Immunopharmacology: challenges, opportunities and research tools. Edinburgh 1st-2nd October 2018.

At the beginning of October 2018 we held a meeting in Edinburgh focussed on the launch of the IUPHAR Guide to IMMUNOPHARMACOLOGY. Invited speakers contributed to productive discussions on the varying challenges and opportunities in immunopharmacology research.

Immunopharmacology: The New Frontier

There has been immense progress in immunopharmacology, but there are insufficient links between the immunological and pharmacological sciences. Thus, we have set up several initiatives.

  • IUPHAR set up an immunopharmacology section (Immuphar) chaired by Francesca Levi-Schaffer.

  • IUPHAR has signed an agreement with International Union of Immunological Sciences (IUIS, President Alberto Mantovani, who has also made major contributions to the field of check-point inhibitors) to ensure collaboration and cooperation.

  • IUPHAR, NC-IUPHAR (chair Steve Alexander), the University of Edinburgh (PI, Pr Jamie Davies) and the Edinburgh database group (IUPHAR/BPS Guide to Pharmacology; www.guidetopharmacology.org) have been able to set up a new database on the drug targets in immunopharmacology, financed by a major grant from the Wellcome Trust. This is www.guidetoimmunopharmacology.org, which has been recently launched and is freely available to all. The BPS finance two staff in the Edinburgh group for which IUPHAR is immensely grateful.

  • To celebrate this launch, a focussed immunopharmacology meeting was organised, which included the Anthony Harmar memorial lecture. This report provides a a summary of the meeting presentations, discussions and outcomes.

The launch of GtoImmuPdb has also been reported in a Nature Review Immunology Web Watch article: A new guide to immunopharmacology (https://doi.org/10.1038/s41577-018-0079-2)

Please read our detail meeting report which summarises the presentations, discussions and outcomes. Download the Meeting Report (PDF)

Access slidesets from the presentations below (or on our website):

Meeting Presentations

 

Anthony Harmer Memorial Lecture: Decision-making in lung immunity Prof. Tracy Hussell Download slides: pptx | pdf
The Guide to IMMUNOPHARMACOLOGY Dr. Elena Faccenda, Dr. Chris Southan and Dr. Simon Harding Download slides: pptx | pdf
Macrophage plasticity in immunopathology and cancer: from bench to bedside Prof. Alberto Mantovani Download slides: pptx | pdf
Targeting Pattern Recognition Receptor signalling for therapeutic approaches Prof. Clare Bryant slides not available
Discovering the right target in inflammatory disease Prof. Iain McInnes slides not available
Is Atherosclerosis a Systemic or a Vascular Immune Disease? Prof. Pasquale Maffia slides not available
Inhibit Activation or Activate Inhibition of Mast Cells and Eosinophils: Which Weapon is Better to Fight Allergic Diseases? Prof. Francesca Levi-Schaffer Download slides: pptx | pdf
IUPHAR: natural products and immunology Prof. Michael Spedding Download slides: pptx | pdf
Human type I interferon up regulation – worth targeting? Prof. Yanick Crow Download slides: pptx | pdf
A review on kinase targets in immunological indications Dr. Dorian Fabbro Download slides: pdf
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The Anthony Harmar Memorial Lecture 2018: Prof. Tracy Hussell

Prof. Tracy Hussell

Lung Disease: think about disease in a different way

Hussell Tracey (Altered)Tracy Hussell is Director, Manchester Collaborative Centre for Inflammation Research (MCCIR) and Professor of Inflammatory Disease, University of Manchester, Oxford Road, Manchester, M13 9PT.

To be healthy is an active process so health must be continually maintained. Is disease a process that can’t sense it is healthy again? We all have different set points. Sterile inflammation can be created by a single missing factor. Generally, while the lung epithelium is intact, then the tissue is non-activated. Epithelial damage is a critical driver, which may permanently change macrophages and the basal state in the lung. Airways macrophages are critical – when washed out, tissues change very quickly.

