Tolerization of a Type I Allergic Immune Response through Transplantation of Genetically Modified Hematopoietic Stem Cells

Abstract

Allergy represents a hypersensitivity disease which affects more than 25% of the population in industrialized countries. The underlying type I allergic immune reaction occurs in predisposed atopic individuals in response to otherwise harmless antigens (i.e. allergens) and is characterized by the production of allergen-specific IgE, an allergen-specific T cell response and the release of biologically active mediators such as histamine from mast cells and basophils. Regimens permanently tolerizing an allergic immune response still need to be developed. We therefore retrovirally transduced murine hematopoietic stem cells (HSC) to express the major grass pollen allergen Phl p 5 on their cell membrane. Transplantation of these genetically modified HSC led to durable multi-lineage molecular chimerism and permanent immunological tolerance towards the introduced allergen at the B cell, T cell and effector cell levels. Notably, Phl p 5-specific serum IgE (and IgG) remained undetectable and T cell non-responsiveness persisted throughout follow-up (40 weeks). Besides, mediator release was specifically absent in in vitro and in vivo assays. B cell, T cell and effector cell responses to an unrelated control allergen (Bet v 1) were unperturbed demonstrating specificity of this tolerance protocol. We thus describe a novel cell-based strategy for the prevention of allergy.

Allergen-encoding bone marrow transfer inactivates allergic T cell responses, alleviating airway inflammation

“…Antibody and allergen-specific IgE-mediated effects were not tested here, as the present studies were intended purely to gain insight into effects on T cells. Expression of neoantigens and allergens using transcriptional targeting approaches is a powerful means to induce B cell tolerance (44,45) in addition to T cell tolerance and can prevent sensitization and allergen-specific IgE production in response to experimental sensitization using model antigens (our unpublished data) or clinically important allergens (46). Mechanistic studies indicate that in double transgenic systems (44,45) and in the polyclonal endogenous repertoire (47), B cell tolerance is mediated principally through cell-intrinsic central tolerance mechanisms, leading to antigen-specific B cell deletion during development and induction of B cell anergy when antigen is expressed in a membrane-bound form.…”

New Developments in the Diagnosis and Therapy of Allergic Rhinitis

“…Çayır otu poleni allerjeni kullanılarak yapılan hayvan deneyleri umut vericidir. Özellikle riskli hastalar için uygun hipoallerjenin üretilmesi ve güvenilir vektörlerin bulunmasıyla profilaktik tedavide uygun seçenek gibi görünmektedir (58).…”

Allergen‐specific immunotherapy: from therapeutic vaccines to prophylactic approaches

“…Allergen-expressing stem cells [122][123][124] Engineered T regulatory cells [126] Engineered Th1 cells [128] E. Passive immunization…”

“…Review: Allergen-specific immunotherapy induce tolerance as has been shown in experimental animal models [122][123][124]. Third, viral-like particleor experimental cell-based forms of prophylaxis may be considered [125][126][127][128].…”