Leicester-led research identifies a new treatment for heart attacks
New research from an international team led by scientists from the University of Leicester is being hailed as a major breakthrough in the treatment of heart attacks and strokes – which it is. But what exactly have Professor Wilhelm Schwaeble and his colleagues discovered and how does it work?
To answer the second question first, it works by inhibiting a pathway.
Tracing a pathway through the body
The human body is full of pathways. In every part of your body – lungs, intestines, muscles, brain, blood, everything – there is a network of chemical pathways so complex that it makes the London Underground map look like a straight line connecting two dots. Every activity in your body involves molecules affecting the way that other molecules transform into still other molecules which then affect yet other molecules further along the pathway. That’s biochemistry.
Finding out about all these chemicals and the pathways they trace within the mammalian body helps us to understand how the introduction of other molecules may boost or inhibit processes within these pathways to counteract the effects of disease. That’s immunology.
Then once that is fully understood, drugs can be developed to introduce carefully controlled levels of these useful molecules. And that’s pharmacology.
Paying one's complements
The human body can be considered as a collection of systems, some of which you will be familiar with: the nervous system, the digestive system, the immune system and so forth. But you may not be familiar with the complement system, although you’ve got one inside you. Rather than being primarily composed of easy-to-identify things like nerves or intestines, the complement system is a group of two dozen or so proteins, swirling around in your blood, mostly in an inactive form.
When activated, these ‘complement components’ work together along pathways to complement the immune system, triggering an ever-increasing ‘cascade’ of reactions that greatly boosts the effects of your antigens – the role of which is to destroy unwanted, invasive pathogens.
What the Leicester-led team were investigating was the way that the complement system affects ischemia/reperfusion injury (IRI).
IRI: the problems of stopping and starting
Ischemia (or ischaemia) is a restriction in blood supply, which could be caused by a medical condition such as atherosclerosis or may be induced deliberately, for example by a surgical clamp during an operation. This causes a reduction in the supply of oxygen to organs and you might think that the best treatment would be to restore that supply of oxygen as soon as possible.
But a sudden return of blood supply to a ‘hypoxic’ organ may cause something called reperfusion injury, which can be even more damaging than the initial ischemia. A sharp increase in oxygen level triggers dangerous inflammation and boosts the number of free radicals, causing oxidative stress (which we discussed last September).
This is effectively the body damaging itself and it’s not good news anywhere but two particularly dangerous places where IRI can occur are the heart (myocardial: MIRI) and the digestive system (gastrointestinal: GIRI).
It has been known since the 1990s that complement inhibitors can reduce the damage done by MIRI but until now no-one has explored the mechanisms involved in more detail. The real merit of the findings of the Leicester team is to have ultimately defined the sole molecular mechanism responsible for a large proportion of the tissue loss in the post-ischaemic inflammatory event that is IRI.
The threefold path
There are three pathways within the complement system: the classic pathway, the alternative pathway and the lectin pathway. The last of these principally involves a protein called mannan-binding lectin (MBL) which binds to a molecule called mannose found on the surface of bacteria and other pathogens.
This binding reaction releases MBL-associated serine protease II (MASP-2) which splits or ‘cleaves’ the complement component C4 into C4a and C4b, which transforms C2 into C4b2a, which cleaves C3 into C3a and C3b… And thus is the cascade created. (Actually the reaction also releases MASP-1 and MASP-3 but studies in mice deficient in those proteases show that their absence doesn’t seem to affect the lectin pathway. Clearly MASP-2 is the important one.)
It has long been accepted that C4 is an essential component of C4b2a and that you simply can’t have the lectin pathway (or indeed the similar classical pathway) without it. But Schwaeble et al overturned this belief by showing that the effects of the lectin pathway on inflammatory tissue in MIRI cases were unaffected by the inhibition of C4 (the absence of which is a hereditary condition). This meant that C3 was also being activated by something that was bypassing the C4 part of the pathway.
The importance of MASP-2
Further tests on MASP-2 deficiency (which has been shown to protect against MIRI) demonstrated that the presence or absence of MASP-2 critically affects this process. In short, it’s not the absence of C4 that inhibits the lectin pathway, it’s the absence of MASP-2. And MASP-2 can be relatively easily inhibited using a monoclonal antibody.
Experiments into gastrointestinal IRI showed that injecting a MASP-2-inhibiting antibody into subjects knocked out the lectin pathway within six hours and kept the pathway inactive for up to 48 hours, with only gradual recovery up to seven days later. Knocking out the lectin pathway prevented the complement cascade from boosting the immune system response.
While the immune system is generally A Good Thing, the aim here was to find a way to artificially inhibit this particular pathway in cases where the immune system isn’t wanted, such as a situation where reperfusion is likely. Although there are two other pathways, it’s the lectin pathway that is vital, as the paper makes clear:
This may seem a very round-the-houses way of finding out what is going on, especially as there was good previously published evidence indicating that complement inhibition may offer a therapeutic approach to treat MIRI. But understanding how and why something happens – in this case, that the lectin pathway is dependent on MASP-2, not C4 – enables the development of a more efficient, more useful, and easily achievable target for medical treatment.
This degree of knowledge at a micro scale has a knock-on effect, another sort of cascade, up to the macro scale. Our understanding of which molecules are affecting each other – and how – ultimately determines what the paramedic has in their bag when they turn up after your heart attack.
Professor Schwaeble from our Department of Infection, Immunity and Inflammation led the team which also included Nicholas J Lynch, Youssif Mohammed Ali, Russell Wallis and Cordula M Stover from ‘III’ plus leading cardiologist Professor Nilesh Samani from our Department of Cardiovascular Sciences. Other team members were in Japan, Austria, New York and King’s College London and at Omeros, a Seattle-based pharmaceutical company which is developing MASP-2-inhibiting monoclonal antibodies for clinical trials.