CD200R transmits negative signal to macrophages and ligand is on epithelium cells. Then antigen relieves signal. Axl continually recognises gas 6 on apoptosis so don’t activate with apoptosis.

Resolution of inflammation gives a different macrophage population – twice as many as before inflammation, which may survey the environment, resolving from a severe inflammatory event, to a new state. There are therapeutic ways of going back, but chronic obstructive pulmonary disease (COPD) and asthma have a permanently active state. MiRNAs are changed in resolved inflammation, therefore let-7b is increased, modifying Toll response changes. Patient becomes less responsive to bacteria – patients are retuned to not die when challenged, but have also lost miRNAs. The basement membrane is normally very thin but becomes permanently changed (Burgstaller et al., 2017, Eur Respir J. 2017 doi: 10.1183/13993003. PMID: 28679607). The tissue is changed, so not just immune effects.

Hyaluranon is a major constituent of the inflamed lung. Is the lung inflamed or is it just because there are a lot of retained immune cells? The latter. Why does matrix persist? Hyaluronic acid synthase is increased (clearance unchanged, hyaluronase unchanged). Matrix turnover means that there are more activated immune cells. The impact of viral infections on lung matrix affects its mechanical stability and structural support. The composition of matrix also indirectly controls inflammation by influencing cell adhesion, migration, survival, proliferation and differentiation. Hyaluronan is a significant component of the lung extracellular matrix and production and degradation must be carefully balanced. Tracy discovered an imbalance in hyaluronan production following resolution of a severe lung influenza virus infection, driven by hyaluronan synthase 2 from epithelial cells, endothelial cells and fibroblasts. Furthermore hyaluronan, due to elevated TNF, sequesters CD44-expressing macrophages. Intranasal hyaluronidase reduces lung hyaluronan restoring function. Hyaluronidase is already used clinically. Digestion of HA restores lung function. Hyaluronidase (available for clinical trials) appears an interesting option. (Hussell T et al., Eur Respir Rev., 2018, doi: 10.1183/16000617.0032-2018. PMID: 29950305).

In cancer the matrix is abnormal, and the immune system is paralysed. In many instances the matrix is stiff. It may be possible to think differently about reactivating the immune system here.

In severe cell death, macrophages clear apoptotic cells, TAMs recognise external phosphatidyl serine. Reverse signalling to STAT1 turning off inflammation, so while apoptosis is going on the tissue is vulnerable to bacterial attack. Axl receptor only in lung so this represents a unique opportunity for targeted therapy. Changed matrix, lost apoptosis, but poorly cleared even if immunity suppressed.

Eight days after influenza, basal cells proliferate requiring Axl receptor to show that damage has happened. Basal cell show hyperplasia if apoptosis continues – most lung disease has this as a hallmark. Axl antagonists allows faster repair. Type 1 interferons (IFNs): Neuropeptide receptors alter away homeostasis Gfra2 part of GDNF family massively increased on lung TAMs. Needs to co-stimulate with ret which is induced by type 1 IFNs. The virus may act via TLR7/8, in epithelium. MMP2 is specifically increased to degrade collagen type IV to degrade basement membrane. Two chemokines bind CXCR2. CCL18 macrophages that drive resolution, no homologue in rodents.

Is COPD then associated with inflamed tissues or trapped inflammatory cells? Possibly like tumours. Will check-point inhibitors also release antigen presenting cells? New therapeutic options await validation.

Slide Downloads: PPTX | PDF


tonyharmar

Anthony Harmar, Professor of Pharmacology in Edinburgh.

In addition to being a brilliant pharmacologist, Tony set up the IUPHAR Edinburgh database group which initiated IUPHAR-DB, which expanded into the IUPHAR/BPS Guide to Pharmacology database (www.guidetopharmacology.org).

 

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Hot Topic: Piezo channels and mechano-transduction in sensory neurons

Piezo channels (Piezo1 and Piezo2) are excitatory ion channels which respond directly to a variety of forms of mechanical stimuli. Two recent papers describe some of the critical roles of Piezo channels in sensory neuron transduction (1, 2). In the first, Murthy et al. (1) demonstrate that Piezo2 mediates both inflammatory and nerve-injury sensitized mechanical pain in mice. In the second, Zeng et al. (2), show that both Piezo1 and Piezo2 are responsible for the baro-receptor reflex that regulates blood pressure and cardiac function.

