Novartis Foundation Bulletin
Issue 16, August 2003
Welcome to the 16th edition of the Novartis Foundation's e-mail Bulletin.
This issue is also available in printable
format.
This issue features:
(Based on presentations given at Novartis Foundation Symposium
260,
'OA joint pain' which was held in
London on 2-4 July 2003)
Osteoarthritis pain goes central
For years osteoarthritis remained the preserve of rheumatologists, with joint erosion assumed as the be-all and end-all of the disease. However,
key findings in pain research are forcing a shake up in current thinking about OA and it is being increasingly seen as a neurological disease with a powerful central
nervous input. At the most recent Novartis Foundation symposium, rheumatologists and neuroscientists came head-to-head to discuss the clinical implications of these emerging ideas.
Osteoarthritis (OA) is on the rise; 13% of people aged over 55 suffer from osteoarthritic joints. And the numbers are set to double in the next 17 years prompting fears of an 'epidemic' driven by the two main risk factors: ageing and obesity.
"The nervous system isn't a passive bystander; it is an important player in the persistence of joint pain," asserts Bruce Kidd
(Bart's & The London School of Medicine, London, UK). Kidd, a rheumatologist, has pinned down one important difference between how people with arthritis and healthy controls process pain. He used a capsaicin-based test that elicits an intense, short-lived pain. While controls soon recover, the arthritic patients develop a neurogenic flare with heightened sensitivity in areas surrounding the affected joints.
Kidd proposes that this hypersensitivity state results from a complex interaction between the immune and nervous systems. Initially, sensory fibres at the site of injury release neuropeptides such as substance P and CGRP. These changes in sensory fibres not only trigger pain directly but also sensitize the peripheral and central nociceptive system leading to a hypersensitivity state. As a result, the person's pain threshold is lowered to the extent that even movements within the normal range become painful. Kidd says: 'We should consider using neuropeptide antagonists to act as modulators in the long term."
This state of hyperexcitability is not confined to humans. Hans-Georg Schaible
(University of Jena, Germany) has used neuronal recordings from cat and rat spinal cords and found that, in addition to substance P, several mediators contribute to this inflammation-induced spinal hyperexcitability: glutamate, neurokinin A, CGRP, prostaglandins and others all of which may serve as potential drug targets. "The CNS is not just a cable from a diseased joint to the brain. It is also modifying the whole pain story for the human being," Schaible asserts.
David Blake (University of Bath, UK) is puzzled as to why people with a rheumatological condition often experience pain that cannot be matched to physical findings, and he believes that it may be a situation similar to amputee phantom pain. Blake set out to test the hypothesis that a mismatch between motor intentions and sensory feedback underlies this type of pain.
With Candy McCabe, he has adapted Ramachandran's mirror experiments and tested them initially on people with complex regional pain syndrome. By practicing movements in the mirrors in a manner that corrects the incongruent perception, pain and stiffness subsided. "In some people we can induce this in seconds" says Blake who believes these findings may have important implications for treating rheumatological pain conditions.
As James Henry (University of Western Ontario, Canada) puts it, "Arthritis should be seen as a disorder not only of the periphery but also of the CNS." The hope is that by examining OA under this new light, researchers are more likely to come up with a host of novel, more effective therapies.
Dr Lisa Melton—Science Writer, Novartis
Foundation, London
This has been abstracted from an article
due to be published in Lancet
Neurology 2(9) on 1st September 2003.
OA joint pain will be published in February 2004 by John
Wiley & Sons, Chichester, UK
(Based on presentations given at Novartis Foundation Symposium 254, 'Immunoinformatics: bioinformatics strategies for better understanding of immune function' which was held in London on 8-10 October 2002)
Are you immunoinformed?
Computational prediction methods have enormous potential for the future of clinical and experimental immunology. The birth of a new field, Immunoinformatics, marks an important step in the understanding of the immune system. The Novartis Foundation recently provided a forum for experts in computational modelling and immunology to discuss how bioinformatic strategies could help us better understand immune function. Given the exponential increase in immunological data coupled with the recent removal of restrictions on genome databases by the
NHGRI, it is becoming increasingly important that such data be efficiently managed and appropriately annotated.
One such expertly annotated resource is the IMGT
system. Marie-Paule Lefranc (Institut de Génétique Humaine, Montpellier,
France) created the international ImMunoGeneTics information system in 1989 that provides an incredibly comprehensive collection of databases and interactive tools. This
web resource specializes in immunoglobulins, T cell receptors, MHC and related proteins of the immune system of human and other vertebrate species. She believes that this will become an increasingly important global resource for many fields from medical research to evolutionary genetics.
Nikolai Petrovsky (Canberra Hospital, Australia) who proposed this symposium
(see his online
report) with Vladimir Brusic
(Institute for Infocomm Research, Singapore), describes how artificial neural networks (ANN) could be useful in clinical practice, for example in predicting the outcome of renal grafts. After training an ANN with renal transplant data, he found that the ANN correctly predicted 85% of successful and 72% of unsuccessful transplants as well as correctly predicting the type of graft rejection. Thus ANN tools could be used for improved donor kidney allocation and for exploring the role of HLA in transplant rejection.
