Blockade of the CD28 and CD40 pathways result in the acceptance of pig and rat islet xenografts but not rat cardiac grafts in mice

Involvement of CCR5 Signaling in Macrophage Recruitment to Porcine Islet Xenografts

“…We have reported previously that blockade of CD154 in conjunction with CTLA4-Fc treatment led to long term pancreatic islet xenograft acceptance and tolerance (19,36), confirming the importance of the CD40/CD40L pathway in islet xenograft rejection. To test the importance of this pathway in the macrophage-mediated effector response, macrophages from rejecting xenografts from CD40 Ϫ/Ϫ recipients were used in our adoptive transfer model.…”

“…Furthermore, blockade of the CD40-CD154 pathway results in the indefinite survival of pig islet xenografts. Interestingly, these long surviving grafts have an extensive lymphocyte infiltrate predominantly of T and B cells and are largely devoid of macrophages (19). Given the unique importance of macrophages in cell mediated xenograft rejection understanding the mechanism for their recruitment to and destruction of xenografts is important and has implications for other forms of inflammation.…”

Autoimmune Diabetes and Resistance to Xenograft Transplantation Tolerance in NOD Mice

“…We have previously shown that treatment of chemically diabetic C57BL/6 mice with DST and anti-CD154 mAb leads to prolonged survival of rat islet and skin xenografts (17,18) and xenogeneic neonatal porcine islet cell clusters (19). Similarly, anti-CD45RB mAb (20), anti-CD4 mAb (21), or coadministration of CTLA4-Fc and anti-CD154 mAb (22,23) leads to prolonged islet xenograft survival in mice. Islet xenograft tolerance has also been reported in monkeys given anti-CD3 immunotoxin, cyclosporine, and steroids (24).…”

Anti-LFA-1 Improves Pig Islet Xenograft Function in Diabetic Mice When Long-Term Acceptance Is Induced by CTLA4Ig/Anti-CD40L

“…These recipients became normoglycemic and produced pig C-peptide up to 6 months after transplantation. Previous experiments in mice receiving fetal pig islets after a short course treatment with CTLA4Ig/anti-CD40L demonstrated long-term histological survival of islets; however, islet function was never explored (3). More recently, various combinations of blocking reagents, including CTLA4Ig/anti-CD40L (4), CTLA4Ig/ anti-inducible costimulator (ICOS) antibody (5,6), or anti-CD40L/anti-LFA-1 antibody treatment (7,8), prolonged survival of allogeneic or neonatal xenogeneic islet grafts in mice.…”