Kerstin Steinbrink
University of Mainz
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Publication
Featured researches published by Kerstin Steinbrink.
International Journal of Cancer | 2000
Julia Steitz; Jürgen Brück; Kerstin Steinbrink; Alexander H. Enk; Jürgen Knop; Thomas Tüting
The melanosomal protein TRP2 expressed by melanocytes and most melanoma cells is an attractive, clinically relevant model antigen for the experimental development of melanoma immunotherapy in mice. A peptide shared by murine and human TRP2 can be recognized by melanoma‐reactive CTL in C57BL/6 mice, as well as in human melanoma patients. Previous experiments demonstrated that gene gun immunization of mice with plasmid DNA encoding autologous murine TRP2 was unable to induce protective immunity against B16 melanoma cells naturally expressing TRP2. In the present study, we investigated whether the use of cDNA encoding xenogeneic human TRP2, which is highly homologous to murine TRP2, would be more effective. Genetic immunization of mice with human TRP2 resulted in coat depigmentation as a sign of autoimmune‐mediated destruction of melanocytes and provided significant protection against metastatic growth of B16 melanoma. Induction of protective immunity was associated with TRP2‐reactive antibodies and CD8+ T cells. Furthermore, immunization with recombinant adenovirus was more effective than immunization with plasmid DNA using the gene gun. Our results provide new insights for the development of antigen‐specific immunotherapy of melanoma. Int. J. Cancer 86:89–94, 2000.
Frontiers in Immunology | 2013
Mario Hubo; Bettina Trinschek; Fanny Kryczanowsky; Kerstin Steinbrink; Helmut Jonuleit
Dendritic cells (DC) are sentinels of immunity, essential for homeostasis of T cell-dependent immune responses. Both functions of DC, initiation of antigen-specific T cell immunity and maintenance of tissue-specific tolerance originate from distinct stages of differentiation, immunogenic versus tolerogenic. Dependent on local micro milieu and inflammatory stimuli, tissue resident immature DC with functional plasticity differentiate into tolerogenic or immunogenic DC with stable phenotypes. They efficiently link innate and adaptive immunity and are ideally positioned to modify T cell-mediated immune responses. Since the T cell stimulatory properties of DC are significantly influenced by their expression of signal II ligands, it is critical to understand the impact of distinct costimulatory pathways on DC function. This review gives an overview of functional different human DC subsets with unique profiles of costimulatory molecules and outlines how different costimulatory pathways together with the immunosuppressive cytokine IL-10 bias immunogenic versus tolerogenic DC functions. Furthermore, we exemplarily describe protocols for the generation of two well-defined monocyte-derived DC subsets for their clinical use, immunogenic versus tolerogenic.
Archives of Dermatological Research | 2000
Kerstin Steinbrink; Lydia Paragnik; Helmut Jonuleit; Thomas Tüting; Jürgen Knop; Alexander H. Enk
Abstract Dendritic cells (DC) are the most potent antigen-presenting cells of the immune system. In this study we investigated the effects of various prostaglandins (PG) on the stimulatory capacity of DC. DC were generated from peripheral progenitor cells in the presence of IL-4 and GM-CSF and stimulated with ¶IL-1, IL-6 and TNF-· on day 7. Simultaneously, PG (PGD 2 , PGE 1 , PGE 2 , PGF 2alpha , PGI 2 ) were added at various concentrations (10 –5 to 10 –9 M ) on day 7. In all experiments, PGE 2 had the most potent influence on the maturation of the DC, followed by other PG in the order PGE 1 >PGD 2 >PGF 2alpha >PGI 2 . In addition, the expression of the surface molecules CD40, CD54, CD58, CD80, CD83, CD86 and the MHC class II molecules was upregulated after stimulation with PG. Analysis of DC supernatants after treatment with PG demonstrated significantly higher amounts of the proinflammatory cytokines IL-1‚, IL-6, TNF-·, and IL-12. Addition of PG to DC induced a markedly enhanced proliferation of both naive and activated CD4 + and CD8 + T cells in alloantigen-induced MLR assays. Assessment of coculture supernatants after restimulation revealed significantly higher amounts of the Th1-cytokines IL-2 and IFN-Á and only minimal amounts of IL-4 compared to control cells. No production of IL-10 was observed. The effects of PG on the maturation of DC and enhanced T-cell proliferation could be mimicked by db-cAMP and forskolin, indicating that they were due to elevated cAMP levels. Collectively, our data show that members of the PG family promote the differentiation of DC and enhance their capacity to induce a Th1 immune response.
