A new, two-pronged strategy to specifically weaken immune responses that target transplanted tissue has shown promise in controlled experiments on mice, according to UC San Francisco researchers who developed the approach.
The study, led by Diabetes Center member Qizhi Tang, PhD, involved using cells from donors to activate immune cells called donor-reactive effector T cells. The researchers then gave the mice a drug called cyclophosphamide, known to specifically kill activated cells.
The researchers said they hope that using this novel treatment strategy at the time of transplantation surgery could spare patients from lifelong immunosuppressive treatments and their side effects. The approach might also be used to treat autoimmune diseases such as type 1 diabetes, the researchers said. The study is published in a recent issue of American Journal of Transplantation.
The study was conducted in mouse studies of islet-cell transplantation— a procedure used to restore insulin secretion and control over glucose levels in the blood in patients with life-threatening diabetes. The treatment allowed more than 70% of mice to accept transplants without requiring any long-term treatment with immunosuppressive drugs.
Up to 80% of the donor-reactive effector T cells were eliminated by this treatment. However, that procedure alone did not prolong survival of transplanted tissue, the researchers said. That required a second step: Some of the mice also received cell therapy—an expanded population of cells called TREGs that quell immune activity. Seventy percent to 80% of these mice accepted the transplants, without requiring any long-term immunosuppressive drugs.
Significantly, when the cell therapy was used only in those cells that specifically target donor tissue, only one-fifth as many cells were needed to prevent transplant rejection, the UCSF researchers found. The bigger bang per cell may bode well for clinical protocols, Tang suggested.
The idea that such a two-pronged approach might work in humans came from the unanticipated outcome of an islet-transplantation clinical trial at UCSF Medical Center, in which a new drug regimen killed effector T cells, allowing another type of immune cell, the TREGs, to quiet the rejection response, according to the researchers. One patient in that study now has functioning islets and has been free from immunosuppressive therapy for more than one year.
Controlled clinical trials to evaluate a similar approach for liver and kidney transplantation are in the planning stage, according to Tang, an associate professor of surgery and the head of the Transplantation Research Laboratory at UCSF. “The clinical trial design incorporates what we found in the mouse islet transplant model,” she said.