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Dr. Gary Levy, a liver specialist in UHN’s Multi-Organ Transplant Program, has for more than 20 years been working on tolerance, or donor organ acceptance by the recipient’s body without the need for long-term immunosuppression drugs. (Photo: UHN)

More than $200,000 has been awarded jointly to UHN and The Ottawa Hospital by the Stem Cell Network for a clinical trial to reboot the immune systems of liver transplant patients, with the aim of eliminating the need for life-long immunosuppressive drugs.

If successful, the research could demonstrate that stem cells isolated from the transplant patient's own   blood could "re-educate" the recipient's immune system to accept the transplanted organ as part of self rather than nonself or foreign. When the immune system recognizes something as foreign, it activates an immune response and attacks the organ as a foreign invader.

Although necessary and successful, the need for long-term immunosuppressive therapy to prevent rejection results in major side effects such as kidney failure and cardiovascular disease, limiting the effectiveness of liver transplantation, explained Dr. Gary Levy, a liver specialist in UHN's Multi-Organ Transplant Program. Immunosuppressive drugs do not fully protect patients against the risk of rejection or developing recurrent disease in the transplanted organ.

Dr. Levy, who is also a Senior Scientist in the Toronto General Research Institute (TGRI), has been working on tolerance, or graft (donor organ) acceptance without the need for long-term immunosuppression drugs for more than 20  years, advancing our understanding  of the immunology of rejection and the development of transplant tolerance.

Help patients lead healthy and normal lives

"We want to develop a therapy that will help patients tolerate their new donor organ, stop any acute or chronic rejection, and also still be able to respond to infections," Dr. Levy says. "In other words, we want to help patients with transplants lead healthy and normal lives."

International competition to create "tolerance" of donor organs or freedom from immunosuppression drugs for transplant patients is a challenge that has attracted researchers from Harvard, Northwestern University and Stanford.  However, despite a decade of work using suitable donor stem cells, less than 100 patients have been treated and results have been mixed.

In a 2016 clinical trial led by Dr. Harold Atkins and Dr. Mark Freedman of The Ottawa Hospital and the University of Ottawa, published in The Lancet, the researchers showed that a procedure that eradicates the immune system and then regenerates a new one by using a patient's own blood stems cells eliminated brain inflammation in 24 patients with early, aggressive multiple sclerosis.

This trial evaluated a treatment called immunoablation and autologous hematopoietic stem cell transplantation which reboots the patients' immune system before it turns against their own bodies. This treatment is similar to one used for treating leukemia patients.  

Stem cells stored for future use

In this procedure, stem cells are first stimulated by medication to migrate from the bone marrow into the blood stream. Once there, a cell separator collects the stem cells from the blood, and they are then purified, frozen and stored for future use.

Chemotherapy drugs are then used to obliterate the patient's diseased immune system. The patient's stored stem cells are infused back into his or her body where they travel through the blood stream to the bone marrow, building a new immune system without any memory of attacking the patient's nervous system.

Drs. Levy and Atkins are planning to use this same procedure on patients who have had a liver transplant, and who have developed recurrent liver disease, uncontrolled rejection of the new donor organ, or who have a high risk of developing serious medical complications from immune suppression. If left uncontrolled, the accumulating damage would require a second liver transplant.

The clinical trial on 10 liver transplant patients is registered on the public clinical trials site of the U.S. National Institutes of Health.

Three post-liver transplant patients have already undergone the stem cell procedure. It's hoped the trial will complete treatment of all 10 patients by the end of 2017.

Patients will be monitored for two years, and evaluated on survival, recurrence of their liver disease and how this treatment might work.  

Future research will expand this to kidney, heart and lung transplant patients and will also test this procedure on patients with autoimmune liver diseases, potentially preventing endstage organ damage and the need for a liver transplant.

The work of the Stem Cell Network has been supported by the Government of Canada, enabling the translation of stem cell research into clinical applications and public policy. Recent funding of $9 million for 31 projects across Canada will enable research to move from lab bench to bedside in areas such as brain injury, liver and kidney disease and breast cancer.

The Ottawa Hospital media release on using blood stem cells to treat early and aggressive multiple sclerosis: Media release

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