Ex vivo coating of islet cell allografts with murine CTLA4/Fc promotes graft tolerance.
To test the hypothesis that blockade of B7-triggered costimulation by donor cells could preclude allograft rejection, we coated crude islet allograft preparations in vitro for 1 h with a murine CTLA4/Fc fusion protein. Murine CTLA4/Fc blocks the proliferative response in primary mixed lymphocyte cultures (MLC) and Con A-stimulated murine spleen cell cultures by 85 to 95%. Responder cells from a primary MLC containing mCTLA4/Fc were hyporesponsive upon restimulation to the same stimulator cells in a secondary MLC lacking mCTLA4/Fc. Because of mutations in the Fc gamma RI and C'1q binding sites of the Fc portion of the murine CTLA4/Fc fusion protein, the molecule binds to, but does not target, cells for Ab-dependent cellular cytotoxicity or complement-directed cytolysis. Although systemic immunosuppression was not applied, 42% (10 of 24) of B6AF1 recipients of islet allografts pretreated with CTLA4/Fc were permanently engrafted. Further, 50% of hosts bearing functioning islet allografts more than 150 days post-transplant were formally proved to be tolerant to donor tissues. A persistent CD4+ and CD8+ T cell infiltrate surrounding, but not invading, islet grafts in tolerant hosts was discerned. In control experiments, 89% (8 of 9) of islet allografts coated with mIgG3, and 100% (n = 10) pretreated with media alone were rejected. Thus, we conclude that 1) B7-triggered costimulation by donor APCs is an important element of rejection, and 2) blockade of the B7 pathway by in vitro allograft manipulation is able to induce tolerance.
Steurer
W
W
Harvard Medical School, Department of Medicine, Boston, MA, USA.
Nickerson
P W
PW
Steele
A W
AW
Steiger
J
J
Zheng
X X
XX
Strom
T B
TB
D000069594:Abatacept; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000494:pharmacology*; D018122:B7-1 Antigen / Q000502:physiology; D018106:CD28 Antigens / Q000276:immunology; D016466:CHO Cells; D060908:CTLA-4 Antigen; D002460:Cell Line; D003208:Concanavalin A / Q000494:pharmacology; D006224:Cricetinae; D006082:Graft Enhancement, Immunologic; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D007108:Immune Tolerance; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000494:pharmacology*; D016381:Islets of Langerhans Transplantation; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016297:Mutagenesis, Site-Directed; D017452:Receptors, IgG / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D003208:Concanavalin A; D000069594:Abatacept