Frontiers in Immunology | 2015
Verena Raker; Matthias P. Domogalla; Kerstin Steinbrink
Dendritic cells (DCs) are highly specialized professional antigen-presenting cells that regulate immune responses, maintaining the balance between tolerance and immunity. Mechanisms via which they can promote central and peripheral tolerance include clonal deletion, the inhibition of memory T cell responses, T cell anergy, and induction of regulatory T cells (Tregs). These properties have led to the analysis of human tolerogenic DCs as a therapeutic strategy for the induction or re-establishment of tolerance. In recent years, numerous protocols for the generation of human tolerogenic DCs have been developed and their tolerogenic mechanisms, including induction of Tregs, are relatively well understood. Phase I trials have been conducted in autoimmune disease, with results that emphasize the feasibility and safety of treatments with tolerogenic DCs. Therefore, the scientific rationale for the use of tolerogenic DCs therapy in the fields of transplantation medicine and allergic and autoimmune diseases is strong. This review will give an overview on efforts and protocols to generate human tolerogenic DCs with focus on IL-10-modulated DCs as inducers of Tregs and discuss their clinical applications and challenges faced in further developing this form of immunotherapy.
European Journal of Immunology | 2003
Sebastian Kubsch; Edith Graulich; Jürgen Knop; Kerstin Steinbrink
We have previously shown that human IL‐10‐treated dendritic cells (DC) induce an antigen‐specific anergy in CD4+ T lymphocytes. These anergic T cells are characterized by an inhibitedproliferation, a reduced production of IL‐2, and additionally display antigen‐specific suppressor activity. In this study we investigated the mechanisms underlying the anergic state and regulatory function of these T cells. We did not observe enhanced rates of programmed cell death of anergic CD4+ suppressor T cells compared to T cells stimulated with mature DC. Cell cycle analysis by DNA staining and Western blot experiments revealed an arrest of anergic CD4+ T suppressor cells in the G1 phase. High levels of the IL‐2‐dependent cyclin‐dependent kinase (cdk) inhibitor p27Kip1 were found in anergic CD4+ suppressor T cells resulting in an inhibited activation of retinoblastoma protein and an arrest of cell cycle progression in the G1 phase. Addition of IL‐2, but not blocking of the CTLA‐4 pathway restored the proliferation of the suppressor T cells. In contrast, both treatments induced a down‐regulation of p27Kip1 and acomplete inhibition of the antigen‐specific regulatory function as demonstrated by high proliferation and enhanced IFN‐γ production of co‐cultured T cells. Further experiments demonstrated thatp27Kip‐expressing regulatory CD4+CD25+ T cells did not contribute to induction of T cell anergy in this model. Our data show that regulatory function of anergic CD4+ suppressor T cells is associated with an arrest in the G1 phase of the cell cycle mediated by increased levels of the IL‐2‐ and CTLA‐4‐dependent cdk inhibitor p27Kip1.
