Bo Nilsson's research projects on thromboinflammation

Cross-talk between the cascade systems and activated platelets

Osama Hamad, Huda Kozarcanin, Kristina Nilsson Ekdahl, Bo Nilsson

Platelet activation during thrombotic events is closely associated with complement and contact system activation, which in turn leads to inflammation. Chondroitin sulfate A (CS-A), released from alpha granules during platelet activation, is a potent mediator of cross-talk between platelets and the complement system. Under physiological conditions, no complement activation seems to occur on the activated platelet surface, but C3 in the form of C3(H2O) is bound to the surfaces of activated platelets. C3(H2O) is a non-proteolytically cleaved but activated form of C3, with C3b-like properties. Platelet-bound C3(H2O) acts as a ligand for leukocyte CD35 and CD11b/CD18, enabling platelet-leukocyte interactions.

Furthermore, we have shown that activated platelets and fibrin elicit activation of the lectin pathway enzymes, MASP-1 and -2 without complement activation. The MASP proteases thereby represent a crossover between the complement and coagulation. Thus, in addition to their traditional role as initiators of secondary hemostasis, platelets also act as mediator and regulator of inflammation in thrombotic events. This project is supported by the Swedish Research Council, VR.
 

Disarming the intravascular innate immune response to improve treatment modalities for chronic kidney disease

Sana Asif, Karin Fromell, Yuji Teramura, Andreea Barbu, Kristina Nilsson Ekdahl, Bo Nilsson

This project is part of the FP7 grant DIREKT coordinated by our group. Chronic kidney disease is worldwide a major cause of end-stage renal disease (ESRD). 800,000 patients in Europe and in the US, respectively, require long-term treatment initially with peritoneal dialysis, followed by hemodialysis and kidney transplantation. Each ESRD patient on hemodialysis costs ≈ €40000 to €80000 per year, has extremely poor quality of life and an average life expectancy of only 4 years.

Kidney transplantation totally changes life for ESRD patients who can then return to normal life, but this treatment is hampered by the low number of available kidney grafts. All these treatments are, however, associated with adverse reactions that cause damaging thromboinflammation, triggered by the intravascular innate immune system, which may lead to poor results and non-function.

The overall aim of this project is to clarify the innate immune mechanisms that cause thromboinflammation and identify nature’s own specific control points of regulation in these adverse reactions. By applying these concepts of regulation in hemodialysis and kidney transplantation, we intend to significantly improve the quality of hemodialysis devices and kidney grafts. We envisage to 1) convey a novel soluble complement inhibitor to the clinical stage via phase 1/2a clinical studies, 2) create of nano-profiled surfaces with low activating properties and 3) generate easy-to-apply one step-coatings for treatment of biomaterials (hemodialysis) and endothelial cell surfaces (kidney grafts) that will significantly improve the treatment modalities of ESRD.

We expect that these advances will result in extended periods during which hemodialysis can be applied to patients and that the quality of life will improve. In kidney transplantation attenuation of innate immune reactions is anticipated to protect the grafts against damage thereby making a larger number of kidneys accessible for transplantation. The novel techniques are also likely to be applicable on other types of implantations, extracorporeal treatments and transplantations and in the future to be used in xenotransplantation and stem cell therapies.
 

Thromboinflammation induced by nanoparticles

Padideh Davoodpour, Jaan Hong, Bo Nilsson, Kristina Nilsson Ekdahl

Nanoparticles (NP) and nanostructured materials are used in a growing number of applications and their use is expected to increase dramatically in the future. We have found that NP of different origin induce thromboinflammation, and our aim is to apply the technology that we developed for elucidating the biocompatibility of biomaterials in contact with blood, to characterize the biological responses and toxicity of NP in contact with tissue fluid/blood plasma/whole blood. We have applied this technology to investigate TiO2 NPs. These particles are widely used and applied in a number of applications e.g. sun protection, white paint and toothpaste etc.

Our investigations have revealed that they are highly thrombogenic, despite that they have been considered to be mostly inert. The project will help to clarify the mechanisms of toxicity of NPs, and help to develop techniques for evaluating the toxicity of present and future NP materials that are disseminated in the environment. This project was supported by AFA.
 

Coatings of liposomes in order to avoid innate immune recognition

Claudia Dührkop, Bo Nilsson, Kristina Nilsson Ekdahl

Drug delivery by liposomes is a technique to contain and neutralize toxic drugs, e.g. various chemotherapies, in order to avoid release of the drug to off-target cells. Liposomes injected into the blood are, however, recognized by the innate immune system, leading to accelerated removal of the particles and to adverse reactions.

Attempts to conceal the surface with polyethyleneglycol (PEG) have been partially successful, but also this coat has been shown to be recognized by the innate immune system. The so-called accelerated blood clearance (ABC) phenomenon has been suggested to be triggered by natural IgM antibodies. In this project, which is supported by the FP7 project DECENT AID, we attempt to find alternative coatings to avoid innate immune recognition and ABC.
 

Prediction of blood compatibility applying in vitro assays analyzing the protein “fingerprint” adsorbed to material surfaces in contact with blood plasma

Jaan Hong, Bo Nilsson, Kristina Ekdahl

Development of biomaterials intended for applications in tissue engineering is time-consuming and costly, due to design of the material and repeated testing in animal models. Therefore, there is a need to find screening techniques that at an early stage can be used to predict the biocompatibility of the material. One of the major properties of a biomaterial that determines the fate of the implant is the recognition by the innate immune system.

We have developed two different tentative screening techniques that are applicable for this purpose. The first one employs the adsorbed protein profile after exposing the material to blood plasma. We have demonstrated that the proportion of complement and coagulation protein profiles, are closely correlated with the biological response.

The second technique is a migration assay that allows blood cells to migrate through a membrane in response activation products generated by the biomaterial in contact with blood plasma. Both assays are at present under evaluation in animal models. This project is supported by FP7 Project BIODESIGN.