Disruption of antigen-induced inflammatory responses in CD40 ligand knockout mice.

Abstract

The objective of this study was to investigate the contribution of the interaction between CD40 and its ligand (CD40L) to antigen-induced airways inflammatory responses. To this end, we used a model involving ovalbumin (OVA) sensitization followed by OVA aerosol challenge in CD40L knockout (KO) mice. OVA-specific IgE and IgG1 were detected in the serum of the sensitized control, but not in CD40L-KO mice. After antigen challenge, sensitized control mice developed airway inflammation that was primarily eosinophilic. This inflammatory response was dramatically reduced in CD40L-KO mice. In contrast, similar numbers of eosinophils were observed in both the bone marrow and the peripheral blood in the sensitized controls and mutant strains after antigen challenge. To investigate the mechanisms underlying these findings, we examined levels of the cytokines IL-5, IL-4, and TNFalpha in both bronchoalveolar lavage (BAL) and serum. Similar levels of IL-5 were detected in BAL and serum of control and CD40L-KO mice; however, negligible levels of IL-4 in BAL and serum and of TNFalpha in BAL were detected in CD40L-KO mice when compared with control mice. Furthermore, we demonstrated that endothelial cell expression of vascular cell adhesion molecule 1 in OVA-sensitized and -challenged CD40L-KO mice was, as detected by immunohistochemistry, markedly decreased compared with that observed in similarly treated control mice. In addition, we locally overexpressed IL-4 and TNFalpha by using an adenoviral (Ad)-mediated gene transfer approach. Intranasal administration of either Ad/TNFalpha or Ad/IL-4 into OVA-sensitized and -challenged CD40L-KO mice did not reconstitute airway eosinophilia. However, concurrent administration of Ad/TNFalpha and Ad/IL-4 upregulated endothelial expression of vascular cell adhesion molecule 1, and resulted in full reconstitution of the inflammatory response in the airways. Together, these findings demonstrate the importance of the CD40-CD40L costimulatory pathway in the full expression of the inflammatory response in the airways.

Deficiency of Act1, a critical modulator of B cell function, leads to development of Sjögren's syndrome

“…BAFF (also known as BlyS, TALL-1, zTNF4, THANK, and TNFSF 13B) has emerged as a critical regulator of B cell survival and maturation in the periphery. Mice deficient in BAFF display severe loss of mature B cells and attenuated antibody responses [8][9][10][11][12][13][14]. The interaction between CD40 and its ligand CD40L is required for T cell-dependent B cell activation and antibody production [10,15].…”

IFN Regulatory Factor-1 Is Required for the Up-Regulation of the CD40-NF-κB Activator 1 Axis During Airway Inflammation

“…Studies from many groups indicate that CD40 probably plays a more general role in immune regulation (6). CD40-CD40 ligand (CD40L) 3 interactions have recently been implicated in airway inflammation (7)(8)(9)(10)(11)(12)(13)(14)(15). Although airway epithelial cells express low levels of CD40, inflammatory cytokines, including IL-1, TNF-␣, and IFN-␥, can all strongly up-regulate the expression of CD40 in airway epithelial cells (16 -18).…”

“…Using CD40L-null mice that were first sensitized and aerosol-challenged with OVA, studies showed the clear involvement of CD40-CD40L interaction in the development of allergic airway inflammation (10). After Ag challenge, sensitized control mice developed airway inflammation, including production of TNF-␣ and IL-4 and expression of VCAM-1.…”

“…After Ag challenge, sensitized control mice developed airway inflammation, including production of TNF-␣ and IL-4 and expression of VCAM-1. This inflammatory response was dramatically reduced in CD40L-null mice (10). A chimeric mouse model based on CD40-null and wild-type mice was used to assess the contribution of bone marrow (BM)-derived and non-BM-derived cells in a CD40-mediated pulmonary inflammation response.…”

Le CD154 plaquettaire : Une nouvelle interface dans l’hémostase et la réaction inflammatoire

“…La place du CD154 dans la réaction inflammatoire est soulignée dans les modèles de souris CD154 -/-, chez qui la réponse inflammatoire à un stimulus antigénique est presque abrogée. Le rôle spécifique du CD154 plaquettaire n'a cependant pas été formellement démontré dans ces modèles [29].…”