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A new look at asthma

Research groups open up prospects for a more efficient method of prevention and treatment

A therapy created at the Biomedical Sciences Institute of the University of São Paulo (ICB-USP) completely blocked the development of asthma in mice, when applied during the initial stages of the allergy process that causes the illness. More efficient than all of the available treatments, the therapy – a type of anti-vaccine that impedes the immunology reactions responsible for asthma – could prevent the illness in children who are the sons and daughters of asthmatics, and eventually improve the situation for adults sufferers themselves.

It was at the Medical School (FM-USP) that the Interdisciplinary Asthma Study Group, coordinated by Milton de Arruda Martins, discovered that the available treatments could be much more efficient. One of the group’s thirteen projects demonstrated that the majority of the deaths from asthma could have been avoided if the patients had taken adequate medication. Another one concluded that the intensity of the symptoms bears no direct relationship to the gravity of the lung inflammation and sends out an alert for the necessity of deciding on the treatment not only through the complaints of the patient, but from objective methods of measuring the inflammation. The studies also provided evidence that moderate physical exercises are essential for asthmatics.

Excess of hygiene
The therapy against asthma developed by the researcher Momtchilo Russo, of ICB-USP, brings a new and promising prospect for dealing with the illness. In mice, the treatment showed itself to be more efficient than all of the others as yet known. It consists in making the organism tolerant to the allergic substances, or that is to say, to avoid that the immunological system activate itself unnecessarily in the presence of these substances, which don’t represent a threat because they are not toxic nor do they multiple themselves in the organism. This line of investigation of an “anti-vaccine” – or technically an induction of tolerance – has in Brazil, one of the world pioneers, Nelson Monteiro Vaz.

It was through the collaboration of Russo with one of Vaz’s students, Ana Maria Caetano, that the idea of the anti-vaccine was born. The new situation is important because the percentage of asthmatics in the world’s population has practically doubled over the last ten years. The phenomenon is attributed to the increase in pollution, but many immunologists believe that this increase is also due to the excess of hygiene of modern life.

To restrict excessively contact with pathogens is to impede the immunological system from adequately maturing. Proof of this is the fact that the incidence of asthma is a lot less often among the children who go to school at an earlier age and those who have siblings or pet animals, factors of exposure to a greater diversity of micro organisms and allergies.

Deactivated allergy
Efficient in mice, the therapeutic proposal of Russo is to deactivate the allergy process by using natural mechanisms of the organism – those that condition the immunological system not to react towards the proteins normally present in foodstuffs. What he did was to mix in the water of the mice subject to asthma, small quantities of the proteins that set off the illness in them. The procedure totally blocked the illness, at least in the mice which hadn’t clearly developed an allergy. As well, it was effective for all types of asthma.

If the strategy of deactivating the allergy process were to show itself as efficient in humans as in mice, it would be possible to produce an oral treatment that would block the asthma in children predisposed to it since they are children of asthmatics. The idea would be to substitute the albumin of egg – the protein use in the tests on mice – with the proteins of the most common allergies or to make a customized vaccine, beginning with the specific proteins to which their parents are allergic.

Other research centers throughout the world are developing studies related to oral tolerance or the other forms of immunotherapies, through inhalants or injections, against asthma. Up until this moment, it is true to say that the most efficient therapies carried out on rats have not had satisfactory results on human beings. However, the experience of Russo of inducing tolerance via oral stimuli has been enthusiastically received by the international scientific community, because the method inhibits exactly the cell that orchestrates all of the other factors responsible for the unleashing of asthma within the organism, the Th2.

In spite of the negative results obtained using guinea pigs that had previously developed clear symptoms of asthma, the treatment could have good results on asthmatic adults since human asthma is produced by immunological reactions much less acute than those presented by the laboratory animals. For example, this is what the immunologist Lauren Cohn, a specialist in lung illnesses at the Medical School of Yale University in the USA, believes. She has become an enthusiast of Russo’s results. Lauren remembered that all of the clinical experiments on induction of tolerance resulted in some kind of improvement of the patients.

How it works
The allergies that cause asthma are associated with the Th2 lymphocytes, blood circulation cells that amplify the immunological reactions and proliferate in the presence of large amounts of pathogens, such as intestinal worms. However, the micro organisms, such as virus and bacteria, induce the production of Th1 lymphocytes. When the Th2s incorrectly become active in the presence of substances unrelated to the parasites, allergies occur, such as those that cause asthma, while the normal production of Th1 results in auto-immune illnesses. The Th2 activate the liberation of crystalline substances called cytokines (of types IL-5, IL-4 and IL-13).

