Paste your essay in here…Daniel Podzimek, University College Roosevelt
(With acknowledgements to Professor van Overveld for the guidance during the Honors Thesis)
Peanut allergies: experimental immunotherapy and the translation to clinical practice.
Abstract
FDA approved treatments for food allergies are scarce. This article investigates the experimental immunotherapy realm, especially in relation to peanut allergies, and provides an overview of the potential of each type of experimental treatment with a specific focus on the translation to clinical practice. Sublingual and Oral Immunotherapy are analyzed, as well as probiotic and helminth-related treatments, Anti IgE-related treatments, cytokine related-treatments, experimental vaccine-related treatments, modified protein related treatments and possible filaggrin related-treatments. All treatments are currently experimental, but illuminate great potential. Each treatment also exhibits experimental flaws that should still be overcome before a translation from “bench to bedside” can be made. The experimental realm is, nevertheless, promising, innovative and rapidly expanding.
Keywords: allergy, food, peanut, immunotherapy, experimental, treatment
Introduction
This article provides a brief overview of experimental immunotherapies in relation to peanut allergies. The potential of each of those possible treatments will be discussed. The main focus will be on the possible applicability of the results in the clinical setting.
Sublingual versus Oral Immunotherapy
Sublingual oral therapy (SLIT), utilizing an environmental allergen, is known to trigger T-regulatory cells and results in a Th1 response in a later stage of treatment [1]. Increasing amounts (micrograms to approx. 2 milligram) of liquid peanut extracts can be held under the tongue, 2 minutes before actual ingestion takes place [2]. The rate of success of SLIT differs, but is thought to be somewhere between 70-80 % [3]. The variety in the rate of success might be due to patient selection, variety in dosage and due to different interpretations of responses (terminology) [3]. The basic concept is that the allergen eventually travels to mucosal sites in order to trigger desensitization and tolerance. An advantage is that the treatment is non-invasive. A risk in such treatment is that if it fails, the treatment itself can actually trigger the allergic response. SLIT immunotherapy has also generated promising results, such as in a study where 18 children with a median age of 5,2 (12 month treatment, daily exposure up until 2 mg) received SLIT. The group that received immunotherapy could ingest 1710 mg of peanut (approximately 7 peanuts) before an allergic reaction occurred, as opposed to the 85 mg in the group that was not treated [4].
In Oral Immunotherapy (OIT), allergen uptake is gradually increased on weekly basis over a period of multiple months. This dosage is approximately 1000x higher than the dose that is administered during SLIT immunotherapy [2]. It is thought to increase or restore tolerance [3]. A 2007 study suggests however that OIT might trigger desensitization but might not be able to evoke lasting tolerance [5]. It should also be noted that this study analyzed egg immunotherapy, rather than peanut immunotherapy. Only 34 % percent of the individuals that were enrolled in a study that exposed the participants to milk and egg OIT actually developed (lasting) tolerance [6]. A 2014 study investigated 39 children (age 1-16) that all showed a clinically significant allergic reaction to a peanut allergens within the first hour of exposure [7]. The therapy, capping at 4000 mg, lasted 5 years with repeated daily dosages. Sustained unresponsiveness after 5 years was observed in approximately half of the children, besides six participants that dropped out due to allergic reactions during the experimental phase [7]. OIT thus displays a promising first step towards prolonged unresponsiveness.
Side effects of OIT have been reported as well, but are usually mild. Examples are rash and painful abdominal cramps. Severe side effects such as anaphylaxis, treated with epinephrine, have been described as well. This mainly occurred during home based-dosing [8].
Risk-to-benefit ratios are, however, for most part unknown. The degree of protection it provides, the underlying age patterns and the actual food responses have been insufficiently investigated [8]. Yet, it should not be denied that OIT is very promising.
Direct comparison studies are limited, but a double blind placebo study did investigate the differences between SLIT and OIT treatments (SLIT/Placebo OIT and OIT/Placebo SLIT) [9]. The participants that enrolled were between 7-13 years old. SLIT treatment was scaled up to 3,7 mg/day, whereas OIT treatment was scaled up to 2000 mg/day. The participants, all had a higher threshold after 12 months [9]. The change in threshold, was however significantly greater within the OIT group. A 141-fold increase of the threshold took place in the OIT group (from baseline), whereas only a 22-fold increase in threshold levels was observed in the SLIT group (from baseline). Adverse reactions were, like mentioned above, mild but more common in OIT [9].
All in all, both SLIT and OIT seem promising. Side effects have been reported, albeit mainly minor ones. Within this experimental phase, OIT has shown to increase the threshold up until a far greater height than SLIT [9].
