Working Group 4

Therapeutic potential of mast cell and basophil targeting strategies

WG leader: Stephan Bischoff (Germany)
Email: undefinedbischoff.stephan(at)uni-hohenheim.de

Vice chair: Frank Redegeld, PhD (The Netherlands)
Email: undefinedf.a.m.redegeld(at)uu.nl

Opens internal link in current windowGroup members

General activities

  • Map the special fields of the working group members, roundtable of participants
  • Exchange knowledge, tools, and experience
  • Clinical and basic research, collaborative research
  • Document existing (provisional) patent positions on mast cell targets within academic groups, which may be interesting to further develop
  • Get in touch with key persons in pharmaceutical industries
  • Find complementary groups to strengthen new grant proposals
  • Brainstorm on potential targets, including ranking of targets
  • Using results from brainstorm to select targets for a FP7/8 grant proposal

Identification of specific therapeutic potential of mast cells or basophils

MAST CELLS

  • Identification of new targets in mast cell activation and survival
  • Inhibition of mast cell activation in allergic and chronic inflammatory (auto)immune disease, and cancer
  • Mast cell involvement in histamine autoregulation in inflammatory (allergic) disorders
  • Mast cell activation/degranulation in Irritable Bowel Syndrome (IBS) and
  • Postoperative Ileus (POI) (triggers, intracellular path-ways, effect of mediators on target cells etc)
  • Novel therapeutic applications of MCs or MC-derived substances
  • Novel application for molecular decoy to modulate the cellular or extracellular matrix interaction that could be used to dissect the role of mast cells in acquired or innate immunity or therapeutic purpose
  • PAR-2 antagonism, inhibitors of tryptase and chymase, apoptosis induction in mast cells (e.g., ABT-747,263), inhibition of CD30L-CD30 interaction (CD40L-CD40, OX40L-OX40)
  • BASOPHILS
  • Basophils as early activators of innate immune responses
  • DISEASE
  • Cutaneous leukocytoclastic vascullitis, Pruritus, Rosacea, Sensitive skin
  • Effect of Enoxaparinum on Urticaria Pigmentosa
  • Wound healing processes under various pathological conditions (i.e. diabetes, ischemia-reperfusion, etc.)

General fields of interest

BASIC SCIENCE

  • Mast cell mediator secretion pathways (histamine, cytokines)
  • Pharmacological validation (particularly H4 receptor ligands)
  • Kinases and kinase inhibitors mostly in receptor signaling (Kit receptor and its signaling)
  • Mechanism of Ig free light chain-induced mast cell activation in vitro and in vivo
  • Synthesis of different molecules (nanoconjugates: polymeric, dendrimeric or inclusion complex types) for biomedical applications
  • Cyclodextrins or modified cyclodextrins drug inclusion complexes with different target
  • Medicinal Chemistry/Drug development comprehensive of ADME studies;
  • Computational Biochemistry; exp. Biochemistry

CLINICAL SCIENCE

  • Inflammation in allergic diseases and chronic allergic diseases
  • Mast cells in human skin disease
  • Preclinical models in inflammation (conjunctivitis, arthritis)
  • Mast cells in non-IgE mediated inflammatory diseases
  • Mast cells as modulators of implantation and placentation
  • Irritable Bowel Syndrome (IBS) and Postoperative Ileus (POI): identify targets and/or therapeutic strategies to treat IBS and POI
  • Human basophils as active players in the (allergic) immune response.

Conception of clinical trials

  • In vivo clinical studies on pathogenesis and therapeutics
  • Phase IIa proof-of-concept clinical trial for the treatment of allergic rhinitis and asthma of the first H4R ligand (UR-63325) initiated in Dec 2010

Designated research focus

  • Identification of mast cell/basophil related targets
  • Consider potent and, especially, safe ways to target mast cells and basophils in a human setting. Will this be on inhibition of (selective) activation, inhibition of migration to target sites, inhibition of differential, or all three together
  • Identification of key factor(s) determining when mast cells act as pro-inflammatory effectors and when they act as down regulators of allergic inflammation
  • Document existing (provisional) patent positions on mast cell targets within academic groups, which may be interesting to further develop
  • Evaluate any preclinical data derived from ex vivo human/in vivo rodent models
  • Translational research
  • Both mouse models (in vivo and in vitro) and human model (in vitro, ex vivo and finally in vivo)
  • To identify any promising compounds (e.g. from literature & through interaction with WG1-3, other Actions such as BM0806, medicinal chemists and Pharma industry) that could be advanced to clinical trials
  • Drug development comprehensive of ADME studies
  • Basophil and organ protection with particular regards to cardiac arrest and renal ischemia/reperfusion injury

Contributions of working group participants

ANIMAL MODELS

  • Animal models for contact sensitivity, IBD, food allergy, asthma, COPD, RA (in collaboration), cancer (melanoma)
  • Deficient mast cell animal model in a NOG background to analyze influence of mast cell in tumorigenicity
  • Several animal models including pregnancy models, mast cell deficiency
  • Human disease models, including induction models (atopy patch test and skin prick test for skin inflammation and food challenges for food allergy)

PHARMACOLOGICAL INVESTIGATION

  • Animal models to test drugs modulating the functions of basophils
  • Updated information on H4R ligand progress at basic & preclinical research level as well as at clinical trials level
  • PAR-2 antagonism, inhibitors of tryptase and chymase, apoptosis induction in mast cells (e.g., ABT-747,263), inhibition of CD30L-CD30 interaction (CD40L-CD40, OX40L-OX40)
  • ADME studies (in silico/experimental)

CELL CULTURE

  • Various mast cell cultures (primary mouse: lung, peritoneal, bone marrow)
  • Mast cell lines available for in vitro testing: signal transduction (PY phosphorylation), mediator release, etc.

BIOPSIES

  • Human skin biopsies for research

TECHNIQUES

  • In vitro assays of basophil activation
  • Ex vivo determination of basophil and mast cell presence in tissue
  • Ex vivo determination of basophil phenotype in blood in-vivo microscopy of the uterus
  • In vitro and in vivo analysis of MC interactions with innate or adaptative immune cells (confocal) immunohistochemistry of animal and human tissue.
  • Synthesize different molecules

CLINICAL TRIALS

  • Conception of clinical trials to define new therapies to target mast cells and basophils

Last updated:

31.10.2014

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Reports

Report Final Conference of COST Action BM1007 (2011-2015)

Mast Cells and Basophils – Targets for Innovative Therapies

Final Report – COST ACTION BM1007 2nd Training School

Jerusalem, Israel, January 20-21, 2014

School of Pharmacy hosts International Training School funded by COST Action BM1007

The School of Pharmacy, University of Nottingham recently hosted an International Training School funded by the COST Action Biomedicine and Molecular Biosciences BM1007 "Mast Cells and Basophils -...

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