Pancreas Islet Allotransplant Maintained with 2 Weeks of Immunosuppression
WESTPORT, CT (Reuters Health) Jun 01 – Researchers have for the first time succeeded in transplanting and maintaining isolated pancreas islet cells into diabetic rhesus monkeys without long-term sustained immunosuppressive therapy, according to a report in the June issue of Diabetes.
Dr. Francis T. Thomas, of the University of Alabama at Birmingham, and colleagues induced diabetes in 11 rhesus macaques with intravenous streptozotocin. Islet cell donors were selected to have multiple donor major histocompatibility complex mismatches with the diabetic recipients.
For immunosuppression, “we used a new drug we developed which wipes out the CD3-epsilon receptor of T cells, including most importantly the T cells in the sessile compartments, such as the lymph nodes and spleen,” Dr. Thomas told Reuters Health. The research team also used 15-deoxyspergualin (DSG) after discovering that it blocks maturation of dendritic cells that present foreign antigens to T cells, Dr. Thomas said.
A 2-week tolerance induction protocol was initiated on the day of transplantation. Three protocols were used, anti-CD3 or DSG, or both. The macaques also received methylprednisolone on days 0 to 2.
Within 3 days after the transplant, the recipients exhibited normal nonfasting blood glucose levels in the absence of exogenous insulin, the investigators report. All seven animals that received the combination tolerance induction protocol maintained prolonged graft survival, four for more than a year. The remaining four macaques failed to become long-term survivors.
None of the recipients exhibited IgG- or IgM-positive flow cytometry antidonor crossmatches, although long-term survivors were immunocompetent with respect to a microbial antigen. Between 6 months and a year after transplantation, peripheral and total T-cell counts recovered to their pretransplant levels.
T-cell amplification was limited, as seen by a lower response to an antigen to which the donor were previously unexposed, Dr. Thomas’ group notes. The investigators also observed “prominent and sustained expression” of interleukin-4 and -10, and normal levels of gamma-interferon. These latter findings indicate upregulation of peripheral T-helper-2 responses, the investigators write. This suggests, they add, that “an immunoregulatory rather than a deletional process underlies this operational tolerance model.”
Dr. Thomas noted that the islet transplantation procedure does not require hospitalization, and can be done in a radiology department using duplex Doppler to image the portal vein, into which the cells are injected. “The patient then gets off the table and goes home,” he added. Dr. Thomas’s group has also demonstrated the potential for using live donors, having achieved successful transplantation of two animals from one donor pancreas.