Gene Therapy | 2000
Helmut Jonuleit; Thomas Tüting; J Steitz; Jürgen Brück; A. Giesecke; Kerstin Steinbrink; Jürgen Knop; Alexander H. Enk
We have developed a culture method for the foreign serum-free generation of highly immunostimulatory, CD83+ human dendritic cells (DC). In this study, we evaluated the feasibility and consequences of endogenously expressing antigens in mature DC using adenoviral vectors. Transduction of DC with Ad-EGFP demonstrated endogenous fluorescence in 50–85% of CD83+ DC. Ad-transduced DC stimulated the proliferation of allogeneic CD8+ and CD4+ T cells at low DC: T cell ratios. However, at high DC: T cell ratios the stimulatory capacity of Ad-transduced DC was suppressed. This immunosuppressive effect was confirmed by demonstrating that the stimulatory function of untreated DC could be suppressed in a dose-dependent manner by addition of Ad-transduced DC. Furthermore, transwell experiments suggested that direct cell contact was required. Taken together, our results demonstrate the feasibility of efficiently expressing antigens in CD83+ DC using adenoviruses. However, immunosuppressive effects must be considered and carefully studied before Ad-transduced DC are employed for clinical trials.
Journal of Gene Medicine | 1999
Thomas Tüting; Julia Steitz; Jürgen Brück; Andrea Gambotto; Kerstin Steinbrink; Albert B. DeLeo; Paul D. Robbins; Jürgen Knop; Alexander H. Enk
The induction of cellular immune responses to melanocyte‐specific enzymes such as the tyrosinase family of proteins is the goal of various clinical studies for the immunotherapy of melanoma. Tyrosinase‐related protein‐2 (TRP2) is an attractive model antigen for preclinical studies in C57BL/6 mice because it is naturally expressed by the murine B16 melanoma and can be recognized by self‐reactive cytolytic T lymphocytes (CTL). Here we describe efforts to develop genetic immunization with dendritic cells (DC) for the immunotherapy of melanoma in this clinically relevant system.
International Journal of Hematology | 2005
Jan Kubach; Christian Becker; Edgar Schmitt; Kerstin Steinbrink; Eva Huter; Helmut Jonuleit
The induction of effective antigen-specific T-cell immunity to pathogens without the initiation of autoimmunity has evolved as a sophisticated and highly balanced immunoregulatory mechanism. This mechanism assures the generation of antigen-specific effector cells as well as the induction and maintenance of antigen-specific tolerance to self-structures of the body. As professional antigen-presenting cells of the immune system, dendritic cells (DC) are ideally positioned throughout the entire body and equipped with a unique capability to transport antigens from the periphery to lymphoid tissues. There is growing evidence that DC, besides their well-known immunostimulatory properties, also induce and regulate T-cell tolerance in the periphery. This regulatory function of DC is strictly dependent on their different stages of maturation and activation. Additionally, immunosuppressive agents and cytokines further influence the functions of maturing DC. The regulatory properties of DC include induction of T-cell anergy, apoptosis, and the generation of T-cells with regulatory capacities. This brief review summarizes the current knowledge about the immunoregulatory role of DC as guardians for the induction of T-cell immunity and tolerance.
