How does CELT's immunology work consider ageing?

Posted on: 29 April 2024 by Rebecca Derrick in Developing the Long-acting Pipeline

29 April each year is the International Day of Immunology, to celebrate the benefits of immunology research.

Created by The International Union of Immunological Societies (IUIS) and European Federation of Immunological Societies (EFIS), the theme of this year’s International Day of Immunology is ‘Immunity Through the Ages: Navigating the Science of Ageing and Immunology’, “where experts in immunology will explore the dynamic relationship between ageing and the immune system” (IUIS). To mark it, we spent some time with Professor Neill Liptrott, the immunology lead within the Centre of Excellence for Long-acting Therapeutics (CELT) to discuss our immunology work and what considerations for ageing look like within that.

What is Immunology?

Immunology, in short, is the study of the immune system, which is how the body protects itself from both internal challenges, such as cell death due to issues with how cells function, and external challenges such as infection. What is thought of as the immune system has many elegant ways of dealing with these challenges and indeed deciding if it should deal with them; anything that perturbs this complex system could lead to illness and disease. In the long term, if it continues to not function as it should, then it can lead to autoimmune diseases, allergies, and cancer.

“Immunological research continues to extend horizons in our understanding of how to treat significant health issues, with ongoing research efforts in immunotherapy, autoimmune diseases, and vaccines for emerging pathogens” – British Society for Immunology.

What was Prof. Neill Liptrott’s immunological journey to CELT?

Prof. Neill Liptrott began studies at the University of Liverpool, starting with a Molecular Biology BSc Hons degree. During the Honours year, he found a particular interest in immunology, and took optional modules in immunology connected to the Immunology department, ran at the time by Prof. Peter Johnson. Neill then stayed in the department where he studied for a Masters in Human Immunity. This saw him engaging in practical work in different labs, but he used the research portion to tie immune signaling to how stem cells maintain their pluripotency, in the Labs of Prof. Patricia Murray.

After graduating, Prof. Neill Liptrott was successful in obtaining a PhD studentship studying Human Immunodeficiency Virus (HIV), specifically the relationship between membrane transporters (that remove medications and other potentially toxic molecules from cells) and co-receptors (that the HIV virus uses to infect cells). The primary supervisor of this PhD was CELT’s co-Director Prof. Andrew Owen, along with Prof. David Back, and they’ve been regularly collaborating on various research projects ever since.

After a post-doctoral fellowship with CELT’s Prof. Saye Khoo, Prof. Neill Liptrott moved towards complex medicines, particularly those that incorporate nanotechnology. The immune system is good at recognising nanomaterials in the body as they can share many physical and chemical characteristics with microbes and microorganisms, which the immune system has evolved to recognise and deal with. As well as issues with their compatibility, understanding how complex medicines interact with the immune system presents an opportunity to develop immunomodulatory materials with applications in therapeutics such as vaccines.

From here, Prof. Neill Liptrott became a Tenure Track Fellow, funded by his and Prof. Owen’s Horizon 2020 infrastructure projects that resulted in the establishment of the European Nanomedicine Characterisation Laboratory (EUNCL), and led on the REFINE project establishing new assays and models for the biological characterisation of nano(bio)materials, alongside many more projects, aimed at understanding the biological-material interface and defining which critical quality attributes are linked to their biological performance.

What is Prof. Neill Liptrott’s immunology focus within CELT?

Prof. Neill Liptrott oversees a group of researchers within the field of immunology, and the work is broad, ranging from their long-acting work for CELT to many complex medicines such as lipidic nanoparticles, polymersomes, virosomes, biomaterials, bacteriophages and more.
Within CELT specifically, the immunology projects overseen by Prof. Neill Liptrott or CELT co-Director Prof. Steve Rannard include:

Determining that the various products created through CELT are compatible with the immune system

Polymers of Prodrug

It’s not possible to make nanoparticles of water-soluble drugs, so Prof. Rannard’s group are researching whether that can be changed through creating polymers (chains) of the prodrug . CELT has previously made ‘polymers of prodrugs’ that have shown promise for long-acting antiretroviral delivery. Interestingly, these polymers consist of nucleotide analogues, something that the immune system sees regularly in the form of nucleic acids. Our work showed that although there is immune recognition of these materials, it seems compatible with their use.

