Role of ICOS pathway in autoimmune and alloimmune responses in NOD mice.
Islet allografts are subject to alloimmune and autoimmune destruction when transplanted into autoimmune prone animals or humans. The ICOS-B7h pathway plays a role in alloimmune responses, but its function in autoimmunity against islet cells is controversial. We investigated the role of ICOS signaling in autoimmune and alloimmune responses in NOD mice. ICOS blockade prevents development of spontaneous disease in pre-diabetic NOD mice. Furthermore, while ICOS blockade prolongs graft survival in a fully mismatched non-autoimmune islet allograft model in C57BL/6 recipients, it has no beneficial effect in reversing diabetes in models of islet transplantation in NOD mice involving autoimmunity alone or both allo- and autoimmunity. Interestingly, ICOS blockade is effective in prolonging heart allograft (not subject to tissue-specific autoimmunity) survival in NOD mice. We conclude that in islet transplantation and autoimmune diabetes, ICOS blockade can be effective in inhibiting alloimmunity and preventing autoimmunity but is ineffective in inhibiting recurrence of autoimmunity.
Ansari
Mohammed Javeed I
MJ
Transplantation Research Center, Renal Division, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Fiorina
Paolo
P
Dada
Shirine
S
Guleria
Indira
I
Ueno
Takuya
T
Yuan
Xueli
X
Trikudanathan
Subbulaxmi
S
Smith
R Neal
RN
Freeman
Gordon
G
Sayegh
Mohamed H
MH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D015551:Autoimmunity; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control / Q000601:surgery; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D007155:Immunologic Factors / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D060889:Inducible T-Cell Co-Stimulator Protein; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D015398:Signal Transduction; D020123:Sirolimus / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; C556692:ICOS protein, human; C556694:Icos protein, mouse; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D060889:Inducible T-Cell Co-Stimulator Protein; D020123:Sirolimus