The Lancet | 2017
Hywel C. Williams; F. Wojnarowska; Gudula Kirtschig; James Mason; Thomas R. Godec; Enno Schmidt; Joanne R. Chalmers; Margaret Childs; S. Walton; K. E. Harman; Anna Chapman; Diane Whitham; Andrew Nunn; J Adams; V Akhras; Alexander Vincent Anstey; C Barnard; Hazel K. Bell; S Blackford; Eva-B. Bröcker; A Carmichael; R.R. Coelho; Fiona E. Craig; K Davies; R Ellis; John C. English; Regine Gläser; Richard Groves; C Günthert; P J Hampton
Summary Background Bullous pemphigoid is a blistering skin disorder with increased mortality. We tested whether a strategy of starting treatment with doxycycline gives acceptable short-term blister control while conferring long-term safety advantages over starting treatment with oral corticosteroids. Methods We did a pragmatic, multicentre, parallel-group randomised controlled trial of adults with bullous pemphigoid (three or more blisters at two or more sites and linear basement membrane IgG or C3). Participants were randomly assigned to doxycycline (200 mg per day) or prednisolone (0·5 mg/kg per day) using random permuted blocks of randomly varying size, and stratified by baseline severity (3–9, 10–30, and >30 blisters for mild, moderate, and severe disease, respectively). Localised adjuvant potent topical corticosteroids (<30 g per week) were permitted during weeks 1–3. The non-inferiority primary effectiveness outcome was the proportion of participants with three or fewer blisters at 6 weeks. We assumed that doxycycline would be 25% less effective than corticosteroids with a 37% acceptable margin of non-inferiority. The primary safety outcome was the proportion with severe, life-threatening, or fatal (grade 3–5) treatment-related adverse events by 52 weeks. Analysis (modified intention to treat [mITT] for the superiority safety analysis and mITT and per protocol for non-inferiority effectiveness analysis) used a regression model adjusting for baseline disease severity, age, and Karnofsky score, with missing data imputed. The trial is registered at ISRCTN, number ISRCTN13704604. Findings Between March 1, 2009, and Oct 31, 2013, 132 patients were randomly assigned to doxycycline and 121 to prednisolone from 54 UK and seven German dermatology centres. Mean age was 77·7 years (SD 9·7) and 173 (68%) of 253 patients had moderate-to-severe baseline disease. For those starting doxycycline, 83 (74%) of 112 patients had three or fewer blisters at 6 weeks compared with 92 (91%) of 101 patients on prednisolone, an adjusted difference of 18·6% (90% CI 11·1–26·1) favouring prednisolone (upper limit of 90% CI, 26·1%, within the predefined 37% margin). Related severe, life-threatening, and fatal events at 52 weeks were 18% (22 of 121) for those starting doxycycline and 36% (41 of 113) for prednisolone (mITT), an adjusted difference of 19·0% (95% CI 7·9–30·1), p=0·001. Interpretation Starting patients on doxycycline is non-inferior to standard treatment with oral prednisolone for short-term blister control in bullous pemphigoid and significantly safer in the long-term. Funding NIHR Health Technology Assessment Programme.
Cancer Research | 2013
Nicole Bacher; Verena Raker; Claudia Hofmann; Edith Graulich; Melanie Schwenk; Ria Baumgrass; Tobias Bopp; Ulrich Zechner; Luzie Merten; Christian Becker; Kerstin Steinbrink
IFN-α is an antineoplastic agent in the treatment of several solid and hematologic malignancies that exerts strong immune- and autoimmune-stimulating activity. However, the mechanisms of immune activation by IFN-α remain incompletely understood, particularly with regard to CD4(+)CD25(high)Foxp(+) regulatory T cells (Treg). Here, we show that IFN-α deactivates the suppressive function of human Treg by downregulating their intracellular cAMP level. IFN-α-mediated Treg inactivation increased CD4(+) effector T-cell activation and natural killer cell tumor cytotoxicity. Mechanistically, repression of cAMP in Treg was caused by IFN-α-induced MAP-ERK kinase (MEK)/extracellular signal-regulated kinase (ERK)-mediated phosphodiesterase 4 (PDE4) activation and accompanied by downregulation of IFN receptor (IFNAR)-2 and negative regulation of T-cell receptor signaling. IFN-α did not affect the anergic state, cytokine production, Foxp3 expression, or methylation state of the Treg-specific demethylated region (TSDR) within the FOXP3 locus associated with a stable imprinted phenotype of human Treg. Abrogated protection by IFN-α-treated Treg in a humanized mouse model of xenogeneic graft-versus-host disease confirmed IFN-α-dependent regulation of Treg activity in vivo. Collectively, the present study unravels Treg inactivation as a novel IFN-α activity that provides a conceivable explanation for the immune-promoting effect and induction of autoimmunity by IFN-α treatment in patients with cancer and suggests IFN-α for concomitant Treg blockade in the context of therapeutic vaccination against tumor antigens.