Well done to Dr Ana Acosta, who successfully defended her PhD today! Ana tackled a challenging and exciting project on the role of HNF1A in monogenic diabetes, generating a new mouse model and validating results in primary human islets. Her work dramatically alters the way we see HNF1A in glucose homeostasis and diabetes. A very productive PhD, performed at University of Lille, with Prof Caroline Bonner, and the University of Leuven, with my team. The 20th PhD student to graduate from my lab, and one of the last from our Leuven days! Great job Dr Acosta!
Our lab has a new study on primary immunodeficiencies out now at Cellular & Molecular Biology! We studied two families with combined immunodeficiency and found mutations in the Calcium channel ITPR3. The mutations reduce the function of the channel, making the channels 100-fold less capable of initiating a Calcium flux after cellular stimulation. T cells from the patient had poor responses throughout the signalling cascade: reduced Calcium flux, poor nuclear localisation of NFAT1 and reduced proliferative burst, explaining the impeded response to infections. The most severe patient required a bone-marrow transplantation to correct the defect, while the other patient is doing well with regular IgIV treatment. The work established ITPR3 as a new cause of primary immunodeficiency, after previously assuming that these Calcium channels had too much redundancy to be a cause of genetic disease. Read the full paper here, or take a look at the illustrated abstract below for a short-cut summary!
Exciting new paper out from the lab on using gene delivery to protect against diabetes. The work is based on the "fragile beta cell" hypothesis, which postulates that some individuals are prone to diabetes because their beta cells are more prone to fail during stress situations. We previously demonstrated that the Glis3-Manf axis was central to dictacting how robust or fragile beta cells were, during stresses either immunological (type 1 diabetes) or metabolic (type 2 diabetes) in origin. Based on this data, we designed a gene delivery system, which essentially tricks beta cells into making more Manf and becomes robust in the face of stress. NOD mice, treated with this gene delivery of Manf, become resistant to diabetes. As the gene delivery system we use harnesses the endogenous insulin promoter (specific to beta cells, and upregulated during cellular stress), we can use low doses of the gene delivery system delivered intravenously, without altering the rest of the body. This gives the system a high potential for clinical translation. Read the full paper here, or check out our illustrated abstract below.
Source of immune signals alters the immune response
Key points:
Researchers have identified source-specific effects of the signalling molecule interleukin 2 (IL2) on the immune response.
IL2 is an important signalling molecule that has been harnessed as a biologic therapy for a number of diseases but can result in unwanted side-effects.
This study, conducted using new mouse models, found that the immune response to IL2 is dependent on the cellular source of the IL2 production.
Their new insight explains the link between IL2 treatments and side-effects, opening up the potential to apply this powerful immune modulator to optimise treatments while avoiding off-target effects.
A detailed update to our understanding of the key immune system signalling molecule interleukin 2 has been published today by researchers at the Babraham Institute. Their findings explain common side effects of IL2-based therapies, and identify potential new uses of IL2 as an immune-modulating biologic drug. This research was only possible thanks to a new mouse model which allowed researchers to control which immune cell types produced IL2. With further research, this understanding of the rules dictating which cells respond to IL2 could allow scientists to optimise autoimmune and cancer treatment while avoiding unwanted side-effects.
Dr Carly Whyte, lead author on the paper who undertook this research as a postdoctoral researcher in the Liston lab, said: "IL2 is a protein that is normally tightly regulated in the immune system because it has such strong effects. However, when IL2 is given as a therapeutic treatment, these normal restrictions on IL2 are overruled. By using mouse models, we have found that the presence of IL2 in certain zones of the immune system leads to some of the same side-effects that we see in human patients treated with IL2. We hope that by understanding more about how IL2 works in different zones, this treatment might be tailored to be more effective."
IL2 is involved in a large number of different communication networks in the immune system, being produced by a variety of cellular sources and affecting a diversity of cell ‘responders’. It is not only needed for maintaining regulatory T cells, which prevent our body’s immune system from attacking itself, but also CD8 T cells, which attack tumour cells and virus-infected cells. Owing to this dual functionality, IL2 has been harnessed to both promote an immune response, and limit one, depending on the target cells. Despite being actively explored in hundreds of ongoing clinical trials, the full therapeutic potential is currently limited by frequently-encountered side-effects.
