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Tolerization of a Type I Allergic Immune Response through Transplantation of Genetically Modified Hematopoietic Stem Cells¹

Ulrike Baranyi^*, Birgit Linhart, Nina Pilat^*, Martina Gattringer^*, Jessamyn Bagley, Ferdinand Muehlbacher^*, John Iacomini, Rudolf Valenta^2, and Thomas Wekerle^2,3,*

^* Division of Transplantation, Department of Surgery, and Division of Immunopathology, Department of Pathophysiology, Center of Physiology and Pathophysiology, Medical University of Vienna, Vienna, Austria; and Transplantation Research Center, Renal Division, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, MA 02115

Allergy represents a hypersensitivity disease that affects >25% of the population in industrialized countries. The underlying type I allergic immune reaction occurs in predisposed atopic individuals in response to otherwise harmless Ags (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 to express the major grass pollen allergen Phl p 5 on their cell membrane. Transplantation of these genetically modified hematopoietic stem cells led to durable multilineage molecular chimerism and permanent immunological tolerance toward 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 nonresponsiveness persisted throughout follow-up (40 wk). 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung, F2310 to T.W. and Fonds zur Förderung der Wissenschaftlichen Forschung, F1815 to R.V.) and in part by the Christian Doppler Association and a research grant from BIOMAY.

² R.V. and T.W. are cosenior authors.

³ Address correspondence and reprint requests to Dr. Thomas Wekerle, Division of Transplantation, Department of Surgery, Vienna General Hospital, Waehringer Guertel 18, 1090 Vienna, Austria. E-mail address: Thomas.Wekerle{at}meduniwien.ac.at

⁴ Abbreviations used in this paper: HSC, hematopoietic stem cell; BM, bone marrow; BMT, BM transplantation; r, recombinant; RBL, rat basophil leukemia; SI, stimulation index; VSV, vesicular stomatitis virus.