Resistance of CD28-deficient mice to autologous phase of anti-glomerular basement membrane glomerulonephritis.
BACKGROUND
The engagement of CD28 on T cells provides an essential costimulatory signal for T-cell activation and differentiation. Recent studies suggest that CTLA4Ig inhibits T-cell activation in vitro and in vivo, prevents acute and chronic allograft rejection, and induces tolerance in some experimental transplantation models.


METHODS
The present study examined the role of the CD28 costimulatory pathway in the induction of experimental anti-glomerular basement membrane (GBM) glomerulonephritis (GN). An accelerated type of anti-GBM GN was induced in wild-type mice and CD28-deficient (KO) mice. After 7 and 14 days, functional parameters, such as serum creatinine, amount of proteinuria, and serum mouse IgG levels were assessed. Histological studies were performed simultaneously to examine glomerular changes by light microscopy and immunoglobulin deposition by immunofluorescence staining. Flow cytometric analysis was undertaken to assess I-A(b) antigen expression on spleen cells.


RESULTS
Anti-GBM GN induction was almost completely prevented in CD28-KO mice. CD28-KO mice had impaired ability to evoke B-cell activation, and developed lower mouse anti-rabbit IgG antibody titers in their serum than wild-type C57BL/6 mice. Furthermore, glomerular deposition of mouse anti-rabbit IgG was not detectable in CD28-KO mice after immunization with anti-GBM antibody.


CONCLUSIONS
This is the first demonstration that the CD28 costimulatory pathway plays a critical role in autologous antibody production in anti-GBM GN, and suggests that effective inhibition of CD28-dependent autologous antibody production could be useful in the treatment of antibody-dependent GN in humans.
Nitta
Kosaku
K
Department of Medicine, Kidney Center, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. nitta@kc.twmu.ac.jp
Horita
Shigeru
S
Ogawa
Shuhei
S
Matsumoto
Masayo
M
Hara
Yasushi
Y
Okano
Kazuhiro
K
Hayashi
Tomohito
T
Abe
Ryo
R
Nihei
Hiroshi
H
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology* / Q000378:metabolism; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001485:Basement Membrane / Q000276:immunology; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005802:Genes, MHC Class II; D006681:HLA-D Antigens / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011817:Rabbits; D013154:Spleen / Q000166:cytology / Q000378:metabolism
D001323:Autoantibodies; D018106:CD28 Antigens; D006681:HLA-D Antigens; D007074:Immunoglobulin G