Assessing the Effect of Immunosuppression on Engraftment of Pancreatic Islets

Abstract

Objective In addition to ischemia and immunologic factors, immunosuppressive drugs have been suggested as a possible contributing factor to the loss of functional islets following allogeneic islet cell transplantation. Using our previously described islet-kidney transplantation model in miniature swine, we studied whether an islet toxic triple-drug immunosuppressive regimen (cyclosporine + azathioprine + prednisone) affects the islet engraftment process and thus long-term islet function. Design and Methods Donor animals underwent partial pancreatectomy, autologous islet preparation and injection of these islets under the autologous kidney capsule to prepare an islet-kidney (IK). Experimental animals received daily triple drug immunosuppression during the islet engraftment period. Control animals did not receive any immunosuppression during this period. Four to eight weeks later, these engrafted IK were transplanted across a minor histocompatibility mismatched barrier into pancreatectomized, nephrectomized recipient animals at an islet dose of ~ 4500 islet equivalents (IE)/kg recipient weight. Cyclosporine was administered for 12 days to the recipients to induce tolerance of the IK grafts and the animals were followed long-term. Results Diabetes was corrected by IK transplantation in all pancreatectomized recipients on both the control (n=3) and the experimental (n=4) arms of the study and all animals showed normal glucose regulation over the follow-up period. Intravenous glucose tolerance tests performed at 1, 2, > 3 months post-IK transplant showed essentially equivalent glycemic control in both control and experimental animals. Conclusion In this pre-clinical, in vivo large animal model of islet transplantation, the effect of triple drug immunosuppression on islet function does not negatively affect islet engraftment, as assessed by the long-term function of engrafted islets.

Glycemic Stability Through Islet-After-Kidney Transplantation Using an Alemtuzumab-Based Induction Regimen and Long-Term Triple-Maintenance Immunosuppression

“…These agents have been shown to lead to islet toxicity or impaired engraftment (7)(8)(9)(10). Therefore, refinement of maintenance immunosuppression in islet transplantation is an important strategy to preserve islet function.…”

Magnetoencapsulated human islets xenotransplanted into swine: a comparison of different transplantation sites

“…On the other hand, the kidney subcapsular space has a high local oxygen tension and is well‐vascularized. It has been repeatedly used for transplantation of unencapsulated islets in diabetic rodent , primate and swine models , with successful restoration of normoglycemia using either syngeneic, allogeneic, or xenogeneic islets. In diabetic rodents, 200 syngeneic islets transplanted into the kidney subcapsular space yielded normoglycemia, in contrast to 800 islets for portal vein transplantation .…”

The Influence of Microenvironment on Survival of Intraportal Transplanted Islets

“…During intraportal islet transplantation, isolated islets are exposed to high levels of immunosuppressive drugs, which are detrimental to islet engraftment/survival and long-term function ( 60 ). Previously, the standard protocol of immunosuppression for islet transplantation included a combination of corticosteroids, calcineurin inhibitors (tacrolimus and cyclosporine), and purine analogs (mycophenolate mofetil).…”