ICOS/B7RP-1 interference in mouse kidney transplantation.
BACKGROUND
Activated T cells play a key role in allograft rejection. T cell activation requires signaling via the T cell receptor as well as costimulatory signals. Inducible costimulatory molecule (ICOS), with its ligand B7RP-1, is a recently discovered costimulatory molecule of the CD28 family. The role of this signaling pathway during the early phases of kidney allograft rejection is not clear so far.


METHODS
Kidneys were orthotopically transplanted from BALB/c to C57BL/6 mice. Animals were assigned to five experimental groups: blocking anti-ICOS monoclonal antibody, ICOS fusion protein, anti-B7RP1 monoclonal antibody, B7RP-1 fusion protein, and control immunoglobulin G.


RESULTS
Survival was significantly reduced in animals treated with ICOS monoclonal antibody (mAb) and B7RP-1 Fc as compared with controls. These animals had also a lower number of apoptotic graft infiltrating T cells, whereas the expression of intracellular interferon-gamma in CD3CD4 T cells was increased. Animals treated with ICOS Fc and B7RP-1 mAb had similar survival and numbers of apoptotic T cells as compared with controls.


CONCLUSIONS
In summary, the blockade of ICOS with ICOS mAb or B7RP-1 Fc reduced the amount of apoptosis of infiltrating lymphocytes and resulted in continuous inflammatory processes with progressive tissue damage and graft failure.
Lutz
Jens
J
Department of Nephrology, Klinikum rechts der Isar, Munich, Germany.
Lu
Ruiyan
R
Strobl
Matthias
M
Huang
Hai
H
Deng
Meihong
M
Wang
Minghui
M
Ouyang
Nengtai
N
Heemann
Uwe
U
D000818:Animals; D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000627:therapeutic use*; D017209:Apoptosis; D018122:B7-1 Antigen / Q000276:immunology / Q000627:therapeutic use*; D017252:CD3 Complex / Q000096:biosynthesis / Q000235:genetics; D016860:CD4 Immunoadhesins / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015870:Gene Expression; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D006085:Graft Survival; D020287:In Situ Nick-End Labeling; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D007424:Intracellular Fluid / Q000378:metabolism; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology; D008024:Ligands; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D018122:B7-1 Antigen; D017252:CD3 Complex; C452842:CD3 antigen, gamma chain; D016860:CD4 Immunoadhesins; C556694:Icos protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D008024:Ligands; D012333:RNA, Messenger