Novel immunotherapy strategy to revert the principle hallmarks of cat allergy

Researchers from the Infection and Immunity Department of the Luxembourg Institute for Health (LIH) have shown the potential of high doses of a particular adjuvant molecule, namely the CpG oligonucleotide, to successfully modulate the immune system’s allergic response to the main cat allergen, Fel d 1, thereby inducing tolerance Reaction triggered and the main characteristics of the cat allergy reset.

Researchers analyzed the molecular mechanisms underlying this tolerance and proposed a pre-clinical allergen-specific immunotherapy approach to improve the treatment and control of this common type of allergy. The full study results were recently published in the prestigious international journal Allergy, the official journal of the European Academy of Allergy and Clinical Immunology (EAACI) and one of the world’s two leading journals on allergies.

Cat allergy is a rapidly growing phenomenon characterized by hypersensitivity and an excessive immune response to certain allergens associated with cats, particularly Fel d 1, a protein typically found in saliva, glands, skin, and fur. Manifestations of cat allergies can range from mild symptoms to the development of severe conditions such as rhinitis and asthma with potentially fatal consequences. While pharmacotherapy is an option for milder forms, only allergen-specific immunotherapy (AIT) can ensure effective and longer-lasting treatment in advanced cases.

AIT typically consists of the subcutaneous injection of gradually increasing amounts of the allergen in question until a critical dose is reached that induces long-term immune tolerance. However, there is still a need to improve the AIT in cats in terms of effectiveness and safety. The researchers hypothesized that the most effective feline AIT could be achieved by optimizing the response of T and B cells of the immune system through immune adjuvants to induce the production of antibodies to Fel d 1 while minimizing inflammatory responses, thereby the immune tolerance to this allergen is increased.

“We tried to explore new means of increasing the anti-inflammatory activity of AIT with the well-known immunomodulatory adjuvant CpG, but at a higher safe dose than before for this type of therapy,” explains Dr. Cathy Léonard, scientist at Allergy and Clinical Research Group Immunology at the LIH Department of Infection and Immunity and co-author of the publication.

To investigate the cellular and clinical effects of AIT based on the injection of the Fel d 1 allergen in combination with a high dose of CpG adjuvant, the team challenged Fel d 1 allergic mice with the allergen, both in the presence and in the presence even in the absence of AIT.

Scientists observed that AIT-treated allergic mice showed significantly improved lung resistance compared to untreated allergic mice, similar to that of non-allergic control mice, with significantly reduced signs of airway inflammation and hypersensitivity. In fact, when studying the Fel d 1 -specific antibodies, the team found that AIT-treated allergic mice had lower IgE levels, which are commonly associated with allergic reactions, and higher levels of IgA and IgG, which may have anti-inflammatory properties .

In addition, AIT-treated allergic mice showed a reduction in the levels of certain proallergic cytokine molecules produced by type 2 helper T cells (Th2) compared to untreated allergic animals. The researchers also found that very soon after the AIT injection, the number of immune cell types involved in allergy regulation and tolerance, namely plasmacytoid dendritic cells (pDCs), natural killer cells, increased in the tissue of AIT-treated mice cells (NKs) , regulatory T cells (T-regs) and regulatory B cells (B-regs). These cells have been found to express higher levels of the tumor necrosis factor alpha (TNF-α) receptor 2 (TNFR-2), with NK cells also producing the TNF-α cytokine, which is known to that it plays a role in suppressing the allergen. specific immune response, whereby these regulatory cells can act as a “brake” for the immune system.

“Later on, we observed a significant increase in TNF-α in the lungs. Interestingly, AIT also triggered the emergence of a novel and unique type of Tregs, known as biTregs, which are better able to treat allergic and inflammatory diseases balance response in response to the antigen, “adds Dr. Léonard added.

Taken together, these results indicate the potent anti-inflammatory and antiallergic effects induced by AIT with a high and safe dose of CpG adjuvant. Notably, however, the researchers found that the mechanism underlying this anti-allergy effect depends on whether the treatment is given as a vaccine to mice that have never been previously exposed to the Fel d 1 antigen and therefore did not show an existing allergic condition or under already established allergic conditions, as is the case with AIT. The elucidation of these alternative avenues opens up new knowledge for the future design of vaccines against preventive and curative allergies using CpG adjuvant.

In translating these results into applications for the pre-clinical setting, scientists developed a delivery system based on the subcutaneous injection of the Fel d 1 / CpG treatment as opposed to the more invasive intraperitoneal route of administration. The results showed the reversal of all allergy characteristics and confirmed the antiallergic effects of the AIT.

Essentially, we propose a preclinical AIT model for cat allergies that mimics the conditions required for clinical AIT studies in humans and is already optimized for future use in translation studies. Various innovations are presented in our study, including the use of an endotoxin-free Fel d 1 allergen, which is mandatory in the clinical setting in order to prevent the occurrence of collateral inflammatory reactions that could impair the desired induction of the tolerance-promoting mechanisms.

In addition, we show for the first time that the use of the maximum dose of CpG tolerated in humans has the ability to modulate the allergic response in combination with a Fel d 1 allergen, with very favorable safety profiles and by a well-established and medically approved Delivery mode. Based on our data, we believe that CpG deserves reassessment as an effective AIT adjuvant in humans and that our work lays the foundation for the development of novel successful immunotherapeutic treatments for allergies. “

Prof. Markus Ollert, Director of the LIH Department for Infection and Immunity and lead author

The results were published in the international journal Allergy with the full title “Comprehensive mapping of immune tolerance reveals a regulatory TNF receptor-2 signature in a mouse model of a successful Fel d 1-specific immunotherapy using a high-dose CpG adjuvant”.

Source:

Luxembourg Institute for Health

Journal reference:

Leonard, C. et al. (2020) A comprehensive mapping of the immune tolerance reveals a regulatory TNF receptor-2 signature in a mouse model of a successful Fel d 1-specific immunotherapy using a high-dose CpG adjuvant. Allergy. doi.org/10.1111/all.14716.