An essential component of our immune system must react to pathogens and invaders and then retrieve damaged organs and cells in our body. These immune cells called neutrophils must be stimulated and can execute this function thanks to certain vascular endothelial growth factor 2 (VEGF-2) receptor. Different receptors and their activation can cause neutrophilic disease. Some respond to pathogens and thus trigger T-cell destruction; whereas others promote immune evasion emphasizing their therapeutic value. However it is still unclear which causes of T-cell infiltration are caused by viral infections or the normal proliferation of neutrophila and thus should lead to treatment strategies that trigger these cells (vesicle fusion).

Researchers from the Centre of Neurodegenerative Diseases and Research Medications at ETH in collaboration with the University Medical Center Basel have investigated this question using the antibody-drug conjugate VCG (short-actingGF2 receptor antagonist). They found that inhibiting the enzyme serine hydroxymethyltransferase (SHMT) which is necessary for the activation of underlying vascular cells reduced the invasion and motility of T-cells following peripheral artery occlusion in mice. They also showed that treatment with a compound that blocked SHMT impaired peripheral artery occlusion in mice.

Several immune cells mediated by VEGF-2 control the pathogens migration and physiology and therefore predispose T-cells to the pathogen. In order to understand the reasons behind immune cell activation and cell infiltration in the peripheral endothelium of the peripheral circulation we used adeno-associated virus (AAV)-based assays explains Arto Pagano senior author of the work published in Nature Communications in March 2019. The Sprague Dawley Professor of Immunometabolology from ETH Zurich has been leading the research for the past years and is currently leading a project to better understand the cellular origin of this autoimmune cell activation process and develop agents against it.

This study analysed the cellular activities of Iba1-positive neutrophils microendothelial T-cells that participate in the blood-clotting process and are important to prevent blood clots. Using post-translational advances in camera-fluorescence phenomenon-based ion imaging the team observed the difference between what is seen in these cells and in healthy mice. First they showed that total neutrophil count (total neutrophils minus T-cells) decreased in bound mice whereas T-cell abundance was not shown to be significantly different between normal and treated tumors. Secondly R-delta (RT-delta which is the time it takes for neutrophils to recover after injury) increased in the neutrophils seen in treated tumors to an inhibitory degree above and beyond that of treated tumors.

This effect was only observed in mice that were treated with VCG as it was not observed in control animals treated with placebo or non-VEGF monoclonal antibodies. The predictive value of the data obtained enabling us to rule out the possibility of accidental infection and other non-infectious factors in the symptoms of type 1 diabetes in animals treated with VCG then as we have shown in mice with VCG supports the therapeutic argument for the benefit of the compound says Pagano.

He calls the potential success of this study a promising biomarker for the potential therapy of T-cell mediated diseases. Significant progress can also be expected-according to the authors reduction of neutrophil counts in tumors reduced as a fast painful and curable way. Moreover using mouse models the study showed that the effect of VCG remained when the drug was combined with a drug known to stimulate short-and long-term neutrophil homeostasis.

With regard to potential use in humans the researchers point out that clinical trials with VCG are already underway in the clinical research programme for type 1 diabetes in Switzerland and Italy. At the moment the available therapeutic options for this type of disease are mainly targeting damaged tissues as an alternative treatment that works. With so-called modified aggressive therapies the possibility exists for progressive reduction of neutrophil counts in T-cells and thus a long-term disability an outcome that disrupts the doctors life and the patients quality of life says Arto Pagano.