Co-stimulatory molecules in islet xenotransplantation: CTLA4Ig treatment in CD40 ligand-deficient mice.
Previous work has demonstrated that short-term systemic administration of cytotoxic T lymphocyte antigen-4 (CTLA-4) Ig blocks human pancreatic islet xenograft rejection in mice and induces long-term, donor-specific tolerance, whereas studies on pig pancreatic islet rejection in mice have failed to demonstrate a role for CTLA4Ig in preventing rejection. Treatment with anti-CD40 ligand (L) monoclonal antibodies alone is somewhat effective in prolonging the survival of islet xenografts, but ineffective when applied to skin xenografts. However, simultaneous blockade of the CD28 and CD40 co-stimulatory pathways prolongs the survival of pig skin on recipient mice. To evaluate the role of CD28 and CD40 co-stimulatory pathways in pig islet-like cell cluster (ICC) xenograft rejection in mice, CD40L-deficient mice transplanted with fetal porcine ICCs were given posttransplant treatment with human (h) CTLA4Ig or a human IgG1 chimeric mAb (hL6). Xenografts were evaluated 6 or 12 days after transplantation. Fetal porcine ICC xenografts were protected from rejection in hCTLA4Ig-treated CD40L-deficient mice, whereas xenograft rejection persisted in untreated CD40L-deficient mice. Simultaneous blockade of the CD28 and CD40 co-stimulatory pathways is mandatory to inhibit ICC xenograft rejection in the pig-to-mouse model, because the CD28 and CD40 co-stimulatory pathways seem capable of efficiently substituting for one another.
Benda
Birgitta
B
Section of Clinical Immunology, Department of Oncology, Radiology, and Clinical Immunology, The Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.
Ljunggren
Hans-Gustaf
HG
Peach
Robert
R
Sandberg
Jan-Olov
JO
Korsgren
Olle
O
D000069594:Abatacept; D000818:Animals; D018106:CD28 Antigens / Q000187:drug effects / Q000276:immunology; D019013:CD40 Antigens / Q000187:drug effects / Q000276:immunology; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D004195:Disease Models, Animal; D005260:Female; D005333:Fetus; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000379:methods; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D034421:Sus scrofa; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014183:Transplantation, Heterologous / Q000276:immunology* / Q000379:methods
D018106:CD28 Antigens; D019013:CD40 Antigens; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D023201:CD40 Ligand; D000069594:Abatacept