Bioinformatics tools such as EpiMatrix and Conservatrix, which search for unique or
multi-HLA-restricted T cell epitopes have accelerated the process of epitope mapping, argues Anne De Groot
(EpiVax, Providence, USA). She highlights the significant advantage, to immunovaccinology, of
in silico epitope selection, followed by confirmatory studies in
vitro, over traditional exhaustive methods of in vitro screening. Her company,
EpiVax have used immunoinformatics to develop novel vaccines and therapeutics for the prevention and treatment of infectious diseases such as HIV, hepatitis C, tuberculosis and some cancers.
A restricted
version of Dr De Groot's EpiMatrix
predictive algorithm is available to researchers. The online version
of EpiMatrix is restricted to the analysis of HIV sequences.
Understanding the emergent complexity of cellular and organismal level immune responses has been slowed by restrictions such as data reduction to single-gene effects. As Paul Kellam
(University College London, UK) explains, this fails to produce a global systems level appreciation. His work focuses on systems level virology using DNA microarrays and viral-specific data resources to provide a detailed cellular context in which viruses replicate. In this way common and distinct antiviral mechanisms may be highlighted, and the effect of different host cell gene expression programs and response of cells to similar or diverse virus types may be
analysed.
The principles of systems-level analysis are not new. In 1948, Norbert Wiener (founder of cybernetics) considered technical and biological systems as objects for the same scientific approach. In the second half of the past century these attempts at systems level understanding of biological
phenomena suffered from inadequate data on which to base their theories and models. The technological advance with which we enter the 21st century, certainly in the field of Immunoinformatics, means that this does not pose the same restriction. Stephan Beck
(Wellcome Trust Sanger Institute, Cambridge, UK) hopes that we might be able to use the fruit of the Human Genome Project to create a digital immune system.
The next section references some of the online resources discussed by the contributors to this
symposium
Brona McVittie—Assistant Editor, Novartis
Foundation, London
(top)
Immunoinformatics: bioinformatic strategies for better
understanding of immune function will be published by October 2003 by John
Wiley & Sons, Chichester, UK
NF254 web resources
BIRN (Biomedical Information Research Network)
COPE (Cytokines online pathfinder
encyclopaedia)
CORBA (Common Object Request Broker Architecture)
DDBJ/DAD (DNA databank of Japan)
EMBL/TrEMBL
FACTS (Functional Association/Annotation of cDNA Clones from Text/Sequence Sources)
FANTOM1 and FANTOM2
(Functional Annotation Of Mouse)
FIMM database
GenBank/GenPept
Gene Ontology consortium
HAVANA (manual curation of the human
genome)
HIV molecular immunology database
HLA nomenclature committee
IMGT databases
IUPAC/IUBMB (nomenclature committees)
Kabat database
KEGG (Kyoto
Encyclopaedia of Genes and Genomes)
PDB (Protein Data Bank)
PIR (Protein Information
Resource)
PROSITE (database for protein families and domains)
SRS (interface which integrates multiple databases and search tools)
SWISS-PROT
SYFPEITHI database
Based on presentations given at Novartis Foundation Symposium 257,
'Anaphylaxis' which was held in
London on 25-28 February 2003)
Bursar's report
My name is Aikaterini Detoraki. I am Greek but I studied Medicine in Italy at the University of Naples Federico II where I graduated in 1999. During my university studies I have had the opportunity to work as an intern student in the Laboratory of Professor Gianni Marone, Director of the Department of Clinical Immunology and Allergy of the University of Naples Federico II. This first laboratory exposure offered me the opportunity to appreciate the relevance of cardiac mast cells in anaphylaxis.
After my graduation I returned back to my own town, but I kept a strong interest in the immunologic mechanisms of anaphylaxis. For this reason I applied to the Novartis Foundation bursary program to attend the Symposium on Anaphylaxis (London, 25-28 February 2003). I was extremely pleased to receive a bursary and travel grant which gave me the great opportunity to participate in a conference attended by a small group of highly qualified scientists. In particular, I appreciated the friendly atmosphere and the opportunity to interact with opinion leaders that I had previously encountered only by reading the scientific literature. I thank the administrators and trustees of the Novartis Foundation for sponsoring an excellent meeting.
Immediately after the Symposium, I started a period of three months of research in the laboratory of Professor Marone. During this period I took advantage of my previous experience working in vitro with purified mast cells. I mainly worked on the expression of the anaphylatoxin receptors expressed on the surface of the mast cell. The anaphylatoxins, C3a and C5a, are small peptides, generated in vitro during complement activation that can occur during systemic anaphylaxis.
