Servicio de Información Comunitario sobre Investigación y Desarrollo - CORDIS

FP6

CVDIMMUNE Informe resumido

Project ID: 37227
Financiado con arreglo a: FP6-LIFESCIHEALTH
País: Sweden

Final Report Summary - CVDIMMUNE (Immunomodulation and autoimmunity in cardiovascular disease and atherosclerosis)

Atherosclerosis, the major cause of CVD, is an inflammatory disease where the immune system plays an important role. Autoantibodies as protection or risk markers and therapy through immunomodulation could be a major advance in prevention and treatment of CVD and is a focus of CVDIMMUNE. One type of antibodies is natural antibodies against phosphorylcholine (anti-PC), an antigen exposed in some bacteria and in phospholipids with platelet activating factor (PAF)-activity, e.g. in oxidised LDL. Our clinical and experimental studies indicate that anti-PC, mainly of IgM type are protection factors against human atherosclerosis and CVD. Our plan is, therefore, to develop anti-PC as a diagnostic tool, which will be tested in several unique cohorts, including healthy individuals and individuals at high risk of CVD. We also believe that anti-PC could represent a novel therapeutic modality, where both polyclonal and monoclonal anti-PC are possible candidates, non-mutually exclusive. Both kinds of anti-PC will be developed and tested in mouse models for atherosclerosis.

In contrast to natural antibodies (which are germ line encoded), arrtiphospholipid antibodies Q (anti-PL) are risk markers for both arterial and venous thrombosis, and our main focus is on novel types of anti-PL against PAF or PAF-like lipids (anti-PAF). These novel risk markers (anti-PAF) will be tested in the same cohorts as anti-PC and in both cases, robust diagnostic kits will be developed. The genetic background of anti-PC and anti-PAF will be studied, e.g. in the Swedish Twin Registry. In a prototypic autoimmune disease, SLE, where the risk of CVD is very high such anti-PL are raised. Annexin A5 is a plasma protein, interfering with phospholipid surfaces and acting as an anticoagulant. We have demonstrated that anti-PL inhibit Annexin A5 binding to endothelium, an effect neutralised by Intravenous immunoglobulins (IVIG) and that Annexin A5 is present in atherosclerotic lesions especially at sites prone to rupture. Based on our findings, we have hypothesised that raising Annexin A5 binding, either by administration of neutralising antibodies from IVIG in individuals with high anti-PI levels, or by administration of Annexin A5 per se, could prevent plaque rupture and atherothrombosis. In summary, CVDIMMUNE combines diagnostic and therapeutic projects and is focussed on the role of the immune system, especially autoantibodies, in atherosclerosis and atherothrombosis.

Objectives

Combining academic and industrial expertise, the CVDLVIMUNE project aimed at:
- investigating novel risk markers for CVD in European patient cohorts;
- investigating irnmunornodulation as a therapeutic strategy for CVD;
- developing documentation for registration of diagnostic ELISA kits in European Union and the United States (US);
- developing proof of concept for at least one pharmaceutical product candidate;
- providing a strong research foundation and knowledge on mechanisms.

Results

ELISA kit and clinical validation of anti-PC
Within CVDIMMUNE, original laboratory data from Johan Frostegard's laboratory regarding anti-PC have been confirmed by Athera, and a robust diagnostic kit for anti-PC-measurements is now commercially available. Product validation for anti-PC including documents for the ECE registration and US notification f.e. linearity, intra-assay and inter-assay, detection limit, hook effect, interference studies, serum / plasma correlations have been successfully performed. By use of this kit, low levels of anti-PC (optimal cut-off varying between cohorts) have been proven to be a novel significant risk marker for CVD in several studies. Of note, the prediction by anti-PC is independent of other risk factors indicating that anti-PC is a novel independent marker of disease.

In the ELSA study on hypertension and progression of atherosclerosis during five years, Athera's kit, like Johan Frostegard's lab data, indicate that there is a significant negative association between atherosclerosis development as determined by Intima-media thickness (IMT). High levels of anti-PC significantly predict decreased IMT. Anti-PC as determined by Athera's kit is stable over a five year period. In the Gothenburg study on acute coronary syndromes, we have found interesting and striking data, which are in line with our first studies. Briefly, low levels of anti-PC (lowest quartile) as compared to higher levels were associated with increased risk of mortality and CVD-morbidity. If cut-off level was decreased to the level defined in the first population based study, the Malmo Diet cancer study, the associations were even stronger. Of note, best effect was seen between 6-18 months after CVD-events. In the study of coronary syndromes including also stable angina, from Mainz, anti-PC was not associated with disease.

Our findings in the ASCOT study where approximately 2 000 hypertensive patients were included in anti-PC determinations are compatible with our previous data, since in patients with controlled blood pressure, low anti-PC gave increased risk. However, in uncontrolled hypertension, anti-PC effects, if present, where overwhelmed by the effects of high blood pressure. Anti-PC may thus play an important role in hypertension, even though treatment had no apparent role in determining anti-PC effects.

Conclusion

CVDIMMUNE has developed a robust kit for anti-PC and have positive data from several independent cohorts, indicating that low levels of anti-PC is associated with increased risk or CVD. We have also convincing data from both in vitro and in vivo experiment where anti-PC and Annexin A5 has potentially anti-atherosclerotic and anti-atherothrombotic effects, respectively.

Dissemination and use

Knowledge and information generated by CVDIMMUNE have been successfully disseminated to scientists, to the general public and to other interested Parties through the participation at congresses by our partners, media broadcasts (newspaper articles, radio and TV) and our project website.

Información relacionada

Contacto

Johan FROSTEGÅRD, (Researcher)
Tel.: +46-8585-89787
Fax: +46-8746-7637
Correo electrónico
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