Allergen-specific immunotherapy: current concepts and future directions
Hundred years ago, Noon first described the clinical improvement of patients suffering from hay fever by a prophylactic inoculation with grass pollen extracts (1). In this special issue of the journal, we take the opportunity to (i) evaluate the historical significance of allergen-specific immunotherapy, (ii) provide the most recent and current views on the immunological mechanisms, (iii) critically appreciate the clinical aspects and evidence-based medicine, including important thoughts on how to best design clinical trials in the future to fulfil the modern regulatory environment for drug development and (iv) look at new developments with regard to the refinements of the compounds used in immunotherapy, such as peptides and recombinant proteins, immunomodulators and adjuvants, including new application routes.
Although Noon’s paper is currently considered as the historical landmark as it was the first controlled study, Ring and Gutermuth (2) illustrate in their contribution on the history of allergen-specific immunotherapy that this pioneer paper should rather be considered as the result of long process of development to which many previous attempts to reach the goal of desensitization by many other authors contributed. In fact, a tight historical and scientific link between allergen-specific immunotherapy and vaccination strategies has always been observed in the development of this kind of therapeutic approach (3).
The current understanding of the immunological mechanisms of allergen-specific immunotherapy
The progress in our understanding the mechanisms underlying allergen-specific immunotherapy has markedly been impacted by our overall understanding on how the adapted immune response and more recently the innate immune system control the response to the challenge with harmless or potentially harmful foreign structures (4). One of the initial key principles and dogma certainly came from the key observations on the Th1- and Th2 responses seen in animal models and subsequently in the human system (5, 6). Meanwhile, it became clear that these immune responses are controlled by regulatory T cells, which explain at least some of the earlier phenomena that were thought to be mediated by the so-called T suppressor cells (7). Furthermore, the identification of new T-cell subtypes, such as Th17- (8), Th22-, or Th9 cells, has added further levels of complexity in what was initially thought to be only a kind of Ying and Yang type of regulation. Because of its presumed simplicity, the model of bee and wasp venom allergy and desensitization in human has served as a paradigmatic constellation for the first and important attempts to understand allergen-specific immunotherapy at the cellular and molecular level (9). As exposed in the review from Jutel and Akdis (10), one of the key mediators of immediate-type reactivity, i.e. histamine, seems to play a key role in shaping the T-cell response and driving the generation of allergen-specific IgG4. In the context of the discussion about putative alternative routes for the application of allergens, the so-called sublingual immunotherapy (SLIT) may finally represent the more physiological way to proceed when applying high dose of allergens with a goal to reach tolerance (11). In contrast to the USA and based on a number of clinical trials and more recently meta-analyses, SLIT is increasingly accepted in European countries and has lead to the formal approval by the European Medicine Agency (EMA). One of the basic aspects in the understanding of the immune mechanisms underlying the sublingual route is a kind of revolution in our paradigmatic view on the role of epithelial dendritic cells such as Langerhans cells. While the classical dogma highlighted initially the pro-inflammatory function of these cells in the skin, we had to learn over the years that the micromilieu to which these cells are exposed has a deep impact on their functional behaviour, the default situation most probably being the induction of tolerance. This seems particularly true for Langerhans cells located in the vestibular part of the oral mucosa (12) that can be considered as the master regulatory dendritic cells. These and many other aspects related to the new findings in our understanding the immune mechanisms underlying sublingual immunotherapy are reviewed in the paper of Novak et al. (13).
Thus, immunotherapy represents a tremendous field of experimental research work in animal models and in patients suffering from allergies and has served to implement our overall understanding of the immune reactivity towards environmental challenges.
Clinical practice with allergen-specific immunotherapy: a lot to do ahead!
Although we still do not fully understand the immune mechanisms underlying immunotherapy, since the first controlled study by Frankland (14) and the impressive number of following trials, there is no more doubt about the beneficial effect of this approach in the management of IgE-mediated allergic diseases. While there are still some discussions whether it is meaningful to combine more than three allergens as it is custom in the USA or to restrict the panel of allergens applied to a minimum supposed to be of real clinical relevance as it is custom in European countries (15), the overall evidence supporting the clinical benefit of allergen-specific immunotherapy is largely supported by several meta-analyses, such as those from the Cochran database (16). While in contrast to immunotherapy against bee and wasp venom allergy where up to 90% positive response is expected (17), there is still a substantial percentage of nonresponders when immunotherapy is applied to either seasonal or perennial allergens. However, it cannot be excluded that at least a part of these nonresponders can be explained simply by the fact of the wrong choice of allergen, the lack of relevant concentrations of major allergen in the natural extracts, the lack of compliance (possibly more relevant for sublingual route) and many other yet to be defined factors that may bias the overall results of clinical trials or in everyday practice. The more recent analysis of a systematic review for sublingual immunotherapy provided in this issue by Radulovic et al. (18) further strongly supports that allergen-specific immunotherapy induces both clinical and immunological tolerance. Whether the classical application time of 3 years will find a scientific rationale or could possibly be extended to a longer period of time remains to be clarified. However, based on the dogma that a chronic disease needs a chronic management, it would not be surprising that in the next 5 or 10 years, the new guidelines will propose to extend the application time beyond 3 years. Also, besides allergic rhinitis, conjunctivitis and asthma (19), the indication of allergen-specific immunotherapy may be extended to atopic dermatitis (20, 21), as it is considered as the first step of the atopic March.
