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21.01.2025 11:14

On the way to curing type 1 diabetes with antibody combination therapy

Inka Burow Stabsstelle Kommunikation
Medizinische Hochschule Hannover

MHH team aims to intervene in the autoimmune process and stop the destruction of insulin-producing beta cells in the pancreas

Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing beta cells are selectively and irreversibly destroyed in the pancreatic islets. As a result, the body can no longer produce insulin. We need this hormone to convert sugar (glucose) from food into energy. Before and during the disease, the pancreatic islets are heavily attacked by T cells and other immune cells, which produce pro-inflammatory messenger substances, in particular cytokines. These messenger substances are cytotoxic, i.e. they damage living cells and are mainly responsible for the destruction of beta cells. Due to their impaired glucose metabolism, T1D sufferers have to inject insulin for the rest of their lives. There is still no cure for the metabolic disorder. However, an antibody called teplizumab, which intervenes in the autoimmune process, has been approved for treatment in the USA since November 2022. This antibody blocks the so-called TCR/CD3 receptor on the surface of almost all T cells, preventing them from attacking the beta cells and delaying the onset of the disease by two to three years.

Professor Dr Anne Jörns from the Institute of Clinical Biochemistry at Hannover Medical School (MHH) now wants to expand this therapeutic approach. Together with her research group ‘Pancreas molecular morphology and diabetes prevention’, the physician is focussing on a combination therapy of the anti-TCR/CD3 blocker with antibodies against the inflammation-promoting cytokines. In this way, she hopes to be able to delay the onset of the disease in the long term or to protect and restore the beta cells after the onset of the disease. The research project is being funded by the non-profit foundation ‘Breakthrough T1D’ (formerly JDRF) from the USA with around 730,000 euros over three years.

Type 1 diabetes causes secondary diseases

According to estimates by the German Diabetes Society, T1D affects around 400,000 people in Germany, at least ten per cent of whom are children and adolescents under the age of 18. The autoimmune disease not only affects the daily lives of those affected, but also causes secondary damage. This is because the high sugar content affects small and large blood vessels as well as the nerves of various organs. As a result, diabetic retinal and kidney diseases, nerve disorders and poorly healing wounds on the feet - also known as diabetic foot syndrome - and cardiovascular diseases can develop or be exacerbated. During insulin therapy, phases of life-threatening hyperglycaemia or hypoglycaemia can also occur.

Stopping the destruction of beta cells

For her work, Professor Jörns uses a rat model for autoimmune diabetes that is very similar to the human disease. The animals with so-called diabetes manifestation, i.e. in which the diabetes is already evident, survive for a maximum of one week without insulin administration. In the studies, the researchers used a T-cell antibody called anti-TCR, which blocks the same T-cells as the anti-CD3 drug teplizumab. They combined this with various therapeutic antibodies against pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interferon-gamma (IFN-gamma). ‘The combination of anti-TCR with anti-TNF-alpha had the greatest therapeutic effect,’ says the scientist. The cytokine antibody anti-TNF-alpha is successfully used in humans to treat inflammatory diseases of the gastrointestinal tract, rheumatoid arthritis and also autoimmune vascular diseases. While monotherapy with a single antibody alleviates diabetes only slightly at best, the combination therapy with two antibodies was able to halt the destruction of the beta cells and protect the pancreatic islets from the harmful activated immune cells. The result: the animals lived diabetes-free for a year - a third of their entire lifespan.

Optimal treatment at the earliest possible stage

‘In humans, this corresponds to a gain of ten to 20 diabetes-free years, but ideally we want to maintain the success of the therapy for life, or at least for many years,’ says Professor Jörns. In so-called gene expression analyses of the various therapeutic approaches, the research team is now investigating which genes with significance for the immune system, for cell damage and regeneration as well as for insulin production in beta cells are activated and which genetic information is converted. To this end, the respective proteins of identified key genes are detected in pancreatic tissue sections using specific antibodies. ‘If we know the molecular mechanisms behind the success of the therapy, we can select the optimal treatment at the earliest possible stage and can transfer this into a translational approach for patients as a further option in everyday clinical practice - both before and after the manifestation of diabetes,’ says Professor Jörns. Type 1 diabetes could then either be completely prevented or at least delayed for a longer period of time in the early stages of the disease if treated before the onset of the disease. However, it is not yet possible to say with certainty how long such a non-diabetic situation will last in humans.

This therapeutic approach to preventing and curing diabetes confirms the importance of cytokines in autoimmune diseases and is therefore an ideal bridge to the research projects ‘Cytokines in inflammatory and tumour diseases’ by Professor Dr Christoph Garbers, Head of the Institute of Clinical Biochemistry. His research into the biological functions of cytokines in inflammatory and tumour diseases primarily strengthens the research focus on infection and immunity as well as the oncological competence network Comprehensive Cancer Center (CCC) Hannover of the MHH.

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For further information, please contact Professor Dr Anne Jörns, joerns.anne@mh-hannover.de.

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A symbolic photo: It shows a lancing device for blood glucose measurement.
Copyright: Karin Kaiser/MHH

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