Notch ligand Delta-like4 inhibits the development of murine experimental allergic conjunctivitis.
BACKGROUND
To investigate the involvement of Notch ligands in the development of experimental allergic conjunctivitis (EC) in mice.


METHODS
To induce EC, wild-type (WT) or IFN-gamma-deficient (GKO) BALB/c mice were immunized with ragweed (RW) in alum followed by RW challenge in eye drops. Twenty-four hours after RW challenge, the conjunctivas, spleens and blood were harvested to evaluate conjunctival eosinophil infiltration, RW-specific cytokine production and serum Ig levels, respectively. Abs against Notch ligands (anti-Jagged1, anti-Jagged2, anti-Delta-like (Dll)1 and anti-Dll4) were injected intraperitoneally into EC-developing mice during the induction or effector phase. As a control, normal hamster IgG (nhIgG) was injected.


RESULTS
Treatment with anti-Dll4 Ab but not the other Abs during the induction phase significantly augmented the severity of EC, as measured by the conjunctival eosinophil infiltration. Anti-Dll4 Ab treatment also significantly upregulated RW-recall IL-4 production and suppressed serum IgE and IgG1 levels. However, anti-Dll4 Ab treatment during the induction phase did not significantly affect the severity of EC in GKO mice. None of the Abs significantly affected the severity of EC, splenocyte cytokine production, or serum Ig levels when administered during the effector phase.


CONCLUSIONS
These observations suggest that Dll4, a Notch ligand, plays a role in suppressing the development of EC, possibly by providing a negative signal for Th2 development during the induction phase. In addition, IFN-gamma may participate in the augmentation of EC by anti-Dll4 Ab treatment.
Fukushima
Atsuki
A
Department of Ophthalmology and Visual Science, Kochi Medical School, Nankoku, Japan. fukusima@kochi-u.ac.jp
Sumi
Tamaki
T
Ishida
Waka
W
Ojima
Ayako
A
Kajisako
Mina
M
Koyanagi
Akemi
A
Koyama
Noriko
N
Yagita
Hideo
H
D048868:Adaptor Proteins, Signal Transducing; D000534:Alum Compounds; D031164:Ambrosia; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D002135:Calcium-Binding Proteins; D003228:Conjunctiva / Q000276:immunology / Q000473:pathology; D003233:Conjunctivitis, Allergic / Q000097:blood / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D016207:Cytokines / Q000378:metabolism; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007117:Immunization, Secondary; D007136:Immunoglobulins / Q000097:blood; D007371:Interferon-gamma / Q000172:deficiency; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology*; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D013154:Spleen / Q000276:immunology / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; D000534:Alum Compounds; D019138:Antibodies, Blocking; D002135:Calcium-Binding Proteins; D016207:Cytokines; C519665:DLL4 protein, mouse; D007136:Immunoglobulins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C041524:aluminum sulfate; D007371:Interferon-gamma