**5. History of sublingual allergen-specific immunotherapy**

Although all story of immunotherapy seems to be a new one, the first routes of immunotherapy dates back to 1911 when two English researchers used water solution of hay fever pollen extracts for treating hypersensitized patients. They noticed that hypodermal inoculation of specific allergen could have some benefit. Without a sound knowledge of basic and clinical immunology immunotherapy was pure empiric, not so widely used treatment for decades [41, 42]. The second very important step in the history of sublingual immunotherapy was the findings of a group of German researchers who showed that sublingual route of allergen-specific immunotherapy could be equally clinical effective as subcutaneous route [4, 43]. They performed a small double-blind placebo control crossover trail. The maximum subcutaneous tolerated dose of a house dust mite (HDM) extract was given sublingual as drops three times daily [44]. They showed an improvement in symptoms and improvement in nasal inspiratory peak flow. A few years later Scadding's and Brostoff proved a clinical efficacy of low dose sublingual immunotherapy in patients with allergic rhinitis sensitized to house dust mites in a double-blind placebo-controlled trial (DB-PCT) [45] whereas Italian allergist were the first one who showed clinical efficacy of SLIT for patients with allergic rhinitis and/or asthma sensitized also to house dust mites. Those study included both adults and children population [46]. In early 1990s, the first commercial available sublingual immune drops were developed. Since the introduction of sublingual immune drops, the scientific community has been seeking for improvement. When evaluating the findings from clinical trials with sublingual immunotherapy drops, it became clear that this therapy was more likely to be effective when administered once daily and higher doses. Moreover, pharmacokinetic studies of SLIT showed that only a very small proportion of liquid extracts was taken up into superficial layer of sublingual mucosa. Searching for a way to augment local allergen uptake sublingual rapidly dissolving tablets were developed. These tablets facilitated the delivery of high concentration of allergen in a small volume. This concept led to the clinical and commercial development of high-dose sublingual AIT using fast-dissolving tablets [47]. Early papers with sublingual allergen immunotherapy demonstrated positive results, and in 1993, the European Academy of Allergy and Clinical Immunology was the first official organization to recognize that sublingual administration could be a "promising route" for allergic desensitization. Two studies from 1999 to 2001 showed a satisfied safety profile of sublingual route for both children and adults [48–51]. From 1998, the World Health Organization recommended SLIT as an "a viable alternative to the injection route in adults" [52]. Wilson Cochrane review from 2003 analyzed 49 randomized control trials (RCTs) with 4589 children and adults affected by allergic rhinitis (with or without asthma or conjunctivitis) and proved clinical efficacy of SLIT over placebo [53]. To date, over 70 double-blind, placebo-controlled trails and several meta-analyses of sublingual allergy immunotherapy drops have been reported. It is important to note that many trails with SLIT drops or tablets were small and/or had an open label design. Over the last 10 years, however, several adequately designed and powered trails have been conducted with grass pollen, as well as with Dermatophagoides pteronyssinus (DP) in both adults and children, and have demonstrated efficacy and safety with this therapeutic approach [10, 54].
