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Immune stimulation is a term commonly found in popular health journals, used by advocates of natural remedies and also by quacks. Just do a quick search on the Internet, and you’ll find thousands of sites claiming that immune stimulation is the magic formula that will make all your health problems disappear – whether it be some harmless stress- related tiredness, sleeping problems or serious conditions such as chronic pain, an autoimmune disease or cancer.
Yet, the scientific basis for immune stimulation does exist, and it is a very useful approach that can be used to fight or prevent infections and cancer.
The potential: what could immune stimulation be used for?
In the wake of antibiotic resistance, the ability to control the immune response by small molecule drugs or by biopharmaceuticals is very enticing: instead of killing bacteria, infections of any kind could be dealt with by stimulating the immune system. While antibiotics are only good for bacterial infections, this is no issue with immune stimulation: deadly epidemics caused by viruses, chronic infections originating from protozoa (think about malaria, sleeping sickness, Chagas’s Disease), fungi (which like to take advantage of a host weakened by chemotherapy or AIDS) and parasitic worms could be treated using stimulation of the immune system.
The other side of the coin is immune suppression. If one is able to control the immune response, then it is possible to both stimulate or to suppress its action. Allergies and auto-immune diseases could essentially be eradicated by suppression of pathologic immune responses. Indeed, there is hardly any disease that does not have an immunological aspect to it. And, if not, then chances are that it can be attacked by using the weaponry of the immune system. This is in fact already happening in cancer immunotherapy.
So it sounds like that all those internet sites were right after all? Well, no. The idea of curing diseases by immune stimulation is admittedly more than a hundred years old, but only in the last decades are we getting close to actual working therapies. Let’s see what the proven ways of immune stimulation are.
Danger Signals are one way of immune stimulation
Danger Signals are used by the immune system to detect pathogens or cell damage. These molecules are usually bits and pieces from pathogens or debris left over after cell damage. Danger Signals are recognised by Pattern Recognition Receptors (1) of the innate immune system, which have been identified and characterised in the last 20 years. The discovery of these Danger Signal receptors gives us the opportunity to develop small molecule drugs that promote or inhibit the function of those receptors, effectively giving us the chance to control the immune response.
In terms of the military analogy of the immune system, scouts (Antigen Presenting Cells or APCs) collect intelligence (=antigen) about the operations of invaders (=pathogens) or the rebels (=cancer) while patrolling the civil population (=cells of the host). In this analogy, Danger Signals are a sort of evidence of threat that will alert the scouts (=APCs get activated), who start to produce messages (=cytokines) and will prompt them to bring back what they find to the Headquarters (=Lymph node). There, the commanders of the immune response (=T cells) receive the messages from the scouts, examine the intelligence and alert the troops.
At least this is how things should go, but as chronic/deadly infections and cancer do exist, it is evident that things do not always go that way. So, how is it that the “invaders” and the “rebels” can bypass the immune surveillance?
Alerting the Antigen Presenting Cells is so important that when it is absent[HM1] , curious things can happen, as was realised with cellular cancer immunotherapy. The main idea behind dendritic cell cancer immunotherapy (2) is to teach the immune system to attack cancer cells by training them to recognise cancer antigens on activated dendritic cells (= scouting Antigen Presenting Cell) to[HM2] T cells. A crucial step in the therapy is the activation of the dendritic cells (DCs) outside of the body in the presence of cancer antigens, which are then reintroduced to provoke an immune response. Importantly, without activation of the DCs, immunosuppressive regulatory T cells are produced and the immune system goes into complete standdown instead of attacking the cancerous cells (3). So, strangely, we could use Danger Signals to treat cancer.
Ok, but Danger Signals are probably dangerous, aren’t they?
That is exactly the trouble: “native” Danger Signals from pathogens and damaged cells have a bunch of side effects. So, the trade- off is to find such molecules that do just enough to alert the immune system, but no more. Molecules with such a profile are few and far between and are still under development. The key to finding them is to understand the interactions of “real” Danger Signals with immune receptors at the molecular level and then design immune stimulators that do the right job. This is what I am working on too, but more about specific Danger Signals in the next post.
By Krisztina Fehér
- Karolina Palucka1 & Jacques Banchereau Cancer immunotherapy via dendritic cells Nature Reviews Cancer 12, 265-277 April 2012 doi:10.1038/nrc3258
- Mantovani, A., Romero, P., Palucka, A.K. & Marincola, F.M. Tumour immunity: effector response to tumour and role of the microenvironment. Lancet 371, 771-83 (2008).