New method of doing blood stem cell transplantation shows exciting promise in mice for treating a wide variety of diseases

Hope for organ transplantation without a matching donor and one-time treatment/lifetime cure for many blood and immune diseases

February 6, 2019

A series of discoveries by researchers at the Stanford Institute for Stem Cell Biology and Regenerative Medicine (ISCBRM) might radically alter organ transplantation, gene therapy, the treatment of autoimmune diseases and many other blood and immune disorders. This week in the journal Nature Communications, Stanford Assistant Professor of Pediatrics, Agnieszka Czechowicz, MD, PhD, and her colleagues published a pair of papers that demonstrate a new method for safely preparing for blood stem cell transplantation in mice, opening the door for a much wider use of the method.

Blood stem cell transplantation is a powerful procedure that can be used to treat a wide range of diseases. By replacing the cells that produce blood and immune cells in the body with similar healthy cells from a donor, a single blood stem cell transplantation can be used to provide a lifetime cure for virtually any blood and immune disease, including genetic diseases such as sickle cell anemia, beta thalassemia and severe combined immunodeficiency (SCID) as well as autoimmune diseases like lupus, multiple sclerosis, and type-1 diabetes, among others. Such transplants can also be performed using patients’ own genetically engineered blood stem cells, not only making it possible to more safely treat blood and immune disorders without the need for a donor, but also creating a vehicle for the delivery of different secreted proteins to treat diseases that have little connection to the blood.

Currently, however, blood stem cell transplantation is used only for the most severe cancers and other life-threatening conditions. This is because the preparation for the transplantation, when chemotherapy or irradiation are used to kill blood stem cells and make room for the transplanted cells, is dangerous. “Right now, the current chemotherapy and radiation used as part of this procedure causes lasting damage, and leaves people vulnerable to severe toxicities and life-threatening infections,” Czechowicz says. “Just the procedure itself can lead to a mortality rate of 5-40% depending on the disease,” making it too risky for treating many disorders that are serious but not life-threatening.

In work she began at Stanford, continued at Boston Children’s Hospital (BCH)/Dana Farber Cancer Institute, and now brings back to the ISCBRM, Czechowicz looked at using antibodies as a gentler method than chemotherapy for preparing the body for a blood stem cell transplant. In these papers in Nature Communications, she and her colleagues show that attaching a drug to an antibody that selectively binds to blood stem cells is highly effective and selective in killing those cells enabling improved transplantation.

In one of these papers, Czechowicz and her colleagues show that preparing mice in this way was not only gentler than standard methods, but also preserved immune function better, leaving the mice less vulnerable to life-threatening infections. Making blood stem cell transplant safer this way may open up the procedure for treating diseases where it is too dangerous now. Czechowicz was the lead author on this paper together with Rahul Palchaudhuri, PhD, of Harvard University, and BCH’s Derrick Rossi was senior author together with David Scadden, MD of Harvard University. Other Stanford researchers contributing to the research were Amelia Scheck, Wendy Pang, MD, PhD, Yan Yi Chan, Emily Walck, Gerlinde Wernig, MD, and Judith Shizuru, MD, PhD.

In the other paper, Czechowicz and colleagues innovatively combined this type of antibody-drug treatment with a short course of immune suppression and showed this similarly enabled safe and effective transplantation with unmatched blood stem cells regardless of the donor. When a patients’ own immune system is attacking pancreatic cells (in type-1 diabetes) or the cells that insulate nerve cells (in multiple sclerosis) for instance, such an approach may be able to switch out the immune cells and cure these conditions with new blood and immune cells.

We were very surprised to find that the transplant would work even when they were immunologically very far apart, enabling completely mismatched transplants.

Perhaps the most exciting result of this research was that doing a transplant using this method led to a situation in which the mice had safely stabilized both kinds of blood stem cells—their original cells and the transplanted ones. The mice’s immune cells learned to be tolerant to both kinds of cells even if they were very immunologically different. “We decided to see how immunologically different the recipient and donor could be and were very surprised to find that the transplant would work even when they were immunologically very far apart, enabling completely mismatched transplants,” Czechowicz says.  Czechowicz shares lead authorship of this second paper with Zhanzhuo Li, MD, PhD, of the National Institute of Allergy and Infectious Diseases (NIAID). Co-senior authors of the paper are Rossi and the NIAID’s Philip Murphy, MD.

This last discovery could transform how organ transplants are done. Currently, in most situations people who need a new heart or liver, for instance, must wait until a donor with a complimentary tissue type can be found. After transplantation, most patients must now take drugs that fight the body’s natural tendency to reject the transplanted organ. These anti-rejection drugs have toxic side-effects and usually have to be taken for life. Transplant recipients who take these drugs are more likely to get cancer, for instance, because the drugs suppress the immune system and leave them more likely to be infected by cancer-causing viruses.

If organ recipients can safely get a blood stem cell transplant from the organ donor when they get the organ, however, the transplanted stem cells will teach the body to accept the transplanted organ as its own. To test this idea, the researchers performed a blood stem cell transplant in mice conditioned with this new regimen and then also transplanted skin from the same donor. The experiments showed that the skin was accepted, even though it was very different immunologically. The results suggest that other organs would also be well tolerated.

“We are continuing to research the use of antibodies to prepare for blood stem cell transplantation, and the results so far indicate that we are moving toward exciting medical treatments for a number of diseases and disorders,” Czechowicz says. 

Czechowicz has been continuing this work at the Stanford University School of Medicine, where she is an Assistant Professor in the Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine.  She is hopeful to translate this work to the patients she cares for at the Lucile Packard Children’s Hospital Stanford and elsewhere.