New compound helps activate cancer-fighting T cells

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Invariant natural killer T (iNKT) cells are powerful weapons our body’s immune systems count on to fight infection and combat diseases like cancer, multiple sclerosis, and lupus. Finding ways to spark these potent cells into action could lead to more effective cancer treatments and vaccines.

While several chemical compounds have shown promise stimulating iNKT cells in animal models, their ability to activate human iNKT cells has been limited.

An international team of top immunologists, structural biologists, and chemists published in Cell Chemical Biology the creation of a new compound that appears to have the properties researchers have been looking for. The research was co-led by Monash Biomedicine Discovery Institute’s (BDI) Dr Jérôme Le Nours, University of Connecticut’s Professor Amy Howell and Albert Einstein College of Medicine’s Dr Steve Porcelli.

The compound – a modified version of an earlier synthesized ligand – is highly effective in activating human iNKT cells. It is also selective – encouraging iNKT cells to release a specific set of proteins known as Th1 cytokines, which stimulate anti-tumour immunity.

One of the limitations of earlier compounds was their tendency to cause iNKT cells to release a rush of different cytokines. Some of the cytokines turned the body’s immune response on, while others turned it off. The conflicting cytokine activity hampered the compounds’ effectiveness.

The new compound – called AH10-7 – is uniquely structured so that does not happen.

“One of the goals in this field has been to identify compounds that elicit a more biased or selective response from iNKT cells, and we were able to incorporate features in AH10-7 that did that,” Professor Howell said.

The robust study, years in the making, also applied advanced structural and 3D computer modelling analysis to identify the underlying basis for the new compound’s success. These highly detailed insights into what is happening at the molecular level open up new paths for research and could lead to the development of even more effective compounds.

The molecular analysis helped validate and explain experimental results.

“By exposing a crystalized form of the molecular complex to a high-intensity X-ray beam at the Australian Synchrotron, we were able to obtain a detailed 3-D image of the molecular interplay between the invariant natural killer T cell receptor and AH10-7,” Dr Le Nours said.

“This enabled us to identify the structural factors responsible for AH10-7’s potency in activating iNKT cells. This valuable insight could lead to the development of even more effective anti-metastatic ligands,” he said.

In the current study, the research team made two significant modifications to an α-GalCer ligand in an attempt to make it more effective. They found that adding a hydrocinnamoyl ester on to the sugar stabilized the ligand and kept it close to the surface of the antigen-presenting cell, thereby enhancing its ability to dock with and stimulate human iNKT cells. In addition, trimming off part of the molecule’s sphingoid base appears to initiate the critical Th1 cytokine bias. Both changes, working in tandem, strengthened the effectiveness of the entire molecular complex in terms of activating human iNKT cells, Professor Howell says.

Original article

Jamie receives 2018 ASBMB Lemberg Medal

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This prestigious medal honours Professor Rossjohn’s significant and sustained contributions to the understanding of the molecular basis underpinning immunity.

Awarded annually, the Lemberg Medal is presented in memory of Emeritus Professor M.R. Lemberg, who was the Society’s first President and Honorary Member. Only three other scientists from Monash University have won this Medal. Professor Rossjohn joins the esteemed company of Professor Anthony Linnane (1973), Emeritus Professor Phillip Nagley (2001) and the Dean of the Faculty of Medicine, Nursing and Health Sciences and Academic Vice-President, Professor Christina Mitchell (2015).

“An outstanding team of researchers who work alongside me, coupled with the continuous and strong support of Monash University, have enabled numerous exciting finds in the area of immunity to be made over the last 15 years,” Professor Rossjohn said

Since his relocation to Monash in 2002 to pursue a program of research centred on structural immunology, Professor Rossjohn has focused on defining the key molecular interactions underlying receptor recognition events that underpin immunity, both from the aspect of protective immune control and with regard to autoimmunity. Such findings were in close collaboration with leaders in the field, including Professor James McCluskey from the University of Melbourne.

For example, Professor Rossjohn, alongside Professor McCluskey and Professor David Fairlie, provided a structural basis of how vitamin B metabolites can be presented by MR1 and recognised by Mucosal-associated T-cells (MAIT cells), thereby revealing an entirely new class of antigen in immunity.

Professor Rossjohn’s research on the immune system, how the body reacts to infection and what happens when the immune system fails has led to a sustained advancement of knowledge in the field of immunity. His work has been generously supported by the Anti-Cancer Council, the NHMRC, and the ARC, including the current Centre of Excellence in Advanced Molecular Imaging.

As the recipient of the 2018 ASBMB Lemberg Medal, Professor Rossjohn will attend the ComBio2018 conference in September to give the Lemberg Medal Lecture.

For more information about the 2018 ASBMB Lemberg Medal, see https://www.asbmb.org.au/awards/jamie-rossjohn/

Original article

Could people living with coeliac disease one day be able to have their cake and eat it, too?

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“If the stomach be irretentive of the food and if it pass through undigested and crude, and nothing ascends into the body, we call such persons coeliacs.”

Although coeliac disease is fairly common, affecting about one in 70 people of European descent, it’s still challenging to diagnose and treat. It’s best known for its classic digestive symptoms – diarrhoea and bloating — but it can also manifest in neurological conditions, skin rashes, osteoporosis, infertility and anaemia, or sometimes nothing at all. Children experience failure to thrive, delayed puberty, cognitive and behavioural issues and tooth enamel problems.

