title: Anti-OX40L alone or in combination with anti-CD40L and CTLA4Ig does not inhibit the humoral and cellular response to a major grass pollen allergen.
abstract: BACKGROUND
  IgE-mediated allergy is a common disease characterized by a harmful immune response towards otherwise harmless environmental antigens. Induction of specific immunological non-responsiveness towards allergens would be a desirable goal. Blockade of costimulatory pathways is a promising strategy to modulate the immune response in an antigen-specific manner. Recently, OX40 (CD134) was identified as a costimulatory receptor important in Th2-mediated immune responses. Moreover, synergy between OX40 blockade and 'conventional' costimulation blockade (anti-CD40L, CTLA4Ig) was observed in models of alloimmunity.
  
  
  OBJECTIVE
  We investigated the potential of interfering with OX40 alone or in combination with CD40/CD28 signals to influence the allergic immune response.
  
  
  METHODS
  The OX40 pathway was investigated in an established murine model of IgE-mediated allergy where BALB/c mice are repeatedly immunized with the clinically relevant grass pollen allergen Phl p 5. Groups were treated with combinations of anti-OX40L, CTLA4Ig and anti-CD40L. In selected mice, Tregs were depleted with anti-CD25.
  
  
  RESULTS
  Blockade of OX40L alone at the time of first or second immunization did not modulate the allergic response on the humoral or effector cell levels but slightly on T cell responses. Administration of a combination of anti-CD40L/CTLA4Ig delayed the allergic immune response, but antibody production could not be inhibited after repeated immunization even though the allergen-specific T cell response was suppressed in the long run. Notably, additional blockade of OX40L had no detectable supplementary effect. Immunomodulation partly involved regulatory T cells as depletion of CD25(+) cells led to restored T cell proliferation.
  
  
  CONCLUSIONS
  Collectively, our data provide evidence that the allergic immune response towards Phl p 5 is independent of OX40L, although reduction on T cell responses and slightly on the asthmatic phenotype was detectable. Besides, no relevant synergistic effect of OX40L blockade in addition to CD40L/CD28 blockade could be detected. Thus, the therapeutic potential of OX40L blockade for IgE-mediated allergy appears to be ineffective in this setting.
authors.affiliation: Department of Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Gattringer
authors.affiliation: Department of Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria.
authors.forename: U
authors.initials: U
authors.lastname: Baranyi
authors.affiliation: Department of Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria.
authors.forename: N
authors.initials: N
authors.lastname: Pilat
authors.affiliation: Department of Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Hock
authors.affiliation: Department of Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Klaus
authors.affiliation: Department of Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria.
authors.forename: H E
authors.initials: HE
authors.lastname: Ramsey
authors.affiliation: Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: F
authors.initials: F
authors.lastname: Wrba
authors.affiliation: Department of Pathophysiology and Allergy Research, Division of Immunopathology, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: R
authors.initials: R
authors.lastname: Valenta
authors.affiliation: Department of Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria.
authors.forename: T
authors.initials: T
authors.lastname: Wekerle
mesh_terms: D000069594:Abatacept / Q000494:pharmacology; D000485:Allergens / Q000276:immunology; D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D023201:CD40 Ligand / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006967:Hypersensitivity / Q000276:immunology*; D007111:Immunity, Cellular / Q000276:immunology*; D056724:Immunity, Humoral / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D053278:OX40 Ligand / Q000037:antagonists & inhibitors / Q000276:immunology*; D031784:Phleum / Q000276:immunology; D011058:Pollen / Q000276:immunology*; D051381:Rats; D012130:Respiratory Hypersensitivity / Q000276:immunology
chemical_list: D000485:Allergens; D018926:Anti-Allergic Agents; D053278:OX40 Ligand; D023201:CD40 Ligand; D000069594:Abatacept
keywords: OX40L; allergy; costimulation; costimulation blockade; suppression