A modern immunotherapy approach to restore the main symptoms of cat allergy

Researchers from the Department of Disease and Immunity of the Luxembourg Institute of Health (LIH) have shown the potential of high doses of a specific receptor molecule, namely CpG oligonucleotide, in altering the allergic response of the immune system to a major cat allergen Fel d 1 stimulates a response that stimulates tolerance and returns the main symptoms of cat allergy.

The researchers analyzed the molecular mechanisms underlying this tolerance and recommended a specific preclinical immunotherapy approach for allergens to improve the treatment and control of this common type of allergy. The full results of the study were recently published in the internationally renowned journal Allergy, the official journal of the European Academy of Allergy and Clinical Psychology (EAACI) and one of the two best journals in the world in the field of allergy.

Cat allergy is a fast-growing phenomenon characterized by hypersensitivity and an overactive immune response to specific allergens associated with felines, particularly Fel d 1, a protein commonly found in the gut. -their saliva, glands, skin and fur. Symptoms of cat allergy can range from mild symptoms to the development of very serious conditions such as rhinitis and asthma, with potentially fatal consequences. While pharmacotherapy is an option for the milder forms, only specific allergen immunotherapy (AIT) will ensure effective and longer lasting treatment in the more advanced cases.

AIT usually involves subcutaneous injection of a gradual increase in the amount of that allergen, until an emergency dose is reached that causes long-term immune intolerance. Nevertheless, there is still a need to develop an AIT cat in terms of efficiency and safety. The researchers hypothesized that the cat could achieve the most effective AIT by optimizing the T-and B-cell response of the immune system through immune therapies to secretion of antibodies against Fel d 1 while reducing inflammatory reactions, thus promoting immune tolerance to this allergen.

“We tried to explore new ways to increase the anti-inflammatory activity of AIT with the known immunomodulatory CpG, but at a higher safe dose than previously used for this type of treatment,” explained Dr. Cathy Léonard, person Allergy and Clinical Science An immunology research group of the LIH Department of Disease and Prevention and the first published author.

To study the cellular and clinical effects of AIT-based injection of the allergen Fel d 1 in combination with a high dose of CpG adjuvant, the team challenged Fel d 1-allergic mice with both the allergen present and without AIT.

The scientists maintained that allergic mice treated with AIT showed significantly better lung strength, similar to non-allergic control mice, compared to untreated allergic mice, with symptoms of airway inflammation and hyper-response greatly reduced. In fact, when they looked at the specific antibodies Fel d 1, the team noticed that AIT-treated allergy mice showed lower levels of IgE, which is usually associated with allergic responses, and levels higher levels of IgA and IgG, which may have anti-inflammatory properties.

In addition, AIT-treated allergy mice showed a decrease in the levels of some pro-allergic cytokine molecules, secreted by helper type 2 T cells (Th2), compared to allergy-free animals without treatment. The researchers also noted that, already shortly after AIT injection, there was an increase in AIT-treated mouse interbreeding in the abundance of immune cell types involved in regulation and tolerance. allergies, i.e. dendritic plasmacytoid cells (pDCs), Natural Killer cells (NKn), regulatory T cells (T-regs) and regulatory B cells (B-regs). These cells were found to express higher levels of the Tumor Necrosis Factor Alpha (TNF-α) 2 (TNFR-2) receptor, with NK cells also expressing the cytokine TNF-α, which known to play a role in suppressing the allergen-specific immune response, thus allowing these regulatory cells to ‘brake’ the immune system.

“At a later stage, we saw a clear increase of TNF-α in the lungs. Interestingly, AIT also stimulated the appearance of a novel and a special type of Tregs, called biTregs, which are even better equipped to produce rebalancing allergy and inflammation.response in response to the antigen “, adds Dr. Léonard.

Taken together, these findings highlight the strong anti-inflammatory and anti-allergic effect induced by AIT with a high and safe dose of CpG adjuvant. Surprisingly, however, the researchers found that the mechanism underlying this immunosuppressive activity varies depending on whether the treatment is administered as a vaccine to mice that has never been before. on the antigen Fel d 1, and thus did not present an existing allergic condition, or under pre-established allergic conditions, as is true in AIT. Clarification of these alternative pathways opens new perspectives for the design of future protective and therapeutic allergy vaccines using adjuvant CpG.

Going further in translating these findings into applications for the preclinical setting, the scientists developed a delivery system based on subcutaneous injection of Fel d 1 / CpG treatment, compared to the more aggressive intraperitoneal route of administration. The results showed that the allergy symptoms were reversed and confirmed the anti-allergic effects of the AIT.

In fact, we propose a preclinical model of AIT for cat allergy, which is similar to the conditions required for human AIT clinical trials and is already used for translational studies in the future. future. In fact, our study includes several novelties involving the use of the allergen Fel d 1 without endotoxin, which is mandatory in the clinical setting, to suppress collateral inflammatory responses. may affect the desired entry of the tolerance stimulation techniques.

Furthermore, we show for the first time that the use of the highest dose of CpG induced in humans has the potential to alter the allergic response when combined with allergen Fel d 1 , with very favorable safety profiles and through fixed and medically-approved delivery method. Based on our data, we believe that CpG deserves reconsideration as an effective AIT adjuvant in humans and that our work lays the foundations for the development of modern immunotherapeutic treatments for allergies. “

Professor Markus Ollert, Director, LIH Department of Disease and Immunity and Lead Author

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