Antigen-Specific Tolerance in Immunotherapy of Th2-Associated Allergic Diseases

Smarr, Charles B.; Bryce, Paul J.; Miller, Stephen D.

doi:10.1615/critrevimmunol.2013007046

Cited by 45 publications

(35 citation statements)

References 184 publications

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“…This is a phenomenon well known in allergy immunotherapy in which administration of the antigen can result in adverse events, including anaphylaxis (41). We have attempted to mitigate this risk by using an immunomodulatory agent, rapamycin, which can induce and maintain the tolerogenic programming, even in the presence of potent TLR agonists.…”

Section: Discussionmentioning

confidence: 99%

Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance

Maldonado

LaMothe

Ferrari

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

370

423

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Current treatments to control pathological or unwanted immune responses often use broadly immunosuppressive drugs. New approaches to induce antigen-specific immunological tolerance that control both cellular and humoral immune responses are desirable. Here we describe the use of synthetic, biodegradable nanoparticles carrying either protein or peptide antigens and a tolerogenic immunomodulator, rapamycin, to induce durable and antigen-specific immune tolerance, even in the presence of potent Toll-like receptor agonists. Treatment with tolerogenic nanoparticles results in the inhibition of CD4+ and CD8+ T-cell activation, an increase in regulatory cells, durable B-cell tolerance resistant to multiple immunogenic challenges, and the inhibition of antigen-specific hypersensitivity reactions, relapsing experimental autoimmune encephalomyelitis, and antibody responses against coagulation factor VIII in hemophilia A mice, even in animals previously sensitized to antigen. Only encapsulated rapamycin, not the free form, could induce immunological tolerance. Tolerogenic nanoparticle therapy represents a potential novel approach for the treatment of allergies, autoimmune diseases, and prevention of antidrug antibodies against biologic therapies.U ndesired immunogenicity can have a profound impact on human health. Allergies, including allergic asthma and severe food allergies, affect ∼20% of the population, and the prevalence has been steadily increasing over the past several decades (1). The prevalence of autoimmune diseases, including multiple sclerosis and type 1 diabetes, is ∼4.5% (2). Unwanted immunogenicity can also affect both efficacy and safety of biologic drugs (3), particularly in the case of protein replacement therapies for the treatment of genetic deficiencies, such as hemophilia A (4) and Pompe Disease (5). Immunomodulatory agents commonly used to control immunogenicity are often broadly immunosuppressive and typically require chronic administration that can lead to reactivation of latent pathogens, development of tumors, and opportunistic infections (6, 7). Therefore, antigen-specific, durable tolerogenic therapy would be highly desirable from an efficacy and safety perspective.Multiple techniques for antigen-specific immunotherapy have been described, although only allergen immunotherapy, wherein low doses of antigen are delivered in the absence of immunomodulating agents, is currently used in the clinic (1). Experimental approaches have included oral administration of antigen, high dose tolerance, and the use of altered peptide ligands (8). Although these methods have been successful in preclinical models, translation to human clinical trials has been largely disappointing (8). Alternative strategies to leverage tolerogenic programming associated with apoptotic cells include conjugating antigen to splenocytes (9-12) or synthetic microparticles (13, 14) or targeting antigen to the surface of red blood cells (15). Other approaches include loading particles with MHC complexes that present relevant peptides i...

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Section: Discussionmentioning

confidence: 99%

Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance

Maldonado

LaMothe

Ferrari

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

370

423

View full text Add to dashboard Cite

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“…tolerance (28,29) and in the mechanism of AIT efficacy (12,30,31). However, specific Treg-based immunotherapies have not been evaluated in the context of food allergy.…”

Section: Discussionmentioning

confidence: 99%

“…In support for a role of Tregs in allergy, the induction of Tregs has been also demonstrated in successful allergen-specific immunotherapy (AIT), where they suppressed almost all aspects of Th2-mediated hypersensitivity (11,12). In addition, transfer of Tregs inhibited and reversed airway hyperresponsiveness, gut inflammation, and related Th2 responses in murine models (13)(14)(15).…”

Section: T Hymic-derived Cd4mentioning

confidence: 95%

Low-Dose IL-2 Induces Regulatory T Cell–Mediated Control of Experimental Food Allergy

Bonnet¹,

Vigneron

Levacher

et al. 2016

The Journal of Immunology

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“…Specific immunotherapy (SIT), however, has a long history of treating allergies by inhibiting Th2 responses. Typically consisting of gradually escalating doses of soluble Ag delivered mucosally or s.c., SIT has been demonstrated to induce both regulatory and Th1 responses that compete with established Th2 responses (2). However, administration of soluble Ag to sensitized patients bears a considerable risk of adverse reactions, thereby necessitating slow dose escalation or coadministration of therapies that minimize anaphylaxis, such as omalizumab (3).…”

mentioning

confidence: 99%

Biodegradable antigen-associated PLG nanoparticles tolerize Th2-mediated allergic airway inflammation pre- and postsensitization

Smarr

Yap

Neef³

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Specific immunotherapy (SIT) is the most widely used treatment for allergic diseases that directly targets the T helper 2 (Th2) bias underlying allergy. However, the most widespread clinical applications of SIT require a long period of dose escalation with soluble antigen (Ag) and carry a significant risk of adverse reactions, particularly in highly sensitized patients who stand to benefit most from a curative treatment. Thus, the development of safer, more efficient methods to induce Ag-specific immune tolerance is critical to advancing allergy treatment. We hypothesized that antigenassociated nanoparticles (Ag-NPs), which we have used to prevent and treat Th1/Th17-mediated autoimmune disease, would also be effective for the induction of tolerance in a murine model of Th2-mediated ovalbumin/alum-induced allergic airway inflammation. We demonstrate here that antigen-conjugated polystyrene (Ag-PS) NPs, although effective for the prophylactic induction of tolerance, induce anaphylaxis in presensitized mice. Antigen-conjugated NPs made of biodegradable poly(lactide-co-glycolide) (Ag-PLG) are similarly effective prophylactically, are well tolerated by sensitized animals, but only partially inhibit Th2 responses when administered therapeutically. PLG NPs containing encapsulated antigen [PLG(Ag)], however, were well tolerated and effectively inhibited Th2 responses and airway inflammation both prophylactically and therapeutically. Thus, we illustrate progression toward PLG(Ag) as a biodegradable Ag carrier platform for the safe and effective inhibition of allergic airway inflammation without the need for nonspecific immunosuppression in animals with established Th2 sensitization.immunotherapy | tolerance | nanoparticles | allergy | Th2 cells

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Antigen-Specific Tolerance in Immunotherapy of Th2-Associated Allergic Diseases

Cited by 45 publications

References 184 publications

Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance

Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance

Low-Dose IL-2 Induces Regulatory T Cell–Mediated Control of Experimental Food Allergy

Biodegradable antigen-associated PLG nanoparticles tolerize Th2-mediated allergic airway inflammation pre- and postsensitization

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