Allergies are recorded as the most common chronic disease in Europe, and it is estimated that 150 million Europeans suffer from chronic allergies. A typical allergic reaction is characterised as a reaction from the innate immune system to the allergen, for example pollen for hayfever sufferers.
Currently, allergies are treated according to the allergen; with antihistamines and decongestants the most commonly used medication used for relieving symptoms. These treatments are however not always effective. There is, therefore, an unmet need for novel therapeutic interventions for allergies, and a recent study published from the University of Queensland in the Journal of Clinical Investigation has reported alleviation of allergy using gene therapy (Al-kouba, 2017).
Memory Th2 cell responses are recognised as a significant contributor of exacerbated allergic diseases. Th2 cells comprise a core part of the adaptive immune system. It has been proposed that minimal bacterial exposure early in life shifts the balance of the Th1/Th2 ratio towards a dominant Th2 immune response. Th2 cells secrete cytokines including IL-4, IL-5, IL-6 and IL-13. This in turn activates IgE antibody production, as well as mast cells and eosinophils (Figure 1).
Figure 1. Allergy response pathway. As part of an allergic response, allergens are presented to naïve T cells, which activates Th2 cells in the presence of IL-4. Th2 cells then release cytokines including IL-3, IL-4 and IL-13. This in turn activates the release of IgE-producing antibodies as well as activating eosinophils and mast cells. Figure adapted from Fujita H, Meyer N, Akdis M et al (2012).
In the study by Alkouba et al. (2017), mice were sensitised with a single administration of chicken ova, an allergen that induces an immune response. This is termed as the ovalbumin challenge and enables researchers to mimic an allergic response in animal models. The researchers isolated bone stem cells from mice and a viral vector was used to insert the gene of interest as part of an ex vivo set up. These stem cells were then reinjected into the mice. The intention is that the modified stem cells aid in ‘switching off’ an allergic response by eliminating T cell memory in the mice. Following this treatment, findings from Al-kouba et al. (2017) reported effective silencing of the T helper 2 cell response, meaning that the mice were desensitised to the allergen.
The implications for the finding reported by Al-kouba et al. (2017) include wider awareness of the therapeutic potential of gene therapy in the context of immunotherapies. In addition, this study suggests that similar experiments can be replicated to evaluate the efficacy for other allergies, including peanut and fish allergies.
The study by Al-kouba et al. (2017) has further shed light on realising the therapeutic capacity of gene therapy, specifically accelerating the pathway for allergen immunotherapies. Future directions should ensure a more robust pre-clinical investigation, meaning the researchers should carry out experiments in primary human cells, followed by ex vivo mammalian tissue studies. Once the results are validated, approval for clinical trials can be sought as part of a Phase I clinical trial to investigate the safety of the therapeutic intervention in human participants. In addition, it will also be relevant to investigate alternative therapeutic targets for gene therapy of asthma, such as Dectin-1, a C-type lectin receptor, and oxidation of Calmodulin-dependent protein kinase II (Ito, 2017; Qu, 2017). Bone marrow stem cells have also been used as a vector for gene therapy as reported in Coleman et al. (2013). Coleman and colleagues addressed the problem of efficacy of autologous haematopoietic stem cell transplantation by restricting antigen expression to dendritic cells. This in turn improved the clinical efficacy of tolerance towards stem cell transplants and overcomes graft rejection. It would be interesting to see whether these two approaches could be combined for a more effective treatment.
Overall, this study contributes to the avenue of novel therapeutic therapies, which may be categorised as personalised medicine. Although safety and clinical efficacy is yet to be investigated in humans, it is very promising to present optimistic results in the treatment of allergies, which could evolve as a single-dose vaccine rather than a life-long prescription of medications. Other factors including choice of viral vector, immunogenicity and method of administration should also be considered in the preclinical stages.
- Al-Kouba J, Wilkinson AN, Starkey MR, Rudraraju R, Werder RB, Liu X, Law SC, Horvat JC, Brooks JF, Hill GR, Davies JM, Phipps S, Hansbro PM, Steptoe RJ. Allergen-encoding bone marrow transfer inactivates allergic T cell responses, alleviating airway inflammation. Journal of Clinical Investigation Insight. 2017:2;2(11).
- Ito T, Hirose K, Norimoto A, Tamachi T, Yokota M, Saku A, Takatori H, Saijo S, Iwakura Y, Nakajima H. Dectin-1 Plays an Important Role in House Dust Mite-Induced Allergic Airway Inflammation through the Activation of CD11b+ Dendritic Cells. Journal of Immunology. 2017, 198 (1) 61-70.
- Qu J, Do DC, Zhou Y, Luczak E, Mitzner W, Anderson ME, Gao P. Oxidized CaMKII promotes asthma through the activation of mast cells. Journal of Clinical Investigation Insight. 2017;12;2(1).
- Coleman MA, Bridge JA, Lane SW, Dixon CM, Hill GR, Wells JW, Thomas R, Steptoe RJ. Tolerance induction with gene-modified stem cells and immune-preserving conditioning in primed mice: restricting antigen to differentiated antigen-presenting cells permits efficacy. Blood. 2013;7;121(6):1049-58.
- Fujita H, Meyer N, Akdis M, Akdis CA. Mechanisms of immune tolerance to allergens. Chemical Immunology and Allergy. 2012;96:30-8.