For researchers interested in studying the roles of Piezo channels in mechano-transduction, useful pharmacological tools, at least for Piezo1, in the form of allosteric activators (3) and an inhibitor (4), have already emerged. Named Yoda1, Jedi1, Jedi2 and Dooku1, they are. May the force………

Comments by Alistair Mathie (@AlistairMathie) and Emma L. Veale (@Ve11Emma), The Medway School of Pharmacy

(1) Murthy SE et al. (2018). The mechanosensitive ion channel Piezo2 mediates sensitivity to mechanical pain in mice. Sci Transl Med. doi: 10.1126/scitranslmed.aat9897. [PMID: 30305457].
(2) Zeng WZ et al. (2018). PIEZOs mediate neuronal sensing of blood pressure and the baroreceptor reflex. Science doi: 10.1126/science.aau6324. [PMID: 30361375].
(3) Wang Y et al. (2018). A lever-like transduction pathway for long-distance chemical- and mechano-gating of the mechanosensitive Piezo1 channel. Nat Commun. 9(1):1300. doi: 10.1038/s41467-018-03570-9. [PMID: 29610524].
(4) Evans EL et al. (2018). Yoda1 analogue (Dooku1) which antagonizes Yoda1-evoked activation of Piezo1 and aortic relaxation. Br J Pharmacol. 175(10):1744-1759. doi: 10.1111/bph.14188. [PMID: 29498036].

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Hot Topics: Role of RTP type D on reward association with cocaine administration

The receptor tyrosine phosphatase (RTP) family is a relatively small group of cell-surface proteins with a simple intracellular enzymatic function in the dephosphorylation of phosphotyrosine proteins. There is less known about the endogenous extracellular ligands which regulate RTP activities in physiological conditions, although some RTPs are activated by cell-surface proteins thought to be expressed on neighbouring cells.

This report [1] from the National Institute on Drug Abuse in the USA focusses on the role of RTP type D on reward associated with cocaine administration. They identify that RTP type D heterozygous knockout mice exhibit lower reward responses to cocaine, and that a novel small molecule that appears to target the enzymatic function of RTP type D is able to reduce cocaine-induced place preference and self-administration in wild type, but not heterozygous knockout mice.

Comments by Steve Alexander (@mqzspa)

(1) Uhl GR et al. (2018). β-Subunit of the voltage-gated Ca2+ channel Cav1.2 drives signaling to the nucleus via H-Ras. Proc Natl Acad Sci USA, pii: 201720446. doi: 10.1073/pnas.1720446115. [Epub ahead of print] [PMID: 30348770]

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Hot topic: (but in this case, stale beer) the long overdue primary pharmacological characterisation of BIA 10-2747

The unfortunate French clinical trial disaster in which the FAAH inhibitor BIA 10-2747 (ligand ID 9001)  left one participant dead and several others with serious neurological adverse events, occurred back in January 2016.  However, the primary publication that describes the properties of this lead compound from its Portuguese originators BIAL has only now appeared in September of 2018 (1).  It is more typical for pharmaceutical medicinal chemistry teams to report their initial in vitro optimisation of a clinical candidate well in advance of Phase 1 (i.e. we might have expected to see this paper circa 2017).  While much has been written about 10-2747 in the last two years, very little peer-reviewed data has appeared (see this slide set and blog post).  In this context, the only BIAL journal paper so far on this compound is a disappointment.  The SAR of the series is only reported as % inhibition determinations rather than the more standardised and usefully comparative IC50s (this means we would actually not curate interaction data from such a paper but we have added the reference to the ligand entry). In addition, they do not address experimentally the irreversibility topic over which there has been some confusion. We would also quibble with the use of  “potent” in the title since an independent report of the initial IC50 binding  (i.e. without pre-incubation for inactivation) was only 7.5 uM (2).

