Xf. Lei et al., DISRUPTION OF ANTIGEN-INDUCED INFLAMMATORY RESPONSES IN CD40 LIGAND KNOCKOUT MICE, The Journal of clinical investigation, 101(6), 1998, pp. 1342-1353
The objective of this study was to investigate the contribution of the
interaction between CD40 and its ligand (CD40L) to antigen-induced ai
rways inflammatory responses, To this end, we used a model involving o
valbumin (OVA) sensitization followed by OVA aerosol challenge in CD40
L knockout (KO) mice. OVA-specific IgE and IgG(1) were detected in the
serum of the sensitized control, but not in CD40L-KO mice. After anti
gen challenge, sensitized control mice developed airway inflammation t
hat was primarily eosinophilic, This inflammatory response was dramati
cally reduced in CD40L-KO mice, In contrast, similar numbers of eosino
phils were observed in both the bone marrow and the peripheral blood i
n the sensitized controls and mutant strains after antigen challenge.
To investigate the mechanisms underlying these findings, we examined l
evels of the cytokines IL-5, IL-4, and TNF alpha in both bronchoalveol
ar 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 TNF alpha 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 im
munohistochemistry, markedly decreased compared with that observed in
similarly treated control mice, In addition, we locally overexpressed
IL-4 and TNF alpha by using an adenoviral (Ad)-mediated gene transfer
approach, Intranasal administration of either Ad/TNF alpha or Ad/IL-4
into OVA-sensitized and -challenged CD40L-KO mice did not reconstitute
airway eosinophilia. However, concurrent administration of Ad/TNF alp
ha and Ad/IL-4 upregulated endothelial expression of vascular cell adh
esion molecule 1, and resulted in full reconstitution of the inflammat
ory response in the airways, Together, these findings demonstrate the
importance of the CD40-CD40L costimulatory pathway in the full express
ion of the inflammatory response in the airways.