Probiotic and helminth-related treatments
The importance of an imbalanced gut in peanut allergy has been highlighted and following that concept, experimental treatments focusing on the (disturbed) microbial balance followed soon. The treatment is based on the administration of a microorganism that are thought to have possible positive health-related effects. A study showed, for example, that children with allergy had a different gut flora than children without allergy. Higher levels of clostridia and lower levels of bifid bacteria were observed [10].
One study investigated the efficiency of the OIT therapy described in the previous section, but then added an additional probiotic component to the treatment to see if this would improve the overall effectiveness of the OIT treatment [11]. This was the first placebo-controlled randomized trial ever conducted within the field of probiotics and food hypersensitivity [12]. Lactobacillus Rhamnosus CMCC 1.3724 was administered together with the OIT-treatment for 18 months, or alternatively a placebo was administered during that time [11]. Nearly 90% of the non-placebo group, receiving the probiotic, was desensitized in contrast to only 7% in the placebo group. In 82% of the treated group, sustained unresponsiveness found place after treatment in contrast to 3,6 % in the placebo group [11]. The study failed to account for the specific influence of the probiotic itself. The results of OIT studies have been provided in the past paragraph, so it is likely to account for at least a part of the obtained results in this experiment. The experiment also failed to establish a baseline by for example treating the participants in the experiment with OIT only, without the probiotic itself. This could give more detailed insight in the actual effect of the probiotic itself, and not the effect of the OIT and the probiotic in symphony.
Further research has to be conducted in the specific dosage and most effective strain of the probiotic itself, but also in the possible age-related pattern behind the fluctuations in the outcome of the trials [13].
Helminths have also been studied, and it has been claimed that they might be able to play a protective role against allergies [14]. It is thought, that helminths can release specific immunomodulating molecules. Those molecules are thought be capable of interacting with the innate and adaptive immune system, and can thus possibly provide protections in the case of inflammation (such as inflammatory bowel disease) or food allergies [15].
Mice that were exposed to Heligmosomoides polygyrus helminths, were not sensitized after exposure to peanut proteins [14]. Anaphylactic signs, as well as peanut-specific IgE were also suppressed in these mice [14].
The first experimental findings are promising. Ideal probiotic strains are sought after, as well as the possible ideal time of introduction. More comparative studies are needed in order to get more insights in optimal doses and the most efficient type of probiotics. Studies that look at the contribution of the probiotic component when it is combined with other experimental treatments, such as for example OIT are also needed [16].
Anti-IgE- related treatments
In terms of food-induced anaphylaxis, reduction or neutralization of IgE is thought to have beneficial effects [3]. IgE plays a crucial role in allergies, as has been shown. TNX-901, an IgG1 monoclonal antibody against IgE, has been introduced with this idea in mind. The monoclonal antibody can mask the epitope of the CH3-region of IgE and can thus block the FcE-receptor binding site on the mast cell, despite the high affinity of IgE for this receptor [17]. With this monoclonal antibody, a double blind randomized trial including 86 patients was set-up. The doses that were administered varied as well. A dose could contain 150 mg, 300 mg, or 400 mg (TNX-901 exposure group), whereas the other group received a placebo. Administrating TNX-901 (or the placebo) took place four times in every four weeks. All were administrated in subcutaneous manner. Within four weeks after the last dose received, an oral challenge with peanut flour followed. The threshold seems to increase with an increase in TNX dosage, which can be interpreted as something promising. This could mean that a high dose might, hypothetically, significantly lower the negative side effects experienced during the peanut allergy.
Nevertheless, a word of caution is needed as a statistically significant association was only found in the 450 mg TNX-901 group. A strong trend however, was found with increasing doses. It was furthermore also mentioned that the therapy seemed to be tolerated in a good manner by the enrolled patients with a low amount of side-effects [17].
Omalizumab is also known for excreting anti-IgE specific capacities. It is mentioned as tool that can reduce in-hospital time, as well as the number of visits of a patient to the hospital [18]. It seems effective, as it has been noted that it does trigger rapid desensitization [18][19]. Unfortunately, this is effect will not last once treatment is discontinued, and it therefore seems only effective in ad hoc treatment, which comes at a price [19].
This also introduces a new problem in the feasibility of this treatment in the clinical practice. Ad hoc treatment, means long term-treatments in the sense that if it is administered, it will most likely not provide lasting tolerance. It will need to be administered more often, and this thus calls for a repetition of the treatment. Therefore, the cost-effectiveness of the treatment is mentioned as a barrier, as well as the limited knowledge about exact dosing of anti-IgE [18]. All in all, the material presented does not seem to lack potential or capabilities, but is rather lacking in the (yet) unpublished replicated results.
Cytokine- related treatments
The cytokine Il-10 is known for playing a role in decreasing food allergy as well, and is thus a current target of research. Lactococcus lactis can be transfected in such a way it can secrete a specific Il-10 cytokine, in a murine model [20].