In particular, we started to look at the phenotypic and functional presence of anaphylatoxin receptors C5a and C3a on mast cells isolated from cardiac tissue of patients undergoing cardiac transplantation. Mast cells were isolated from ventricles obtained from patients with dilated cardiomyopathy undergoing heart transplantation. Cells were dispersed by treatment, followed by exposure to a mixture of enzymes (DNAse, hyaluronidase and pronase). Mast cells were partially purified using a series of techniques. After purification, cardiac mast cells were stained with toluidine blue and counted in a haematocytometer to determine the purity and the viability of these cells. Cardiac mast cells were evaluated for cell surface expression of C5a receptor using the flow cytometry. Using this technique we obtained preliminary evidence of the presence of both C5a and C3a receptors on human cardiac mast cells. In contrast, these receptors were not detected on mast cells purified from human lung parenchyma. The C5a receptor was also functionally detected on human cardiac mast cells. In fact, when these cells were exposed to increasing concentrations
(10-7 to 10-5) of C5a they released two mediators present in secretory granules of mast cells (histamine and tryptase). The releasing activity of C5a was extremely rapid reaching a plateau within two minutes of exposure to the agonist.
We also obtained preliminary evidence that C5a and C3a can induce the directional migration (chemotaxis) of human heart mast cells in vitro, using a modified Boyden chamber.
This three months experience in the laboratory of Professor Marone in Naples has been particularly important for me for a series of reasons. First, for the opportunity to work on cardiac mast cells: a cell population difficult to obtain but extremely interesting to study. Second, for the possibility to look into an area that has always fascinated me: the mechanisms of human cardiac and systemic anaphylaxis. And third, for the interaction with qualified scientists that helped me to learn about many aspects of this kind of research. I would like to thank Professor Marone for being more than just a host for twelve weeks.
I fully appreciate the Novartis Foundation's support for giving me the opportunity to have an extremely rewarding experience. I am indebted to Allyson Brown from the Novartis Foundation for the support before, during and after the Symposium on Anaphylaxis. Since my return to Greece, I have remained in contact with my colleagues in Naples, and I hope to start a fruitful collaboration.
Dr Aikaterini Detoraki—Laboratory of Radiology, Heraklion, Greece
(top)
Anaphylaxis will be published in December 2003 by John
Wiley & Sons, Chichester, UK
The Novartis Foundation bursary scheme
The aim of the bursary scheme is to fund young scientists to attend Novartis Foundation
Symposia and subsequently spend up to 12 weeks in the department of one of the symposium participants. Applicants (of any nationality) must be aged between 23-35 years on the closing date for application. They must be actively engaged in research on the topic covered by the symposium and should not already have accepted an invitation to participate in that symposium.
For details of the bursary scheme and forthcoming bursaries see:
http://www.novartisfound.org.uk/bursary.htm
or contact the bursary scheme administrator:
E-mail: bursary@novartisfound.org.uk
News from the Foundation
Meetings
Open Meetings:
The next Novartis Foundation Open meeting on Pathological pain: from
molecular to clinical aspects will take place on 3 October 2003
in Japan in collaboration with Novartis Foundation (Japan) for the
Promotion of Science.
Other forthcoming open meetings include:
-
Biology of IGF-1: its interaction with insulin in health and malignant states on Friday 17th October 2003
To book your place at these meetings please contact the open meetings organizer
tel +44 (0) 20 7636 9456
fax +44 (0) 20 7436 2840
e-mail: openmtg@novartisfound.org.uk
Full details of Novartis Foundation Open Meetings can be found at: http://www.novartisfound.org.uk/open.htm
Symposia:
The most recent symposium took place at the Foundation 2-4 July entitled OA
joint pain. Chaired by David Felson, Multipurpose Arthritis and Musculoskeletal Diseases Center, Boston University School of Medicine, Boston, USA
Discussion meetings:
The next discussion meetings to take place are:
-
Contributions of the pharmaceutical industry to healthcare in developing countries (with NIMS) on Monday 3 November 2003
-
The science of well-being: integrating neurobiology, psychology and social science (with the Royal Society) on Friday 21 November 2003
-
Why is life dependent on water? (with the Royal Society) on Friday 5 December 2003
Publications
We are pleased to announce the recent publication of:
Development of the cardiac conduction system
(Novartis Foundation Symposium 250)
Autism: neural basis and treatment possibilities
(Novartis Foundation Symposium 251)
For details of this, and other recently published books and how to order see:
http://www.novartisfound.org.uk/nbook.htm
Book Sale 2003
Many of our out-of-print symposium volumes are available at vastly reduced prices in this year's book sale.
See http://www.novartisfound.org.uk/booksale-03.htm
for details of the titles and how to order them or e-mail bulletin@novartisfound.org.uk
for more details.
Publicity
Dr Lisa Melton, the Foundation's Science writer has recently published the
following:
Amazing patient stories in the Novartis Annual Report
2002, p 9-12
Dimmer switch for the immune system
"Immunology is being transformed by the discovery of a cell that can be targeted to turn the immune system up and down. Lisa Melton finds new treatments in the pipeline."
in Medicine Today , June 2003, Vol 3(11), p 6-7 and
Osteoarthritis pain goes central in the Lancet
Neurology, September 2003, Vol 9(2), p 524
Hospitality
Details of all conference facilities and accommodation available at the Foundation can be found at
http://www.novartisfound.org.uk/hosp.htm
Personalia
Full details of personalia and activities at the Novartis Foundation can also be found in the Foundation's
2003 Annual report and handbook.
If you would like to receive a copy of the handbook, please send an email including postal details to
bulletin@novartisfound.org.uk
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