Cellular and Humoral Mechanisms of Immune Tolerance in Immediate-Type Allergy Induced by Specific Immunotherapy

Haemophilia A (HA) is a blood clotting disorder caused by various genetic deficiencies in the factor VIII (FVIII) encoding F8 gene. Patients receiving FVIII replacement therapy are at risk of developing neutralizing antibodies (FVIII inhibitors) rendering the FVIII replacement therapy ineffective. Immunological tolerance towards FVIII can be achieved through immune tolerance induction (ITI) protocols in some patients but this is a lengthy and costly desensitization programme. Long-term eradication of inhibitors in HA patients could be achieved by antigen-specific immunotherapy targeting CD4+ T cells since formation of FVIII inhibitors is T cell dependent. Here, we report a peptide-based, antigen-specific immunotherapy designed to specifically re-establish immune tolerance to FVIII through the development of antigen-processing-independent epitopes (apitopes). We identified two FVIII immunodominant peptides in immunised human leukocyte antigen (HLA) DRA*0101/DRB1*1501 transgenic (HLA-DR2tg) mice that were optimised for tolerogenicity. These modified peptide analogues were initially screened for recognition using FVIII-specific T cell hybridoma clones from FVIII-immunised HLA-DR2tg mice. The FVIII apitopes were promiscuous and bound common human HLA-DRB1*haplotypes. The combination of these two FVIII apitopes (ATX-F8-117), administered according to a dose escalation protocol, promoted T cell tolerance towards FVIII in HLA-DR2tg mice. Furthermore, treatment with ATX-F8-117 significantly reduced FVIII inhibitor formation. ATX-F8-117 regulates both anti-FVIII T cell and B cell responses, specifically the generation of FVIII inhibitors, revealing peptide-based antigen-specific immunotherapy as a promising approach to both suppress and treat inhibitor formation in susceptible HA patients.

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CpG Adjuvant in Allergen-Specific Immunotherapy: Finding the Sweet Spot for the Induction of Immune Tolerance

Frontiers in Immunology ◽

10.3389/fimmu.2021.590054 ◽

2021 ◽

Vol 12 ◽

Author(s):

Guillem Montamat ◽

Cathy Leonard ◽

Aurélie Poli ◽

Ludger Klimek ◽

Markus Ollert

Keyword(s):

Immune Tolerance ◽

Specific Immunotherapy ◽

Allergic Diseases ◽

Prolonged Treatment ◽

Cpg Odn ◽

Allergen Specific Immunotherapy ◽

Immune Modulator ◽

The Past ◽

Limited Success ◽

Ige Mediated

Prevalence and incidence of IgE-mediated allergic diseases have increased over the past years in developed and developing countries. Allergen-specific immunotherapy (AIT) is currently the only curative treatment available for allergic diseases that has long-term efficacy. Although AIT has been proven successful as an immunomodulatory therapy since its beginnings, it still faces several unmet needs and challenges today. For instance, some patients can experience severe side effects, others are non-responders, and prolonged treatment schedules can lead to lack of patient adherence and therapy discontinuation. A common strategy to improve AIT relies on the use of adjuvants and immune modulators to boost its effects and improve its safety. Among the adjuvants tested for their clinical efficacy, CpG oligodeoxynucleotide (CpG-ODN) was investigated with limited success and without reaching phase III trials for clinical allergy treatment. However, recently discovered immune tolerance-promoting properties of CpG-ODN place this adjuvant again in a prominent position as an immune modulator for the treatment of allergic diseases. Indeed, it has been shown that the CpG-ODN dose and concentration are crucial in promoting immune regulation through the recruitment of pDCs. While low doses induce an inflammatory response, high doses of CpG-ODN trigger a tolerogenic response that can reverse a pre-established allergic milieu. Consistently, CpG-ODN has also been found to stimulate IL-10 producing B cells, so-called B regulatory cells (Bregs). Accordingly, CpG-ODN has shown its capacity to prevent and revert allergic reactions in several animal models showing its potential as both preventive and active treatment for IgE-mediated allergy. In this review, we describe how CpG-ODN-based therapies for allergic diseases, despite having shown limited success in the past, can still be exploited further as an adjuvant or immune modulator in the context of AIT and deserves additional attention. Here, we discuss the past and current knowledge, which highlights CpG-ODN as a potential adjuvant to be reevaluated for the enhancement of AIT when used in appropriate conditions and formulations.

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