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Immunology Update - November 2017

Welcome to the next installment of our regular update where we report on research from the world of immunology, highlighting work from BSI members that has hit the headlines over the past few weeks.


T cells better armed to fight cancer

T cells form a vital component of our adaptive immune system. They circulate our bodies, fighting off various threats from bacteria to viruses, and in some instances, cancer.  Their specialised killing abilities depend upon their cell surface receptor (T cell receptor, TCR) that recognises specific antigens expressed on their targets’ cell surface.

Harnessing T cells’ ability to destroy cancerous cells has been a focus of many cancer immunotherapies. However, there are a variety of limitations that restrict the potential of such therapies. From the tolerogenic tumour microenvironment, to the immune cells’ intrinsic regulatory mechanisms, many hurdles stand in the way.

Through genetic engineering, T cells have been generated with modified TCRs specific for cancer antigens that can also overcome some of the transformed cells avoidance mechanisms, such as MHC.I downregulation.

New work, led by BSI member Dr Mateusz Legut from Cardiff University, has developed this idea further, creating engineered T cells with an increased ability to target and kill cancer cells.

Using CRISPR, the paper, published in the journal Blood, describes how genetic deletion of the T cells’ endogenous receptor eliminates the competition it imposed on the engineered TCR and the possibility of dangerous hybrid TCR formation. Consequently, the resultant transgenic T cells express more of the cancer-specific TCR and are thus more efficient at targeting the cancer and a thousand-fold more sensitive to antigen expressed by the cancer.

Dr Mateusz Legut said, “The T cells we made using genome editing do not have any of their own T cell receptors left, and therefore the only receptor they can use is the one specific for cancer. As a result, these cells can be a thousand times better at seeing and killing cancer than the cells prepared using the current methodology.”

Read the full press release here.

Read the full article here: Legut et al 2017 Blood DOI: https://doi.org/10.1182/blood-2017-05-787598

 


Could sunlight provide a therapy for rheumatoid arthritis?

Rheumatoid arthritis (RA), among many other autoimmune diseases, is associated with vitamin D deficiency.

Many studies have demonstrated the immunosuppressive effects of the active derivative of vitamin D, 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3). Studies on peripheral blood T cells show that 1,25-(OH)2D3 inhibits the proliferation and production of pro-inflammatory cytokines whilst promoting the expression of regulatory markers. Cells within the site of inflammation, the synovial tissue, in rheumatoid arthritis patients seem to still actively synthesise the active vitamin D3 derivative and express the receptor. This has encouraged the idea of vitamin D as therapy for the T cell driven autoimmune disease.

Recent work by a team of scientists, including BSI members Dr David Sansom and Dr Louisa Jeffery, from University College London and the University of Birmingham, shines light on the matter. Their paper, published in Journal of Autoimmunity, reports that although the immunosuppressive effects of 1,25-(OH)2D3 on peripheral blood T cells of patients with RA is equal to that of controls, this is not reflected in T cells from the synovial fluid. The synovial tissue is enriched in phenotype-committed, inflammatory memory T cells, which show a significantly reduced response to the anti-inflammatory effects of 1,25-(OH)2D3. However, the paper suggests this is due to epigenetic effects and chromatin remodelling, opening up a potential for epigenetic modulators in future treatment of RA.

Dr Louisa Jeffery, University of Birmingham, said: “Our research indicates that maintaining sufficient vitamin D may help to prevent the onset of inflammatory diseases like rheumatoid arthritis. However, for patients who already have rheumatoid arthritis, simply providing vitamin D might not be enough. Instead much higher doses of vitamin D may be needed, or possibly a new treatment that bypasses or corrects the vitamin D insensitivity of immune cells within the joint.”

Professor Karim Raza, University of Birmingham, said, “Our findings were unexpected as we initially thought that cells from the inflamed rheumatoid joint would respond just as well to vitamin D as cells from the blood. The fact that they don’t has important implications for how we think about using vitamin D to treat inflammation.”

Read the full press release here.

Read the full paper here: Jeffery et al 2017 Journal of Autoimmunity DOI:https://doi.org/10.1016/j.jaut.2017.10.001

 


New potential uncovered for a diabetes drug to help organ transplantation

Patients who have received an organ transplantation are currently required to take immunosuppressive drugs that affect the immune system as a whole, rendering the individual susceptible to many serious diseases. New research by a team from Queen Mary University of London may open up an alternative.

The paper, co-authored by BSI member Dr Madhav Kishore and published in Immunity, reports that modulating regulatory T cell metabolism can cause their increased migration into tissues. 

Regulatory T cells (Tregs) have an immunosuppressive function and, through a variety of different direct and indirect mechanisms, inhibit effector T cells, the main perpetrator of transplant rejection.

The team outline a specific pathway for the metabolic regulation of Treg migration in both mice and humans. Through studying human individuals with a genetic mutation that increases the activity of the glucokinase enzyme, which is responsible for a pivotal step in the pathway, they demonstrated the migratory patterns of Tregs into tissues. This uncovers the potential for a diabetes drug under development, which targets this pathway, to be repositioned to aid organ transplantation.

Professor Federica Marelli-Berg, who led the research, said, “With this research we’ve hit upon a completely different way to stop organ rejection. Our next step is to take the drug into clinical trials. If the trials are successful, these findings could prove to be life-changing for patients who have had a transplant.”

Read the full press release here.

Read the full paper here: Kishore et al 2017 Immunity  DOI:http://dx.doi.org/10.1016/j.immuni.2017.10.017