image: These are serial images of mouse eyes transplanted with islets from mismatched (allogeneic) donors showing long-term graft survival only in recipients that were treated transiently with anti-CD40L (CD154) monoclonal antibody around transplantation (peri-transplant). Note that the last treatment was given on day 7 after transplant (POD7). view more
Credit: Diabetes Research Institute, University of Miami
It is said that the eyes are the window to the soul, but they may also open the door for discovering new ways to achieve immune tolerance to transplanted islets in type 1 diabetes, according to research from the Diabetes Research Institute (DRI) at the University of Miami Miller School of Medicine. The findings, which were published online on January 31st in Diabetologia, the journal of the European Association for the Study of Diabetes (EASD), show that islets transplanted in the eye can survive and function long-term without continuous immunosuppression, and, moreover, that initial islet transplants within the eye of the recipient may lead to long-term peripheral immune tolerance in other transplant sites. The study was conducted in experimental and preclinical (non-human) models of diabetes.
In type 1 diabetes (T1D), the insulin-producing islets cells of the pancreas have been mistakenly destroyed by the immune system, requiring patients to manage their blood sugar levels through a daily regimen of insulin therapy. Islet transplantation has restored natural insulin production in people with type 1 diabetes, as DRI scientists have published. However, patients who receive islet transplants require life-long immunosuppression to prevent rejection of the donor cells. Not only does extended use of anti-rejection drugs pose serious side effects, but the immune attack against the transplanted islets can still occur despite the use of these agents. DRI scientists have been investigating ways to reduce or eliminate the need for anti-rejection therapy, one of the major research challenges which stands in the way of a biological cure for T1D.
Using a previously established approach that they pioneered, Midhat Abdulreda, Ph.D., DRI assistant professor of surgery, and Per-Olof Berggren, Ph.D., Mary Lou Held Visiting Scientist and adjunct professor of surgery at the DRI, and director of the Rolf Luft Research Center for Diabetes and Endocrinology at the Karolinska Institutet in Stockholm, Sweden, transplanted islets within the anterior chamber of the eye of the experimental and preclinical recipients. Another group received islets implanted in the kidney. Both groups were transiently treated with anti-CD154/CD40L blocking antibody around the transplant period. The antibody prevents the interaction between certain molecules (CD40-CD40L) on the surface of immune system cells that play a key role in transplant rejection. DRI researchers have been specifically focused on this immune pathway because it is particularly promising for islet transplantation.
After performing the initial transplants and administering the antibody treatment, the team then went on to transplant additional islets within the kidney of the experimental group of recipients to evaluate any potential effect on immune tolerance in a site elsewhere in the body.
In both recipient groups - those receiving an initial islet transplant in either the eye or the kidney along with the short-term treatment with the anti-CD154 antibody - results showed immunosuppression-free islet survival for more than 300 days. Notably, of the group that initially received islet transplants in the eye, more than 70 percent exhibited survival of the second islet transplant in the kidney for more than 400 days without continued immunosuppression, compared to 30 percent of the recipients that initially received islets in their kidney. Additional studies in the preclinical model showed reduced donor-specific immune reactivity in the blood, consistent with induced peripheral immune tolerance.
"The preliminary findings in these study models of diabetes demonstrate the establishment of immune tolerance towards transplanted islets and their long-term protection from immune attack long after stopping anti-rejection therapy. Further testing in human subjects is needed to validate this approach for people living with type 1 diabetes," said Dr. Abdulreda.
"This approach may help to positively impact the success of islet transplantation for future treatment of diabetes," according to Dr. Berggren.
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About the Diabetes Research Institute
The Diabetes Research Institute at the University of Miami Miller School of Medicine leads the world in cure-focused research. As one of the largest and most comprehensive research centers dedicated to curing diabetes, the DRI is aggressively working to develop a biological cure by restoring natural insulin production and normalizing blood sugar levels without imposing other risks. Researchers have already shown that transplanted islet cells allow patients to live without the need for insulin therapy. Some study participants have maintained insulin independence for more than 10 years. The DRI is now building upon these promising outcomes through its BioHub strategy, a multidisciplinary, three-pronged approach for addressing the major challenges that stand in the way of a cure: eliminate the need for anti-rejection drugs, reset the immune system to block autoimmunity, and develop an unlimited supply of insulin-producing cells. For more information, please visit
Journal
Diabetologia