Tolerization of a type I allergic immune response through transplantation of genetically modified hematopoietic stem cells.
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.
Division of Transplantation, Department of Surgery, Center of Physiology and Pathophysiology, Medical University of Vienna, Vienna, Austria.
Ulrike
U
Baranyi
Birgit
B
Linhart
Nina
N
Pilat
Martina
M
Gattringer
Jessamyn
J
Bagley
Ferdinand
F
Muehlbacher
John
J
Iacomini
Rudolf
R
Valenta
Thomas
T
Wekerle
D000485:Allergens / Q000008:administration & dosage* / Q000235:genetics* / Q000276:immunology; D000818:Animals; D052179:Antigens, Plant; D029662:Betula / Q000235:genetics / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000379:methods; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006967:Hypersensitivity / Q000145:classification / Q000235:genetics* / Q000276:immunology*; D007108:Immune Tolerance / Q000235:genetics*; D007428:Intradermal Tests; D051379:Mice; D008807:Mice, Inbred BALB C; D031784:Phleum / Q000235:genetics / Q000276:immunology; D010940:Plant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D011058:Pollen / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic; D019172:Transplantation Conditioning
D000485:Allergens; D052179:Antigens, Plant; C076049:Phl p V protein, Phleum pratense; D010940:Plant Proteins; D011993:Recombinant Fusion Proteins; C061312:Bet v 1 allergen, Betula