08: Sublingual Immunotherapy

Hay fever, which is a Type I hypersensitivity (or immediate hypersensitivity) is an allergic inflammation of nasal airways provoked by exposure to cedar pollen in most cases. The symptoms include sneezing, blocked nose, runny nose, itchy eyes and can interfere with everyday quality of life. It is estimated that 25% of Japanese population is affected by it. On the other hand, according to Dr. Kimihiro Okubo, Professor of Department of Otolaryngology at Nippon Medical School, in most cases, hay fever is not really understood correctly by many, and as a result, the diagnosis and treatment have not been correct, either.

Professor Okubo has been working on an extensive research development and clinical application of the new treatment of hay fever; indeed, hay fever is something anyone can suffer from. This treatment is called “Sublingual Immunotherapy”. Sublingual Immunotherapy involves putting a liquid of antigen under the tongue. It's more or less like curing by licking. In short, the goal of this therapy is: Even when pollens enter the body, the allergic symptoms will not occur as the body's immune response to pollens has been suppressed.

The use of subcutaneous allergen-specific immunotherapy has been around for many years. This treatment in which allergen extract is injected subcutaneously into the extensor side of the upper arm, successfully treated hay fever sufferers. On one hand, this is a radical treatment; however, this treatment is rather complex in that the adjustment of the quantity and density of antigen to administer are quite complicated. In addition, the fact those injections are painful and have to be administered by a doctor, require the patients to visit doctor’s office frequently. For these reasons, the number of medical institutions that carry this treatment out has been limited.

Speaking of easier method for “food allergy” and also from previous experiences, it has been known that by ingesting foods that causes allergy little by little, one can actually suppress the immune responses. However, this oral hyposensitization of antigen has not been proven to work for hay fever. One of the reasons stated by Professor Okubo is that it is the problem of the position of a lymph node as this is the place where an antigen meets lymphocytes first.

Induction of Local Immunity by the Sublingual Administration
Generally speaking, when the antigen goes into the body, it is first recognized by lymphocytes located in the lymph nodes, and as a result, can lead to cause immunoreaction or, on the contrary, to restrain reactions. In case of food allergy, in oral hyposensitization therapy, the food that causes allergy is taken orally, and the antigen will first be taken into the lymph nodes that are in the immune organ of the intestinal tract, the "Peyer's patches", and there the lymphocyte will recognize the antigen for the first time, and from then on, the allergic reaction will gradually mitigate.

Therefore in terms of allergen immunotherapy, it is necessary that the location where the allergy occurs and the location of the lymph nodes that induce immune tolerance be closely placed to each other. Thus, Dr. Okubo came up with the idea to have a lymphocyte recognize an antigen where the allergy is actually taking place. Hay fever is the result of allergic reaction in the airway system, and it is in the “upper respiratory tract” that one can find a lymph node in its neighborhood. Therefore when we want the lymph node of the rhinopharynx to be shown of the antigen first, it is ideal to put drops of allergen extract under the tongue.

From Fundamental Research to Clinical Studies
From the theory as described above, Professor Okubo began his basic research to measure the absorption of the antigen in the mucous membranes in the mouth in 1995. And through the university ethics committee, he started the clinical trial of sublingual immunotherapy for patients with cedar pollen allergy in the year 20001).

From the results of this clinical trial, Professor Okubo said, " It is now very clear that sublingual immunotherapy is a treatment that is highly effective." "Compared to the group of placebo-controlled group, Sublingual immunotherapy applied group’s improvement of QOL and symptoms have seen significant improvement statistically, especially in the area of QOL. "

Sublingual immunotherapy is a promising treatment method, so what is the medical mechanisms behind this? According to Professor Okubo, “We found that the so-called Regulatory T cells, which play the central role for immune tolerance, increase in patients who received sublingual immunotherapy.” 2) There are several types of regulatory T cells, and in patients who received sublingual immunotherapy, a “Tr1” type regulatory T cells that produce IL-10 had been produced more. IL-10 is a cytokine that is known to suppress immunoreaction. In sublingual immunotherapy, it is thought that the allergic onset is held in check by the complicated immunosuppression function of this Tr1 cell.

From Clinical Research to Practical Application
“Currently, we are in the process of adopting this therapy to general clinical places”, says Dr. Okubo. In 2014, the new therapy has received manufacturing approval and soon the medicines will be sold in various places. Professor Okubo tells us, "It's the very first medicine against cedar pollen allergy designed for sublingual administration in the world."

The first treatment is initiated under the supervision of a physician, but the patients themselves can do it from the second time. In allergen immunotherapy by subcutaneous injection, outpatient’s weekly visits were required, but with sublingual immunotherapy, the patients do not have to anymore.

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