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Immunomodulatory Effects of Antigen-Pulsed Macrophages in a Murine Model of Allergic Asthma

Department of Pharmacology and Pathophysiology, Faculty of Pharmacy, Utrecht University; and Institute of Infectious Diseases and Immunology, Department of Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands

Address correspondence to: Dr. A. J. M. van Oosterhout, Ph.D., Department of Pharmacology & Pathophysiology, Faculty of Pharmacy, Utrecht University, P.O. Box 80.082, 3508 TB Utrecht, The Netherlands. E-mail: A.J.M.VanOosterhout{at}Pharm.uu.nl

Macrophages (M) play an unique role in the activation and regulation of T cells through their ability to modulate specific costimulatory and cytokine signals. Here we investigated the immunomodulatory effects of allergen presentation by M in a murine model of allergic asthma. Purified peritoneal M were pulsed with ovalbumin (OVA) (OVA-M), or the immunodominant epitope OVA_323–339 (OVA_323–339-M), and characterized for cell surface markers, cytokine production, and antigen-presenting capacity toward OVA_323–339-specific DO11.10 T cells. Antigen-pulsed M were injected (intravenously) in OVA-sensitized Balb/c mice that were repeatedly challenged with OVA or saline aerosol. Administration of OVA-M inhibited airway eosinophilia and hyperresponsiveness to methacholine concomitant with a reduced interleukin (IL)-4 and IL-5 production by T cells upon OVA stimulation in vitro. Interestingly, OVA-induced IL-10 levels remained unchanged, whereas interferon- could not be detected. In contrast to OVA-M, OVA_323–339-M administration had no effects on these asthma manifestations. Additional in vitro studies demonstrated that OVA-M, but not OVA_323–339-M, produced high levels of IL-10 upon interaction with the DO11.10 T cells. This IL-10 production by the OVA-M was dependent on MHC–TCR and CD86–CD28, but not CD80–CD28 or CD40–CD154 interactions. Our data suggest that IL-10 production by allergen presenting M plays a crucial role in successful immunotherapy.

Abbreviations: airway hyperresponsiveness, AHR • bronchoalveolar lavage fluid, BALF • enzyme-linked immunosorbent assay, ELISA • fluorescence-activated cell sorter, FACS • heat-inactivated rat serum, hRS • interferon-, IFN- • immunoglobulin, Ig • interleukin, IL • Iscove's Modified Dulbecco's Medium, IMDM • lymph node, LN • lipopolysaccharide, LPS • macrophage, M • ovalbumin, OVA • phosphate-buffered saline, PBS • enhanced pause, Penh • T-cell receptor, TCR • transforming growth factor, TGF • T helper 2 cells, Th2 cells

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