An important and clinically mostly relevant issue, which is not been solved so far, is whether it makes sense to apply immunotherapy in a very early phase of the development of allergic diseases. Indeed, there is some evidence supporting the concept of a putative ‘window of opportunity’ in infancy and/or early childhood (22) where one may speculate that an intervention with immunotherapy would make sense. There is currently no doubt about the long-term benefits of immunotherapy for established allergies but there is still a great need for a formal prove of the putative effect of this approach in view of prevention in the development of further sensitizations (23). In this regard, there is so far no clear consensus on the design of clinical trials and some thoughts have been proposed by the GA2LEN Consortium for this anniversary issue as reported by Bousquet et al. (24). One of the key aspects among many others remains the design of protocols aimed to evaluate immunotherapy in children.
Despite a number of guidelines published in the past for the design of clinical trials (25) as well as for their reporting (26), there is a great need for consensus in this field as the competent authorities in Europe (EMA) and in the USA (FDA) are now requesting specific strategies designed to provide clinical efficacy and safety for new and sometimes established therapies applied in the paediatric population. As exposed by Kaul et al. in their review (27), the regulatory authorities are also keen to obtain convincing results in the paediatric population before a marketing authorization is provided. The obligation of performing clinical trials in children combined with the request of a long-term observational time will generate an interesting debate and certainly provide substantial hurdles in the design and practical realization of such studies in children. These new developments and requirements may have a substantial impact on the production and delivery for so-called named patient products (NPP) and thereby contribute to a substantial sliming of the market of therapeutic allergens, leading some companies either to disappear or to focus on either sublingual or subcutaneous ways or to invest substantial amounts of budgets in new developments, such as those presented later. As a further consequence of the regulatory requirements for therapeutic allergens, the physicians and the patients will be assured that the products will comply to the minimal three hurdles for approval, i.e. quality (according to Good Manufactory Practice, GMP), safety and efficacy (according to Good Clinical Practice, ICHE6-GCP). Moreover, further studies on immunotherapy will also need to be convincing with regard to the fourth hurdle, i.e. cost-effectiveness relationship, an issue of increasing importance and put forward by the health technology assessment agencies (HTA).
Allergen-specific immunotherapy: quo vadis?
Although the use of full natural extracts with high content in major allergens still represents the golden standard in immunotherapy, there have been a number of approaches to optimize the efficacy and concomitantly reduce the risk of side-effects such as anaphylactic reactions. Besides the use of chemically altered allergens and allergoids, there has been an increasing interest in the development of alternatives either by recombinant technology or by the addition of immunomodulators (28). Interestingly, the introduction of biotechnology in allergy diagnosis through the use of well-defined and possibly clinically more relevant recombinant proteins will allow us to precisely define the sensitization profile of our patients. The obvious ultimate consequence of these refined diagnostic tools will be the use of genetically modified allergens with reduced allergenicity to better fulfil the real requirements in the fields of efficacy and safety in immunotherapy. We would also be able to dramatically reduce the proportion of number nonresponders simply because of the fact that we have a better insight into the clinically relevant allergens and reduce the risk of mistakes attributed to cross-reactivity. It is expected that the first recombinant and hypoallergenic allergen derivates will officially be approved by competent drug authorities in the near future.
Another approach, which has been considered for many years, is the use of peptides mimicking B-cell epitopes, which cross-link allergen-specific IgE on effector cells. The first encouraging clinical trials have been completed as exposed by Larché (28). Interestingly, peptide immunotherapy can be used for conventional subcutaneous as well as sublingual immunotherapy. The tolerance induced by this approach is most probably mediated by regulatory T cells secreting high amounts of IL-10. However, further investigations are needed to better understand how these peptides induce tolerance in vivo. Clearly, the use of peptides derived from allergens relevant for bee and wasp allergy should represent an ideal investigational model to obtain additional insights into this respect.
Besides efficacy, the safety aspect of immunotherapy has always been an issue of concern. In this regard, the availability of a recombinant antibody directed against IgE has been shown to represent an interesting approach to reduce the risk of immunotherapy-related systemic reactions as reviewed by Kopp (29). However, besides the reduction in anaphylactic reactions, it is still not clear how this approach can improve the efficacy of immunotherapy at the immunological level. Currently, this question attracts the attention of many researches as the use of anti-IgE in the context of allergen-specific immunotherapy could be extended to a large number of patients with high risk to develop systemic reactions, such as those suffering from mastocytosis or severe food allergy (30).
As mentioned previously, the current standard route of application, i.e. the subcutaneous way, cannot be considered as the most physiological mode of delivery. Therefore, a number of other approaches including the oral, bronchial, nasal and intralymphatic ways have been evaluated in few studies with some interesting results. However, considering the rather demanding aspect of this kind of approach, the search for a more physiological mode of delivery is still undergoing. In this regard and based on our knowledge emerging from the role of Langerhans cells in sublingual immunotherapy, it is obvious to follow alternative approaches to the subcutaneous way such as the epicutaneous patch administration as reported by Kündig et al. (30). Indeed, the first results of pilot clinical trials seem rather promising. If epicutaneous mode of delivery of allergens, either as natural extracts or as recombinant proteins with or without adjuvants, proves to be efficient, besides its safety aspect, it could be a highly interesting alternative needle-free approach, especially for the propagation of immunotherapy in infants and small children, once the issue of the ‘window of opportunity’ has been solved.
Since the report of Noon in Lancet in 1911, allergen-specific immunotherapy remains the only causative treatment for IgE-mediated allergic diseases in the 21st century. In the next few years, with regard to the most common allergens, such as birch, house dust mites or hymenoptera, we will observe how high-quality, efficient and safe natural extracts or recombinant allergens approved by regulatory drug authorities will replace the NNP. Owing to the tremendous progress made in the last 20 years in our understanding of the immune mechanisms underlying immunotherapy, the strategies aimed to improve the safety and efficacy of this causal therapy as well as the consideration of the regulatory environment in which all these developments have to move on, it is expected that this field will experience a fast development to the benefit of the allergic patients.
Conflict of interest