both for B and T lymphocytes. We review here the emerging field of antigen-specific cytometry and describe the most widely used state of the art and future technologies that offer exciting new options to analyze and isolate specifically those lymphocytes that are directly involved in the immune reaction to given antigens, options that have already spurred research, diagnosis, and therapy beyond scope.

B-Lymphocytes↗
PubMed2004

Plasma cell-like morphology of Th1-cytokine-producing cells associated with the loss of CD3 expression.

Here we clarified the morphology and phenotype of interleukin (IL)-17- and interferon (IFN)-gamma-producing cells in both in vitro and in vivo situations. Oligoclonal activation of normal peripheral blood mononuclear cells with the superantigen Staphylococcus aureus enterotoxin B and polyclonal activation with phorbol myristate acetate/phytohemagglutinin were used as in vitro models. This study was extended to various in vivo situations such as rheumatoid arthritis, dermatomyositis, and normal activated lymph nodes. The phenotype of IL-17- and IFN-gamma-producing cells was evaluated by immunohistochemistry using the CD3 and CD4 T-cell markers, the CD20, CD38, kappa and lambda light chain B-cell lineage markers. The expression of two chemokine receptors, CCR6 and CCR7, involved with their associated ligands CCL20 and CCL19/CCL21 in the migration of T lymphocytes, was evaluated in tissue sections. After both polyclonal and oligoclonal activation, IL-17+ and IFN-gamma+ cells acquired a plasma cell-like morphology associated with a high secretory activity, the reduced expression of CD3, and no change of CD4 expression. In rheumatoid arthritis, dermatomyositis, and activated lymph nodes, both IL-17- and IFN-gamma-producing cells had the same morphology. These Th1 cytokine-producing cells were CD4(+)-, CD3-, and B-cell lineage marker-negative. In both in vitro and in vivo situations, expression of CCR6 or CCR7 was not associated with a particular subset. In conclusion, activated T-helper CD4(+) T cells, by their release of cytokines, seem to have functional similarities with plasma cells secreting immunoglobulins.

Antigens, CD↗
PubMed2004

The IkappaB kinase complex and NF-kappaB act as master regulators of lipopolysaccharide-induced gene expression and control subordinate activation of AP-1.

Toll-like receptors (TLRs) recognize conserved products of microbial pathogens to initiate the innate immune response. TLR4 signaling is triggered upon binding of lipopolysaccharides (LPS) from gram-negative bacteria. Using comparative gene expression profiling, we demonstrate a master regulatory role of IkappaB kinase (IKK)/NF-kappaB signaling for immediate-early gene induction after LPS engagement in precursor B cells. IKK/NF-kappaB signaling controls a large panel of gene products associated with signaling and transcriptional activation and repression. Intriguingly, the induction of AP-1 activity by LPS in precursor B cells and primary dendritic cells fully depends on the IKK/NF-kappaB pathway, which promotes expression of several AP-1 family members, including JunB, JunD, and B-ATF. In pre-B cells, AP-1 augments induction of a subset of primary NF-kappaB targets, as shown for chemokine receptor 7 (CCR7) and immunoglobulin kappa light chain. Thus, our data illustrate that NF-kappaB orchestrates immediate-early effects of LPS signaling and controls secondary AP-1 activation to mount an appropriate biological response.

B-Lymphocytes↗
PubMed2003

Substitution in position 3 of cyclosporin A abolishes the cyclophilin-mediated gain-of-function mechanism but not immunosuppression.

Binary complex formation between the immunosuppressive drug cyclosporin A (CsA) and cyclophilin 18 is the prerequisite for the ability of CsA to inhibit the protein phosphatase activity of calcineurin, a central mediator of antigen-receptor signaling. We show here that several CsA derivatives substituted in position 3 can inhibit calcineurin without prior formation of a complex with cyclophilin 18. [Methylsarcosine(3)]CsA was shown to inhibit calcineurin, either in its free form with an IC(50) value of 10 microm, or in its complex form with cyclophilin 18 with an IC(50) of 500 nm. [Dimethylaminoethylthiosarcosine(3)]CsA ([Dat-Sar(3)]CsA) was found to inhibit calcineurin on its own, with an IC(50) value of 1.0 microm, but was not able to inhibit calcineurin after forming the [Dat-Sar(3)]CsA-cyclophilin 18 binary complex. Despite their different inhibitory properties, both CsA and [Dat-Sar(3)]CsA suppressed T cell proliferation and cytokine production mainly through blocking NFAT activation and interleukin-2 gene expression. Furthermore, to demonstrate that [Dat-Sar(3)]CsA can inhibit calcineurin in a cyclophilin-independent manner in vivo, we tested its effect in a Saccharomyces cerevisiae strain (Delta12), in which all the 12 cyclophilins and FKBPs were deleted. [Dat-Sar(3)]CsA, but not CsA, bypassed the requirement for cellular cyclophilins and caused growth inhibition in the salt-stressed Delta12 strain.

Amino Acid Substitution↗