Induction of donor-specific tolerance to islet allografts in nonhuman primates

Pancreatic tissue grafting is by far the most physiological therapeutic solution to the insulin deficiency of diabetes. Recent clinical trials have indicated somewhat successful use of nonsteroidal immunosuppressive regimens and a successful nonhuman primate trial using CD154 for costimulation blockade was reported. However, these protocols need to be replaced with safe and efficacious ones in which long-term allotolerance would make these treatments routine in a clinical setting. With the specific objective of testing whether peripheral infusions of stem cells or stem cell fractions in conjunction with islet allografting would induce allograft tolerance, we have established a macaque diabetic model. The macaques were rendered diabetic by streptozotocin and required daily doses of insulin to maintain lower blood glucose levels. The diabetic macaques then received islets and stem cells from unrelated and MHC-mismatched donors without any immunosuppression. In our initial analysis, 5 of 7 macaques that received stem cell infusions at the time of islet allografting have shown allograft survival longer than the group of macaques that received islets without the stem cell infusion. One of these five macaques has been normoglycemic for 10 months, with no exogenous insulin. This macaque received stem cell population enriched for CD34+ cells with depletion of CD18 cells, which have shown low or no allostimulatory potential in mixed lymphocyte cultures. Increased levels in insulin and C-peptide levels were shown in the macaques after islet transplantation.