“It has such a broad spectrum of symptoms that some people don’t even know they have it,” says Dr Hugh Reid, who’s studying coeliac with his team in the Infection and Immunity group in Monash’s Biomedicine Discovery Institute. “Gastroenterologists think it’s very much underdiagnosed.”

Using the Australian Synchrotron facility, Dr Reid and his team look at how individual protein molecules behave when a coeliac patient ingests gluten. “It’s basically a train wreck.”

First off, gluten contains the amino acid proline. Enzymes in the gastrointestinal tract that break strings of amino acids into smaller fragments, or peptides, can’t chop up proline-heavy proteins very well. “Instead of peptides of just one to a few amino acids long, you can get up to 10 to 20 amino acids on that fragment,” says Reid.

Another thing all coeliac patients have in common is an increased amount of an enzyme called transglutinase 2 (TG2). It transforms one of these amino acids into a version that’s negatively charged, effectively making it “sticky”.

These sticky strings then bind to HLA molecules, specialised protein complexes embedded in the outer surface of our cells. They perform the critical task of scooping up protein fragments and presenting them to T-cells, the roving border patrol of the immune system.

If the receptors on the surface of a T-cell mesh with a peptide on an HLA molecule in just the right way, an alarm goes out and the troops are called in. This is how the immune system distinguishes self from non-self, harmless proteins in food from dangerous bits of bacteria. It’s a complicated system that works astonishingly well – most of the time.

Because there are so many possible combinations of the 20 amino acids, we produce many different HLA molecules to present peptides and many different specialised T-cells to recognise them. Coeliac patients have been dealt a rotten hand here – they have genes that produce one or two HLA versions with a particular affinity for these specific long, sticky strings of gluten residues.

Then, one of their T-cells mistakenly recognises this particular peptide presentation as being harmful, and unleashes a massive inflammatory response that damages the lining of the intestine and produces autoantibodies that can go on to attack other organ systems.

“The thing that makes this extraordinary is that this [peptide presentation] just happens to be the lock that this [T-cell receptor] key fits,” says Reid. “It’s just terribly bad luck.”

Original article 

Rheumatoid arthritis study rated among top by journal

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A study by researchers in the Monash Biomedicine Discovery Institute’s (BDI) Infection and Immunity Program has shed light on the structures behind the genetic factor that predisposes people to getting the autoimmune disease rheumatoid arthritis (RA).

The study by first author Dr Yi Tian Ting has been ranked an ‘Editors’ Pick’, among the top-rated papers published by the peer-reviewed ‘Journal of Biological Chemistry’.

“It’s quite an honour to be among the 50 to 100 selected out of 6600 papers published each year,” said Dr Ting, who is profiled in the journal.

“For our article to be recognised among the leading publications that have contributed to this field is always good,” she said.

The researchers investigated the protein MHC Class II, an immune receptor that acts as a sentinel by protecting the body against microbial infection. It does this by presenting small protein molecules from pathogens on its surface, which are subsequently recognised as a threat by cells of the immune system. This in turn leads to an inflammatory response to kill the invading infectious organism.

In autoimmune disease, including rheumatoid arthritis, this can go wrong and the body fails to differentiate between self and foreign protein molecules. In RA, MHC Class II binds to protein molecules from the joint or cartilage that has been modified during inflammation, leading to a damaging auto-immune response.

Although MHC Class II has several subtypes, found in different individuals, certain subtypes are common to RA. This study showed that joint/cartilage-derived protein molecules bound to these RA-associated MHC Class II subtypes in a highly similar way. This makes the binding region common to all a possible target for treatment; a single key that could unlock a common treatment.

The investigators used protein crystallography, a powerful technique allowing them to crystallise the MHC Class II molecule with the bound protein molecules. The crystals were then exposed to radiation at the Australian Synchrotron. The resulting diffraction pattern was used to produce a 3D ‘map’ of the MHC Class II that showed ‘binding pockets’ that might be targeted by potential drugs to prevent the self-proteins from binding.

“Identifying the differences between these subtypes on a molecular basis means that treatment in the future could be more efficient and personalised,” Dr Ting said.

“This may provide insight to why some patients would respond better or worse than others to a particular treatment based on the MHC Class II subtypes they inherited, which are associated with severity and progression of rheumatoid arthritis,” she said.

Currently there is no cure for RA, a complex and debilitating disease.

Dr Ting worked on the paper with senior authors Professor Jamie Rossjohn, Head of the Infection and Immunity Program, and Dr Hugh Reid, Senior Research Fellow, Biochemistry & Molecular Biology, as part of a collaboration with scientists at Janssen Research and Development, part of Johnson & Johnson. The research complements Janssen’s research which includes drug design and patient responses.

Dr Ting said the new Johnson & Johnson Innovation Partnering Office at Monash (JJIPO@MONASH) that opened last fortnight would strengthen the collaboration.

 

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Monash extends collaboration with Janssen on psoriasis prevention

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Monash University announced an extension of its collaboration with Janssen Biotech, Inc., one of the Janssen Pharmaceutical Companies of Johnson & Johnson, where researchers will investigate triggers of the immune-mediated disease, psoriasis, and focus on the discovery of potential new treatment approaches to prevent psoriasis.

Professor Jamie Rossjohn, from the Biomedicine Discovery Institute, Faculty of Medicine, will lead the research team at Monash University on the three-year research program.

“We’re delighted to be working alongside Janssen once again in a joint effort to broaden our knowledge around this condition and develop novel treatments for psoriasis,” Professor Rossjohn said.

Original article