CD137-mediated immunotherapy for allergic asthma

Abstract

The prevalence of asthma continues to increase. Asthma is caused by a Th2 cell-driven immune response. Its optimal treatment remains a challenge, and a sufficient immunotherapeutic approach to treating asthma has yet to be found. Using a murine asthma model, we show that a single injection of an anti-CD137 (4-1BB) mAb prevents the development of airway hyperreactivity, eosinophilic airway inflammation, excessive mucus production, and elevated IgE during the observation period of 7 weeks. Most importantly, even established disease is completely reversed by anti-CD137 mAb administration. The protection is associated with markedly reduced Th2 cytokine production and increased secretion of the Th1 cytokine IFN-γ. While B lymphocytes are partly depleted, the number of CD8 + T cells is increased. Blockade of IFN-γ and depletion of CD8 + T cells during treatment with anti-CD137 mAb reduces in part but does not abrogate the protective effect of CD137 mAb. In contrast, CD137 mAb-mediated CD4 + T cell anergy is critical for the observed effects, since transfer of CD4 + T cells from CD137 mAb-treated mice conveyed protection. These data demonstrate, for the first time to our knowledge, the capacity of anti-CD137 mAb to ameliorate allergic asthma, and they indicate CD137 as a possible target for therapeutic intervention in this disease. IntroductionAsthma, which has increased substantially in prevalence in the last 2 decades, is characterized by airway hyperreactivity (AHR) to a variety of specific and nonspecific stimuli; chronic airway inflammation with pulmonary eosinophilia; mucus hypersecretion; and increased serum IgE levels (1). Asthma is believed to be a result of an inappropriate Th2 cell-mediated immune response to common aeroallergens in genetically susceptible individuals. Although the immunological mechanisms that induce asthma or allergies are relatively well characterized, the specific mechanisms that downmodulate Th2 cell-driven allergic inflammatory responses in the lung are poorly understood. Current therapies for asthma, such as inhaled corticosteroids and β 2 -agonists, relieve symptoms but do not reverse the progression of or cure this disease, and a sufficient immunotherapeutic approach to treating asthma has yet to be found. So far, it is not clear whether there are certain molecular interactions that could be targeted to either suppress ongoing lung inflammation or prevent the recurrence of asthmatic symptoms when airborne allergens are repeatedly encountered.One causal strategy to control asthma is to directly modify T cell activation by targeting costimulatory interactions that are involved in this process (2). Optimal T cell activation requires at least 2 signals, provided by recognition of peptide-MHC proteins by the TCR, and by interaction of T cell costimulatory receptors with their ligands on APCs. The ligation of the CD28 molecule on T cells to B7-1 or B7-2 on APCs is essential for naive T cell survival and differentiation. Memory T cell responses are often CD28

Critical role for syndecan-4 in dendritic cell migration during development of allergic airway inflammation

“…First, the role of SDC4 in allergic asthma was investigated by comparing SDC4 À / À versus wild-type (WT) mice in a murine asthma model [15][16][17] . Histological analysis of haematoxylin and eosin (H&E)-stained lung sections showed less inflammatory infiltrates in the airways of OVA-immunized SDC4 À / À mice compared with WT animals (Fig.…”

“…To test the therapeutic potential of an anti-SDC4 Ab treatment during an ongoing allergic inflammation, we immunized BALB/c mice with OVA first and injected the anti-SDC4 Ab after an asthma phenotype was already fully established, similar as described before 15 . Treatment of OVA-immunized mice with anti-SDC4 Ab clearly reduced inflammation in the lung (Fig.…”

“…Left lung was fixed in 10% formalin and stained with H&E (MERCK, Darmstadt, Germany). For objective evaluation and quantification of the degree of pulmonary inflammation, lung sections were scanned with a digital camera (Visitron systems, USA, five shots per lung) and analysed with HistoClick-Software based on morphometric image analysis developed in our laboratory 15,16 . The degree of inflammation is expressed as the number of pixels that correlate to the stained cells of interest.…”

“…OVA-specific IgE and IgG 1 serum levels were measured by a sandwich enzyme-linked immunosorbent assay according to a standard protocol 15,16 . Briefly, 96-well microtiter plates (Nunc, Roskilde, Denmark) were coated overnight with 10 mg ml À 1 OVA diluted in bicarbonate buffer (pH 9.6).…”

“…Splenocytes or mediastinal lymph node cells (5 Â 10 6 cells per ml per well) were isolated and restimulated in vitro with 200 mg ml À 1 OVA in culture medium (RPMI medium supplemented with 10% FCS, 100 U ml À 1 penicilin and 100 mg ml À 1 streptomycin) 1 day after the airway function test. Cytokines were measured in supernatants from restimulated spleen or lymph node cells after 3 days using DuoSet ELISA kits (R&D Systems, Minneapolis, USA) according to the manufacturer's instructions 15,16 .…”