Implant of antiretroviral tenofovir alafenamide (TAF)

TAF is potent, so you don’t need as much of it to be as effective as other medications. This is a helpful property when creating long-acting drugs. Orally administered TAF is well tolerated, so the group is researching whether the reactions are the same in this new long-acting delivery when administered subcutaneously. Others have shown this may not be the case, so Prof. Liptrott’s group are developing new 3D models to study these local immune reactions.

Niclosamide

Repurposing of niclosamide for use in COVID-19, dengue, and indications such as cancer chemotherapy and neurodegenerative diseases is an active area of research globally. Niclosamide has quite potent immunomodulatory potential, one of the many reasons it’s use in these diseases is so attractive. However, our work has shown that it may enhance, rather than inhibit, immune responses depending on when it is administered. Working with Prof. Owen and Prof. Rannard, we are investigating if long-acting formulations of niclosamide would be safe and effective in neurodegenerative diseases.

Dengue fever

We recently secured Higher Education Innovation Funding, from UK Research and Innovation, to collaborate with Drugs for Neglected Diseases initiative, screening their analogues of niclosamide for immunomodulatory activity, something which may be important in the treatment of dengue. The team are involved in the cell biology and immunology considerations of a long-acting version of the medication.

What are the considerations around ageing within CELT immunology work?

A consideration in all immunology work is interindividual variability. There are metabolic differences in people of differing age, whether that is chronological age or biological age. This can put a strain on their immune system, making it function less effectively. Although we and others primarily conduct our work as ‘healthy volunteers’, it is critical to consider how these responses may differ in actual patients, particularly in an ageing population. Chronological age is the age we are, though some people are older and still fit. Biological age is the consideration that the ‘age’ of a cell may not match the age of the person; some younger people have illnesses that can mean certain cell types are worn and ‘older’ though they are young. Inflammaging is the term used to describe inflammation-induced ageing and is what happens when a person’s cells are exposed to a chronic background of inflammation from various sources, this means they may respond differently to immune challenges.

When the pharmaceutical industry creates new therapeutics, they must be compatible with the intended patient group they were developed for. This means we must consider chronological and biological ageing throughout our research to ensure safe use of new therapeutics, particularly complex medicines, like long-acting formulations. Sometimes ageing isn’t just a consideration of an individual difference but a priority consideration during immunological research, such as inflammation being a big consideration within any HIV research. A person with HIV’s immune system can often be constantly stimulated if that person doesn’t have access to good antiretroviral therapies, so researchers must remember the difference in biological age when creating drugs that need to work effectively for everyone.

We need to understand the interactions between a new therapeutic and an aged system to determine its effect on different groups of the population. This can be more complicated within long-acting therapeutics research, as the drug and/or delivery device have been designed to stay in the system for as long as possible; making it difficult to withdraw a dose once it has been administered.

We live in an increasingly ageing population while medical technologies are developing. This is of importance, because research can’t just be for drugs that will be effective for people at the age they are now. It would not be surprising if, in the next few years, our long-acting work will see more and more projects working towards treating an ageing population, i.e. a long-acting drug works for someone now, will it still work for them in 10 years, when they’re 60, 70, etc.?

We know age has many implications and we may find that, with long-acting therapeutics, ageing has no implications. However, until we know if that’s the case, it will always be a constant consideration to make sure we’re always creating effective medication, safe and effective for the intended population sub-group. Prof. Liptrott’s team are ensuring that the compatibility of these therapeutics, with the immune system, are established prior to deployment in clinical trials and beyond.

#DayofImmunology and #ImmunityandAging

Find out more about the International Day of Immunology.

Find out more about the Nanotherapetics Hub within CELT.