Comments by Chris Southan (@cdsouthan)

  1. Kiss et al  (2018). Discovery of a Potent, Long-Acting, and CNS-Active Inhibitor (BIA 10-2474) of Fatty Acid Amide Hydrolase.  ChemMedChem, [Epub ahead of print]. [PMID:30113139].
  2. van Esbroeck et al. (2017) Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474 Science, 356(6342):1084-1087 (PMID: 28596366)

 

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Hot topic: Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor

In this multi-author, multi-centre publication [1] lead by Denise Wootten and Patrick Sexton from the Monash Institute of Pharmacological Sciences, there is reported a 3.3 Angstrom structure of one of the more unusual G protein-coupled receptors. The CGRP receptor is a target for the recently FDA-approved monoclonal antibody erenumab targetting migraine. The receptor is unusual because of its modulation by a trio of accessory proteins exemplified here by RAMP1, which influence both the pharmacological and signalling profiles of the GPCR. Recent structural approaches to studies of GPCR have moved into investigations where a G protein is included. The Liang paper has a Gs heterotrimer attached, and, in addition, has the natural ligand, CGRP bound to the receptor. The report on this six molecule complex thus allows a major advance into the interaction between a GPCR, its endogenous agonist, the requisite G protein AND a modulatory protein.

Comments by Steve Alexander (@mqzspa)

(1) Liang YL et al. (2018). Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor. Nature, doi: 10.1038/s41586-018-0535-y. [Epub ahead of print]. [PMID: 30175587]

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Hot Topic: β-Subunit of the voltage-gated Ca2+ channel Cav1.2 drives signaling to the nucleus via H-Ras

This paper [1] extends previous studies demonstrating a key role of voltage-gated L-type Ca2+ channels in the modulation of activity-dependent gene transcription. Earlier work in cultured neurons had already shown that L-type channel activity is required to activate gene expression through different signaling pathways, including the Ras/MAPK pathway [2-4]. This is confirmed in the present study (primarily in experiments with HEK-293 cells) but there are important differences in the way nuclear signaling gets activated. In contrast to previous models [2], it is shown that the Ras/MAPK pathway is turned on by a direct physical interaction of the L-type channel (only Cav1.2 was studied) with Ras through the channel’s beta-subunit. Moreover, this interaction requires binding of extracellular Ca2+ to the pore-forming alpha1-subunit but no Ca2+ influx through the channel. Also no binding of calmodulin to the channel is required. This strongly suggests a direct conformational coupling of Cav1.2 to Ras activation and adds to other evidence of conformational coupling of L-type Ca2+ channels [5-6]. However, further experiments are required to demonstrate that this mechanism also exists in neurons.

Comments by Jörg Striessnig, University of Innsbruck

(1) Servili E et al. (2018). β-Subunit of the voltage-gated Ca2+ channel Cav1.2 drives signaling to the nucleus via H-Ras. Proc Natl Acad Sci USA, 115(37):E8624-E8633. doi: 10.1073/pnas.1805380115. [PMID: 30150369]

(2) Dolmetsch RE et al. (2001). Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway. Science, 294(5541):333-9. [PMID: 11598293]

(3) Wu GY et al. (2018). Activity-dependent CREB phosphorylation: convergence of a fast, sensitive calmodulin kinase pathway and a slow, less sensitive mitogen-activated protein kinase pathway. Cold Spring Harbor Perspect Biol, 98(5):2808-13. [PMID: 11226322]

(4) Hagenston AM & Bading H (2018). Calcium signaling in synapse-to-nucleus communication. Mol Pharmacol, 3(11):a004564. doi: 10.1101/cshperspect.a004564. [Epub ahead of print]. [PMID: 30021858]

(5) Krey JF et al. (2013). Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons. Nat Neurosci 16:201-9. [PMID: 23313911]

(6) Li B et al. (2016). Sequential ionic and conformational signaling by calcium channels drives neuronal gene expression. Science 351:863-7. [PMID: 26912895]

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