Allergen-derived long peptide immunotherapy down-regulates specific IgE response and protects from anaphylaxis

Abstract

To evaluate a long peptide‐based allergy vaccine in a murine model, CBA/J mice were sensitized with low dose alum‐adsorbed phospholipase A2 (PLA2), a major bee venom allergen. Presensitized mice were treated by daily i.p. injections of a mixture of three long overlapping peptides (44‐ to 60‐mer) spanning the entire PLA2 molecule (100 μ g/peptide) for 6 consecutive days. This therapeutic approach induced a sharp drop in PLA2‐specific IgE, an increase in specific IgG2a, and a marked T cell hyporesponsiveness. T cell cytokine secretion was characterized by a shift from a Th2 to a Th1 profile. Prophylactic treatment of naive mice with long peptides prior to sensitization with PLA2 induced a comparable modulation of B and T cell responses. Upon i.p. challenge with native PLA2, presensitized mice treated with the long peptide mixture were fully protected from anaphylaxis. This indicated that allergen‐derived long overlapping peptides were safe and able to modulate an established Th2 response or to prevent its development. Furthermore, long peptide‐based immunotherapy provided clinical protection against anaphylaxis, thus appearing as a promising approach of the therapy of allergic diseases.

Heat denaturation, a simple method to improve the immunotherapeutic potential of allergens

“…However, SIT is time consuming, costly and bears the risk of allergic side effects. The latter can be reduced by pretreatment with anti-histamines [27,28], or by the use of allergen-derived peptides [17][18][19], chemically modified allergens [29,30] or recombinant allergens [11][12][13]31] with a reduced capacity to bind IgE. For instance, by producing fusion proteins of major allergens, one aim was to reduce IgE binding and therefore the allergic side effects, while yet retaining the immunotherapeutic potential due to preserved T cell epitopes, changes in protein folding and relative exposure of B cell epitopes [9].…”

“…For the same reasons, short, synthetic peptide sequences corresponding to T cell epitopes from the allergen have been used for SIT. This approach was able to modify surrogate markers of allergy including cutaneous responses to allergen challenge and ex vivo parameters of T cell activation [17][18][19]. Finally, chemical crosslinking of allergens by use of bi-functional aldehydes to produce so-called allergoids [20] has been shown to reduce reactogenicity with IgE while yet improving antigen processing, Th1 cytokine secretion, and efficacy [21][22][23].…”

Antigen-Independent Suppression of the Allergic Immune Response to Bee Venom Phospholipase A2 by DNA Vaccination in CBA/J Mice

“…SIT is a burdensome procedure requiring 3-5 years of treatment and has to be conducted under medical supervision because it causes undesirable side effects in 15% of patients (4). In addition to modulating Ig production, SIT operates by decreasing both Ag-specific T cell proliferation (5-7) and IL-4 secretion (8), as well as triggering the prototype Th1 cytokine IFN-␥ (9,10).…”

“…In addition to immunotherapy with short synthetic peptides (11), large recombinant allergen fragment (12), and long synthetic peptides (9,10), gene vaccination appears as a safe and inexpensive alternative to classical immunotherapy (13). Recent findings by several laboratories have shown that immunization with DNA vectors encoding human allergens triggers a strong Th1 response to these allergens in rats and mice (14 -17).…”

Phase I Malaria Vaccine Trial with a Long Synthetic Peptide Derived from the Merozoite Surface Protein 3 Antigen

“…Our previous experience with synthesis of long polypeptides (Ͼ100 amino acids) showed that we could produce good-manufacturing-procedure material quickly and efficiently for clinical studies (13,28). Long synthetic peptides (LSP) have been shown to be safe and immunogenic in preclinical (2,5,26,27,36,44) and clinical (20,28,45) trials and, therefore, should be considered good candidates for a phase I trial.…”