Previous explanations for these side-effects were based on the high doses of IL2 when given as a biologic drug, but Prof. Adrian Liston and his team were able to demonstrate that the cell-type making IL2, and the location of those cells, dramatically change the consequences of IL2 exposure. Dr Kailash Singh, co-lead author, explains "Our genetically modified mouse models showed that the immune responses are varied depending on the source of IL2. Our findings revealed that the IL2 response is very much context-dependent, and is not solely due to the concentration of IL2."
Prof. Liston, a senior group leader in the Institute’s Immunology research programme, said: “This work changes the way we think about IL2 as a decades-old therapeutic molecule, demonstrating that it is not just the dose of the IL2 that matters, but also where it is located in the body. Putting together the pieces of this cause and effect intricacy has involved several remarkable scientists and over a decade of research. It was only by bringing together experts in animal research, flow cytometry and immunology, that we had the know-how to tackle the complexity of this question. We’re increasingly aware of the therapeutic power of the immune system, and these findings provide a new avenue of investigation for designing biologic drugs.”
Dr James Dooley, joint senior author of the study, said: "The next generation of biologics will be smarter and tailored to the biology of the disease. This work teaches us that one route of smart design of IL2 is to target delivery to different parts of the body, potentially allowing us to drive very different therapeutic outcomes in patients."
Our new paper out at Nature Immunology was my 200th scientific paper! A good time to look back on the portfolio.
First, my coauthors:
My most frequent coauthor is James Dooley, no surprise since we've run the lab together these last 14 years! 67 articles coauthored, a good third of my papers. We've had a lot of staff and students trained in our lab over these years (165, to be exact), including a few who changed the direction of our lab - Stephanie Humblet-Baron coauthored 46 papers and Susan Schlenner coauthored 17, both are now professors at the University of Leuven. Vaso Lagou also coauthored 17 papers as a post-doc, before moving over to the Sanger. Jossy Garcia-Perez and Dean Franckaert were both PhD students, with 15 coauthorships, now working together at CellCarta. Our major collaborators come through clearly: Carine Wouters (28 papers) and Isabelle Meyts (15 papers) on the clinical side, An Goris (15 papers) on genetics, and Michelle Linterman (18 papers), Patrick Matthys (16 papers) and Sylvie Lesage (11 papers) for immunology.
The research topics come out via the key words from the titles. Tregs, Foxp3, T cells and the thymus all leap out, but looking closely you'll see pretty much every branch of immunology represented. A special call-out to my favourite cytokine, IL2 (with 14 papers, and getting stronger) and our microRNA papers (22 papers, but it was just a phase).
The work is pretty evenly split between mouse and human, although we tend to use "mouse" a lot more in the title. In terms of topics, 88 papers work on autoimmune diseases, with 17 touching on diabetes. 40 papers intersect with cancer biology or cancer immunology, 30 papers are on primary immunodeficiencies (across both mouse and human, but spread out over so many genes and syndromes they don't pop out here). 15 papers papers are on neuroimmunology, a current strength of the lab.
Finally, the journals that published our work! Really thrilled to see Nature Immunology up there, with 8 papers. We have a scattering of other top journals, Cell, Nature, Science, Nature Medicine, Nature Neuroscience, Nature Genetics all get a mention. Our most popular journals, however, are The Journal of Allergy and Clinical Immunology (10 papers), which has published some of our key work on primary immunodeficiency in both mouse and human, and Immunology and Cell Biology (10 papers), the Australian and New Zealand society journal (and a pleasure to work with!). I've been told by senior researchers that publishing anything below the top tier "dilutes my record", but I'm proud of all the science we do, and work to make sure that every story finds a home and every staff member or student with data gets to show it on the international stage.
Wednesday, November 9, 2022 at 11:56AM 
