Tolerizing agents

Abstract

Described herein is the development of fusion proteins useful for inducing tolerance in a subject. In particular embodiments, the tolerizing agents are useful for influence autoimmune, inflammatory, and / or allergic reactions. Example tolerizing fusion proteins contain a targeting portion (which delivers the fusion protein) and a toleragen or allergen or other antigen to which tolerance is desired in a subject. In particular examples, it is demonstrated that a pσ1 fusion protein, when administered orally, facilitates systemic and mucosal tolerance. Also described is the nasal delivery of fusion proteins, for instance for restoring immunogenicity.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This is a continuation of U.S. application Ser. No. 12 / 294,380, filed Sep. 24, 2008, which is the U.S. National Stage of International Application No. PCT / US2007 / 065278, filed Mar. 27, 2007, which was published in English under PCT Article 21(2), which in turn claims the benefit of U.S. provisional application No. 60 / 786,446, filed Mar. 27, 2006. All of the above-listed applications are hereby incorporated by reference in their entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was made with government support under contracts AI018958, DE012242, AI043197, DC004976, and DE013812 awarded by the National Institutes of Health. The government has certain rights in the invention.FIELD OF THE DISCLOSURE[0003]This disclosure relates to agents and compositions useful in stimulating tolerance to an immunogen. In particular, it relates to mucosal targeted fusion proteins that can be applied, for instance, th...

AI Technical Summary

Benefits of technology

[0011]Described herein is the development of M cell-targeting Ag delivery systems using recombinant reovirus pσ1. Recombinant pσ1 of reovirus has been genetically fused to OVA (OVA-pσ1). It is demonstrated that this fusion protein, when administered orally, facilitates systemic and mucosal tolerance induction by innate- and / or acquired-types of Treg cells. Also described is the nasal delivery of a OVA-pσ1(m) or OVA-pσ1(Δ) fusion protein for restoring OVA immunogenicity.

[0012]Thus, there is provided herein a new approach to delivering highly virulent and antigen-specific tolerizing agents, which uses a ligand (such as a mucosal targeting ligand) fused to a specific antigen to induce host unresponsiveness solely to that antigen. The ligand portion of the protein can be fused a broad range of antigens (toleragens), enabling the generation of tolerance to a number of autoimmune disease antigens, inflammatory disease antigens, allergens, and biological therapeutic molecules (e.g., botulinum toxin), for instance. The fusion proteins are capable of regulating peripheral tolerance subsequent to nasal or oral application.

Problems solved by technology

Indeed, tolerance is so strong that oral immunization only succeeds in inducing mucosal and systemic immunity when potent mucosal adjuvants, vectors or other special delivery systems are employed (Fujihashi et al., Acta. Odontol. Scand. 59:301-308, 2001).

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