Immunotherapy: From the beginning

Prior to 1906 the term ‘allergy’ was still unknown, the aetiology of hay fever and asthma unclear. During the latter part of the 20th Century however, a dramatic change in the prevalence of allergies occurred. Globally, an explosive increase in allergic diseases has been observed – particularly in those countries with a Western lifestyle.

This unexpected development has resulted in enormous health and socioeconomic problems over a short period of time, as allergies have become an archetype of disease in modern civilisation. They have come to not only reflect the substantial changes in our lifestyle, but also those of our environment and living conditions, necessitating entirely new approaches to diagnosis and therapy.

The Dawn of a Science

Dunbar Allergy TherapeuticsThe term ‘allergy’ was first coined in 1906, by Austrian physician Clemens Freiherr von Pirquet (1874 - 1929), to describe the state of a pathologically altered immunologic reactivity or ‘hypersensitivity ‘. Only a few months earlier in 1905, hygienist William Philipps Dunbar (1863 - 1922) had published an article in which he claimed to have extracted from pollen what he considered to be the active toxic substance.

William Philipps Dunbar (1863 - 1922)

Dunbar later attempted to use the extract in a specific passive immunisation therapy. Although he was unsuccessful, the conviction prevailed that toxins from the pollen were responsible for the symptoms of hay fever.

Other scientists began to fervently work on this problem and among them was Alexandre Besredka (1870 - 1940), who in 1907 proposed a complex 3-stage mechanism of action for allergies. He identified the point of reaction in the brain cells as had been demonstrated for tetanus toxins by Emil von Behring (1854 - 1917) and Shibasaburo Kitasato (1856 - 1931) in 1890.

Besredka who was the first to use the term anaphylactic shock, believed that it should be possible to eliminate the dangerous effects of the toxins by a so-called ‘vaccination anti-anaphylactique’, although this was soon disproved. The vaccinations were found to be of minimal benefit in some cases and their effect short-lived.

Finally, a breakthrough

Around this time, Leonard Noon (1878 - 1913) was studying at Cambridge where he attended lectures at the famous St. Bartholomew’s Hospital in London. Together with his friend John Freeman (1877 - 1962), Noon also spent some time at the Institut Pasteur in Paris in 1905/06. The two researchers engaged in intensive studies of fungi and bacteria, and the immunisation of guinea pigs. Fascinated by grass pollen, Noon became aware of the pollen aetiology of hay fever demonstrated by Charles Harrison Blackley (1820 - 1900).

In 1911, a breakthrough finally came as Freeman and Noon became the first to succeed in performing specific immunotherapy with grass pollen extracts at St Mary’s Hospital in London.

An earlier report by H.Curtis in the 1900 ‘The immunising cure for hay fever’ is suggested by some people to be the first report of an attempt to immunise against the disease. This described the administration of an extract of ragweed flowers and pollen, given orally every day.

While they were still convinced of the toxin concept, Freeman and Noon assumed, unlike Dunbar, that active immunisation with pollen extract was possible. In the source of the therapy, they monitored the reactivity of their hay fever patient with conjunctival provocation tests. They observed that a single drop of a 1/5000 dilution of the grass pollen extract produced according to Dunbar’s method was still sufficient to trigger a conjunctival reaction in sensitive patients.

In this first use of parental immunotherapy, they administered very low, increasing doses of the pollen extract by intradermal injections at intervals of 3-4 days. Following this therapy, the researchers demonstrated an improvement in hay fever symptoms. Even at this early stage researchers observed that applying doses which were too high, or increasing the doses too rapidly, could trigger side effects (including anaphylactic shock).

In February 1913, only 2 years after their discovery, Leonard Noon died from florid pulmonary tuberculosis at the age of only 35. His obituary was published in The Lancet.

Allergy Therapeutics Graph

Increase in allergies in the 20th century

Defined and acknowledged

After decades of successful application, specific immunotherapy was appropriately recognised in 1998 by a position paper compiled by an international expert commission under the auspices of the World Health Organisation (WHO). This was the first time specific immunotherapy was designated as the single causal therapy of type 1 allergies. The term ‘allergy vaccination’ was also used for the first time, pointing to similarities with active vaccines which are also casual agents.