The pre-treatment described above, significantly lowered the risk of anaphylaxis in the treated mice [20]. Furthermore, antigen-specific serum IgE was lowered and inhibited. IgG1 production decreased as well, but gut IgA increased [20]. An additional advantage was observed as well as the exogenous IL-10 that was produced by the Lactococcus lactis, could up regulate IL-10 secretion in the Peyer’s Patch as well [20].
TGF-B is also thought to play a role in evoking tolerance. Studies have already highlighted the possible beneficial effects of TGF-B in mother milk [3][18]. The study, investigating oral uptake, indeed concluded that TGF-B can induce enough activity in the intestinal mucosa to evoke tolerance against food allergies [18].
Experimental vaccine- related treatments
T Cell Epitope-Based Peptide Vaccines, use synthetic peptides that match sequences of allergen T cell epitopes. The strength of the idea lies in the facts that tolerance might be reached, without the adverse IgE- associated side effects. Clinical trials with this vaccine took place, albeit in relation to animal danders and bee venom and not in relation to food allergies [2]. Knowledge of T cell epitopde-based peptide vaccines for peanut allergy related application is thus more limited. Identification of dominant peanut allergen epitopes is crucial. Ara h 1 and Ara h 2 have been mentioned in such a context [2]. A Th-2 type response (IL-5) was seen as well, thus suggesting that the peptides do contain epitopes that are involved in the pathogenesis of peanut allergies. The vaccine could be administered subcutaneously, or via the nasal pathway [2]. Studies in mice models where anaphylaxis was triggered highlighted that the vaccine, when administrated subcutaneous or intra-nasal, could significantly decrease plasma histamine [21]. The vaccine consisted of 30 overlapping Ara h 2 20-mers [2].
Modified peanut protein- related treatments
The philosophy behind this treatment is again focused on IgE. The treatment has a slightly different approach than the anti-IgE treatment approach described above, because this treatment is primarily focused on recognizing IgE binding sites. Once identified, bindings sites can be mutated in such an way that IgE cannot bind them anymore. Important though, is the preservation of the immune-stimulating capacities of the protein. A 2001 study already concluded that it is possible to actually modify hypoallergenic proteins, so that they can be immunotherapeutic in allergic diseases [131]. Modified E.Coli can for example be delivered via the rectum. This pathway is preferred, to keep the risks of side effects as low as possible. The bacterial vector enhances a specific cellular response, such as a Th-1 response [3]. This model was investigated in mice. Heat-modified E.coli containing modified Ara h 1; Ara h 2 and Ara h 3 were used in the murine model. The other group of mice received a placebo. Those that received rectal treatment had fewer symptoms and fewer fluctuations in body temperature (as described in the introduction). There was also a relative decrease in histamine release after the exposure to the peanut [3]. The particular treatment is still being studied intensively.
Possible filagrin-related treatments
Although it might not be one of the broad and major edge-cutting ideas within the framework of immunotherapy at this moment, in contrast to for example OIT and SLIT treatment as well as pro-biotic treatments, it is important to briefly highlight the filagrin related treatments that are investigated. Resourceful background information and nuances within filagrin-related or skin-barrier related peanut allergies have been given in past sections. Therefore it is good to use this more specific treatment, an applied treatment, as an example of the current possibilities. Topical anti-inflammatory agents play a crucial role in treatment, as inflammation can reduce filagrin expression [22]. Th-2 cytokines are known to reduce filagrin-expression as well. This thus means, that interfering with the allergy itself, can also directly impact the filgarin-deficiency. “ Intercepting “ the allergy thus not only means that the symptoms will decrease, but it can also play a crucial role in the restoration of the skin barrier [22]. A more genetically motivated approach to the problem can be utilized as well. Currently, screening is used to identify those compounds that up-regulate filagrin expression. Additionally, protein-translation machinery can also be targeted in order to restore “normal” protein expression [22]. In short, this all happens “far” from the bedside at this moment. A clinical application seems (still) pre-mature at this point. Genetic sequencing is promising nowadays, and relatively inexpensive as time has developed. More insights into the effect of the barrier restoration should be obtained [22]. Another study also investigated this barrier enhancement in closer detail. Emollient therapy was the main focus of this study. 124 neonates were included in this study. The study design was a randomized controlled trial. In the U.S and the U.K. Emollient therapy had to be applied everywhere on the body, starting at week 3 after birth of the newborn. It had to be applied at least one time a day. The control group did not do this. A significant protective effect was observed, and the risk of atopic dermatitis decreased by 50%. No adverse side effects were mentioned [23].
Conclusion
Currently, official FDA approved food allergy treatments are extremely rare [12].
Patients can, however, carry anti-histamines in addition to an epinephrine auto-injector [12].
It is, however, of utmost importance to realize that (almost) all other presented approaches towards peanut allergy are solely experimental. The field is promising and advances are made rapidly, but more elaborate research is needed for a breakthrough.