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

• Published in: Clinical and experimental allergy Vol. 46; no. 2; pp. 354 - 364
• Main Authors: Gattringer, M., Baranyi, U., Pilat, N., Hock, K., Klaus, C., Ramsey, H. E., Wrba, F., Valenta, R., Wekerle, T.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.02.2016; Wiley Subscription Services, Inc
• Subjects: Abatacept - pharmacology; Allergens - immunology; Allergies; allergy; Animals; Anti-Allergic Agents - pharmacology; CD40 Ligand - antagonists & inhibitors; costimulation; costimulation blockade; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Hypersensitivity - immunology; Immunity, Cellular - immunology; Immunity, Humoral - immunology; Lymphocyte Activation - drug effects; Lymphocytes; Mice; Mice, Inbred BALB C; OX40 Ligand - antagonists & inhibitors; OX40 Ligand - immunology; OX40L; Phleum - immunology; Pollen; Pollen - immunology; Rats; Respiratory Hypersensitivity - immunology; suppression; T cell receptors; suppression; allergy; costimulation; costimulation blockade; OX40L
• ISSN: 0954-7894; 1365-2222
• DOI: 10.1111/cea.12661

Summary 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 and Clinical Relevance 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.