These cytokines command the production of the principal ingredients that cause asthma: mucus, IgE antibodies and a type of white blood cell or leukocyte that provokes the inflammation, the eosinophils. Russo used various breeds of mice, capable of developing the types of asthma that occur in human beings – with more eosinophils or more cytokines IL-5 or IL-13, or IgE antibodies. To induce the asthma, previously aware of thesubstance capable of triggering it off, Russo injected into the mice egg albumin mixed with aluminum hydroxide, a substance that provokes the production of Th2 in the organism. Thus, he educated the immunological system of the mice to recognize the egg albumin as an antigen which, along with the aluminum hydroxide, should also be fought against with Th2.

The process, called sensibilization or immunization, turned the mouse allergic to albumin, capable of developing asthma when the pulmonary mucous membrane comes in contact with this protein. The procedure was carried out twice with a seven day interval. On the 14th and 21st days, Russo made the rats breath in albumin so as to start off the asthma. Twenty four hours later, the sensibilized mice and a group of normal mice were submitted to physical exercise and to bronchial constriction substances – which constrict the bronchi musculature – so as to compare the level of obstruction and of lung inflammation of the two groups.

The evaluation was done by measuring the quantity of eosinophils, mucus and antibodies typical of the asthma of the lungs of mice. The blood was analyzed, as well as cuts of lung tissue (to observe the cells) and liquid injected into the lungs of the mice (a process called bronco-alveolar washing, which is the injection of a liquid, followed by aspiration for analysis). All of the examinations proved that the sensibilized mice had developed asthma.

The experiment was repeated, the only change being that the second time, before beginning the induction, the mice received the “anti-vaccine”, capable of blocking the allergy reaction of the immunological system that causes the asthma: for five straight days, 1% of the albumin was mixed with the animals’ water. The idea was to provoke tolerance, or that is to say, to make their defense system become accustomed to recognizing albumin as a normal food protein against which they should not react.

Total blockage
With this treatment, Russo managed to totally block the development of the asthma, eliminating both the hyper-reactivity – muscular contraction of the bronchi – and the abnormal production of the pulmonary ingredients typical of asthma. The process was successful with all of the groups of mice, which means that it has worked for all of the types of asthma. This includes a group of mice especially resistant to developing tolerance and a further group, transgenic, which naturally presented 50% more eosinophil leukocytes than normal, therefore being extremely allergic and asthmatic.

Even better than that was the verification that the blocking of the asthma was not obtained through an increase of immune-suppressor cytokines or of cytokines that averted the production of Th2 to Th1, which could represent undesirable alterations in the defense system. The experiment was repeated three times, with the start of the treatment being at different times: on the day of the start of the first immunization, on the day of the second and shortly after the first aspiration of albumin, when the mouse was already allergic to the substance.

In the first case, the success continued to be total, in the second the allergic reaction was reduced considerably – the eosinphils were blocked, but not the hyperactivity -, while in the third it produced a worsening of the illness. What is lacking is the development of a therapy for human beings, which, in the place of albumin, the most common allergic proteins would be administered orally, in order to develop tolerance of the organism to these agents.

While he is waiting to see who wants to develop the anti-asthma “vaccine” for human beings, Russo is working to make his therapy effective for patients who are already asthmatic. For this reason, he has begun new studies with mice, submitting them to therapies that combine the induction of tolerance with manipulations which de-activate the immunological system. The idea is to temporarily de-activate the immunological system of the mice, clearly asthmatic, so as then to induce tolerance.

Chronic, fatal and in dear expansion

Asthma is the most frequent chronic illness in childhood, one of the most common in adults and one of those in clear expansion throughout the world: according to the World Health Organization (WHO), every year asthma reaches close to 150 million people, killing 180,000 of them. In Brazil it is estimated that it hits between 7% and 15% of the population and has already claimed 20% of the children in certain regions.

We are dealing with an allergic illness of the lungs that provokes permanent inflammation in the air passages and obstructs the passage of air both through the swelling of the bronchial walls and in the exaggerated production of mucus. The inflammation is the result of a reaction of the immunological system due to certain allergic substances such as atmospheric pollution, mites, pollen, virus and inhaling chemical products.

Added to this is the hyper-reactivity of asthmatic bronchi, that is to say, the tendency for the smooth muscles that are involved to overreact in the face of stimuli such as strong emotion, cold, intense physical exercise, smoke or low air humidity: these stimuli cause the liberation into the blood stream of various substances such as histamines and leukotryenes that contract the smooth musculature.

The Project
Modulation of the Polar Immunological Reactions in Immunological or Genetically Manipulated Animals (nº 99/03778-3); Modality Thematic project; Coordinator Dr. Momtchilo Russo – Biomedical Sciences Institute of USP; Investment R$ 295,488.28 and US$ 123,789.25