Anti-CD86 (B7.2) Treatment Abolishes Allergic Airway Hyperresponsiveness in Mice

Abstract

Allergic sensitization in asthma develops as a consequence of complex interactions between T cells and antigen-presenting cells. We have developed several in vivo models to study allergen-specific T cell and B cell function and their relevance to allergic airway hyperresponsiveness (AHR), focusing on the role of the costimulatory molecules CD80 and CD86. Treatment of mice with anti-CD86, but not anti-CD80, significantly inhibited increased serum levels of ovalbumin (OA)-specific IgE and IgG1, airway eosinophilia, and AHR both after 10 d of OA aerosol exposure (in the absence of adjuvant) and after intraperitoneal sensitization followed by repeated airway challenges. Inhibition of AHR was associated with decreased IL-4 and IL-5 levels in the BAL fluid of sensitized mice, suggesting impaired Th2 function in anti-CD86-treated animals. This effect was not seen when mice received treatment only before allergen challenge, indicating that anti-CD86 acts through inhibition of allergic sensitization and not simply by inhibiting the influx of inflammatory cells. These data suggest that the CD86 costimulatory ligand plays a major role in the development of allergic inflammation and AHR in allergen-challenged mice. Further, this study demonstrates that T-B cell interactions during allergic sensitization are amenable to therapeutic manipulation and that selective blockade of accessory signals can be an effective means for modulating distinct T cell functions.

CpG Oligodeoxynucleotides Can Reverse Th2-Associated Allergic Airway Responses and Alter the B7.1/B7.2 Expression in a Murine Model of Asthma

“…Our finding of increased B7.1 expression is similar to the finding of Chiaramonte et al (19). Although CpG depression of B7.2 expression has not been previously reported, our finding that suppression of B7.2 by CpG-ODN may be involved in the reduction of Th2 responses is compatible with findings that B7.2, but not B7.1, preferentially costimulates the initial production of IL-4 (35) and that anti-CD86 (B7.2), but not anti-CD80 (B7.1) treatment of mice significantly inhibited Ag-induced AHR, eosinophilia, and Ag-specific IgE, which was associated with the reduction of IL-4 and IL-5 (36,37). Taken together, the above findings suggest that the suppressive effects of CpG -ODN on Th2 responses involve at least two immunoregulatory pathways.…”

Critical Role for IL-13 in the Development of Allergen-Induced Airway Hyperreactivity

“…In addition, it has been demonstrated that airway eosinophilia can occur without the development of AHR (7,47). In contrast, T cells, rather than eosinophils, correlate directly with the development of AHR (7,8,45,48,49). Our results clearly show that T cells producing IL-13 are critical for the development of AHR, because transfer of IL-13 ϩ/ϩ Th2 cells but not IL-13 Ϫ/Ϫ Th2 cells, induced the development of AHR.…”

Eosinophil Major Basic Protein-1 Does Not Contribute to Allergen-Induced Airway Pathologies in Mouse Models of Asthma

“…This lack of an observed effect mediated by the release of the most abundant ESGP suggests that AHR is either dependent on other less abundant ESGPs, eosinophil effector functions other than degranulation, or is a pathophysiologic response mediated by the activity of another cell type(s). As noted in several studies, activated CD4 ϩ T cells recruited to the lung in response to allergen challenge were likely candidates to mediate eosinophil-independent effects (25,30,31). Furthermore, genetic studies linking AHR and T cells (29,32) or studies linking AHR and T cell-derived cytokines that have little or no direct effect on eosinophil proliferation and/or function (e.g., pulmonary expression of IL-13) (27,28), further support a relationship between AHR and T cells.…”

“…These studies can be divided into three groups: 1) studies that demonstrate that airway eosinophilia can occur without AHR (21); 2) mouse models that show that AHR occurs in the absence of a significant airways eosinophilia (22)(23)(24)(25)(26); and 3) studies that disassociate the kinetics of eosinophil recruitment to the lung and the development of AHR (27). Moreover, several studies in the mouse link AHR directly with T cell activities independently of eosinophil effector function (25,(27)(28)(29)(30)(31)(32). Therefore, while a preponderance of evidence suggests that eosinophil effector functions are responsible for Ag-induced AHR, data from in vivo studies using mouse models have, in some cases, been in conflict with this hypothesis.…”