UC San Francisco researchers have recently developed a two-pronged approach to the problem of organ transplantation rejections seen in recipients. The strategy aims to weaken specific immune responses that affect transplanted tissue.
The results in controlled mouse experiments (islet cell transplantation studies) have shown promise so far: 70 percent of the mice did not reject the transplants without using any long-term immunosuppressive treatment.
The goal of the strategy is to spare patients from having to undergo lifelong immunosuppression, along with its side effects. At the same time, the strategy is also geared toward treating Type 1 diabetes and similar autoimmune diseases, according to the researchers.
The approach in the study, led by Diabetes Center member Qizhi Tang, Ph.D., involves the use of donor cells to activate donor-reactive effector T cells. A drug — cyclophosphamide — is then given to kill the activated cells.
This method is not sufficient on its own, though.
A second step is needed: The mice received cell therapy that used TREGs, an expanded cell population, to suppress immune activity. The results revealed 70 to 80 percent of mice did not reject the transplants without long-term immunosuppression.
The researchers found out that only a fifth of the cells were required to prevent rejection. In this light, Tang suggested that a bigger bang per cell may be good news for more advanced clinical protocols.
This two-pronged method may bode well for humans because of an unexpected clinical trial outcome at UCSF Medical Center. Here, a new drug treatment killed effector T cells and allowed TREGs to suppress the rejection response. Today, one patient has functioning islets without the need for (more than one year of) immunosuppression.
Over the years, transplant teams have tested immunosuppressants in close proximity to the time of the surgery to target effector T cells — thus lowering transplant rejection chances. Still, there was expectation that some sort of lifelong immunosuppressant treatment would be necessary.
UCSF researchers discovered in the recent islet transplant study in humans that the drug Efalizumab (by Genentech) did a great job of suppressing the effector T cells. On top of this, it also increased the TREGs significantly. This phenomenon allowed one patient to completely stop immunosuppression treatments. Tang said that this has raised the hopes for preventing organ transplant rejection.
Together with TREG research pioneer Jeffrey Bluestone, Ph.D., and Mary Margaret Clausen, UCSF professor of metabolism and endocrinology, Tang has developed methods for body TREG collection to expand the population in the lab and to return these to the patient.
One phase I clinical trial that evaluates TREGs in Type 1 diabetes treatment has recently finished recruiting patients. Early this year, the follow-up phase II of the trial is set to begin recruitment.
Tang and her colleagues have explored another method of potentially growing human TREGs in the lab, also aimed to protect transplanted tissue, which has been approved by the U.S. Food and Drug Administration. Since liver grafts are more resistant, the study decided to go with liver transplants first.
Currently, the approval for kidney transplant patients is still actively sought. The trials are estimated to begin early in 2015.
