Beneficial effects of costimulatory blockade with anti-inducible costimulator antibody in conjunction with CTLA4Ig on prevention of islet xenograft rejection from rat to mouse.
BACKGROUND
Costimulatory signals have been reported to play an important role in islet-xenograft rejection, although the precise mechanisms remain unknown. The aim of the present study was to determine a role of a novel costimulatory molecule, inducible costimulator (ICOS), in rat islet-xenograft rejection in conjunction with CTLA4Ig with respect to cellular as well as humoral immune responses.


METHODS
Isolated rat islets were transplanted into the liver of streptozotocin (180 mg/kg) induced diabetic mice. Cellular immune responses to islet xenografts, and productions of anti-rat antibody in mice were examined by flow cytometry (FACS) after transplantation.


RESULTS
Intrahepatic rat islet xenografts were rejected in mice within 8 days after transplantation. FACS analysis revealed an expansion of CD8(+) T cells in the liver as well as a production of anti-rat antibody in recipient mice in association with rejection. The treatment with anti-ICOS antibody in conjunction with CTLA4Ig produced a marked prolongation of islet-xenograft survival with neither expansion of CD8(+) T cells nor production of anti-rat antibody, whereas, in contrast, those treated with anti-ICOS antibody or CTLA4Ig alone did not have prolonged survival, and CD8(+) T cells were expanded.


CONCLUSIONS
These findings demonstrate that cellular rather than humoral immune responses are considered responsible for islet-xenograft rejection from rat to mouse and that the blockade of costimulatory signals with anti-ICOS antibody in conjunction with CTLA4Ig has a favorable effect on prevention of islet xenograft rejection.
Nabeyama
Kentaroh
K
Department of Surgery I, Fukuoka University School of Medicine, 7-45-1, Nanakuma, Jonanku, Fukuoka 814-0180, Japan.
Yasunami
Yohichi
Y
Toyofuku
Atsushi
A
Nakano
Masahiko
M
Satoh
Masayuki
M
Matsuoka
Nobuhide
N
Ono
Junko
J
Kamada
Masafumi
M
Uede
Toshimitsu
T
Todo
Satoru
S
Ikeda
Seiyo
S
D000069594:Abatacept; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival; D018796:Immunoconjugates / Q000627:therapeutic use*; D060889:Inducible T-Cell Co-Stimulator Protein; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D011917:Rats, Inbred Lew; D014183:Transplantation, Heterologous / Q000276:immunology*
D000906:Antibodies; D000945:Antigens, Differentiation, T-Lymphocyte; C556694:Icos protein, mouse; C556695:Icos protein, rat; D018796:Immunoconjugates; D060889:Inducible T-Cell Co-Stimulator Protein; D000069594:Abatacept