Stanford Medicine, November 8, 2022
A technique developed at Stanford Medicine allows mice with diabetes to accept unmatched islet cells and durably restore blood sugar control without immunosuppression or graft-versus-host disease.
Mice with diabetes appeared cured of the disease after transplantation of insulin-secreting pancreatic islet cells, according to a Stanford Medicine study. The animals’ immune systems were coaxed to accept the donated cells prior to transplantation through a three-pronged process that could be easily replicated in humans, there searchers said. No immune-suppressing treatments were necessary after the transplant to prevent rejection of the foreign islet cells.
“Clinically, the implications are very promising,” professor of developmental biology Seung Kim, MD, Ph.D., said. “There are many people with diabetes in the world who would benefit from receiving islet cells.”
The problem is that islet transplantation requires chronic immune suppression, most commonly with drugs, to prevent rejection. Methods for resetting and preparing a recipient’s immune system for transplantation have been developed to avoid this, but they typically include high-dose radiation and chemotherapy, which are too toxic for most people with diabetes.
“Our research suggests that it may be possible to use an unrelated donor and avoid the toxic pre-treatment methods that have been required,” Kim said.
Kim, who directs the Stanford Diabetes Research Center and the JDRF Center of Excellence , is the senior author of the study, which was published Nov. 8 in Cell Reports. Lead authors of the research are former postdoctoral scholar Charles Chang, PhD, and graduate student Preksha Bhagchandani.
“The publication of Dr. Kim’s work provides evidence toward a pathway to promote tolerance to transplanted is lets without systemic immune suppression,” said Esther Latres, PhD, vice president of research at JDRF, a global funding organization dedicated to ending Type 1 diabetes.
The findings also have implications that reach far beyond diabetes. The technique, which builds on earlier work at Stanford Medicine, may open the door to a new type of organ transplant that doesn’t require an immunologically matched donor or years on immune-suppressing medication.
The dual-transplant approach
The trick is to perform two transplants rather than one. Years ago, researchers from Stanford Medicine including Samuel Strober, MD, professor of immunology and rheumatology, showed that replacing the recipient’s immune system with that of the organ donor — through a process called a blood stem cell transplant — prior to organ transplant ensures that the organ will be viewed as “self” and won’t be rejected by the body. (This is also the treatment for cancers of the blood and immune system, such as leukemia and lymphoma.)
But the high-dose radiation and chemotherapy necessary to kill the recipient’s blood stem cells exacts a heavy, potentially fatal toll, and often leaves patients infertile. It also sets the stage for the new immune system to attack other healthy tissues and organs that it perceives as foreign — a condition known as graft-versus-host disease.
Further studies by Strober and others, including study co-author and professor of medicine Judith Shizuru, MD, PhD, showed it’s possible to hobble, rather than eliminate, the recipient’s immune system before introducing the donor’s stem cells. The result is a hybrid immune system, made up of both donor and recipient stem cells, and a reduced likelihood of graft-versus-host disease. The hybrid or chimeric, immune system is also less likely to reject the transplanted organ, particularly if it is immunologically well-matched. In 2020, Strober and his colleagues showed that most people who received kidney transplants from fully matched siblings were able to stay off immunosuppressive drugs for at least two years.
Until now, the conditioning regimen to accomplish this chimeric immunity was too harsh for use in non-life-threatening situations, and the organs had to be at least partially immunologically matched to avoid the drugs.
In the current study, Kim and his colleagues experimented with a three-pronged approach to prepare diabetic recipients for the stem cell transplant. They combined low-dose radiation, one dose of an antibody that selectively targets and kills blood stem cells (which give rise to immune cells), and another antibody that targets mature immune cells called T cells. They found that was enough to allow the donor cells to establish themselves in the animal’s bone marrow and create a fully functioning, chimeric immune system without the severe side effects seen with other methods. These diabetic animals were then able to accept a transplant of islet cells from the stem cell donor, even if that animal was completely immunologically mismatched.
“We had a notion that we could get the bone marrow ready to accept the donor stem cells with less toxic, alternative approaches,” Kim said. “We found we could reduce the radiation dose by 80% and replace broad-acting chemotherapy drugs with targeted antibodies. The animals rapidly gained back the weight they had lost due to the disease and were able to maintain normal blood glucose levels until the study ended after more than 100 days.”
The mice were no more susceptible to infection than control mice, showing their immune systems were functioning normally, and they could breed and give birth to healthy pups.
“This is exciting for many reasons,” Kim said. “This approach could be applied to autoimmune diabetes, including Type 1 diabetes, and suggests that completely mismatched islet cells could be used for transplant. Beyond diabetes, it has important implications for solid organ transplants.”
One caveat in the study is that the donor stem cells and islet cells must come from the same animal, and human islet cells are difficult to procure. Kim and colleagues in the Stanford Pancreatic Islet Replacement and Immune Tolerance Initiative are investigating whether functional islet cells could be created in the laboratory from pluripotent stem cells, or if a small population of human islet cells can be grown and expanded in the laboratory to make many more transplantable islet cells.
“If we are successful, we could see a future where we can treat people with diabetes at an early age to prevent or mitigate a lifetime of health problems,” Kim said.
The study was funded by the JDRF, the National Institutes of Health (grants R01 DK107507, R01 DK108817, U01DK123743 and P30 DK116074), the Stanford Maternal and Child Health Research Institute, the Stanford Medical Scientist Training Program, the H.L. Snyder Foundation, the Stanford Diabetes Research Center Islet Core, the Reid family, and the Skeff family.
Chang is an employee and stockholder of Jasper Therapeutics, Inc., and study coauthor Judy Shizuru is a co-founder, stockholder and director of the company.
Charles A. Chang, Preksha Bhagchandani, Jessica Poyser, Brenda J. Velasco, Weichen Zhao, Hye-Sook Kwon, Everett Meyer, Judith A. Shizuru, Seung K. Kim. Curative islet and hematopoietic cell transplantation in diabetic mice without toxic bone marrow conditioning. Cell Reports, 2022; 41(6) DOI: 10.1016/j.celrep.2022.111615
Nguồn: Stanford Medicine