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Designing custom cells to improve regenerative medicine

By Betty Zou  •  Sep 9, 2016

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Sunnybrook-led team receives funding for transformative project

A team of researchers led by Sunnybrook Research Institute senior scientist Dr. Juan Carlos Zúñiga-Pflücker is among the first to receive funding through the University of Toronto’s Medicine by Design initiative. Their project, which seeks to overcome some of the most critical barriers associated with stem cell therapies, is one of 20 that will share a $27-million investment over three years.

One of the greatest challenges facing cell-based therapies, including those using stem cells, is the rejection of newly transplanted cells by the recipient’s immune system. Strategies to prevent rejection rely on suppressing the entire immune system, which increases risk of infection and malignancies. Zúñiga-Pflücker, who is also chair of and professor in the department of immunology at U of T, and his team of six researchers from U of T and its affiliated hospitals are working on a three-pronged approach to make the immune system more receptive to transplant-based treatments. These therapies—in which cells, tissues or organs are transplanted into a patient to restore function—are a key pillar of regenerative medicine.

“We are going to use diabetes and the pancreas to demonstrate as proof of principle that we can not only generate an organ, but that we can also create an immune tolerant state that will allow regenerated organs to be accepted and fully functional,” says Zúñiga-Pflücker. He is partnering with Dr. Naoto Hirano, an associate professor in the department of immunology at U of T and senior scientist at the Princess Margaret Cancer Centre (PMCC), to design a T cell that could prevent loss of the insulin-secreting beta islet cells in patients with Type 1 diabetes.

Most cases of Type 1 diabetes are caused by the individual’s own immune system, including T cells, which mistakenly sees its beta islet cells as foreign and destroys them. This autoimmune attack hinders attempts to replace the lost cells with lab-generated beta islet cells. Zúñiga-Pflücker and Hirano are creating a purpose-built T cell that, instead of killing beta islet cells, would subdue the immune response and promote tolerance of islet cells. This work will capitalize on Zúñiga-Pflücker’s expertise in making T cells from stem cells, which will then be modified in a two-step process to recognize beta islet cells and become immunosuppressive.

Complementing this approach is the research of Drs. Tracy McGaha and David Brooks, both associate professors in the department of immunology at U of T and senior scientists at the PMCC, on generating a local, suppressive immune environment. By manipulating a specific set of immune cells, they hope to alter the inflammatory response that typically occurs in patients with Type 1 diabetes to one that enables the production of suppressive T cells.

Tackling the problem of transplanted cells themselves, the third part of the project aims to disguise the foreign cells to help them slip past the immune system undetected. Drs. Andras Nagy and Derek van der Kooy, both professors in the department of molecular genetics at U of T, and Dr. Cristina Nostro, an assistant professor in the department of physiology at U of T and a scientist at the Toronto General Research Institute, are working to create a new type of stem cell by altering its genetic makeup in such a way that it does not elicit an immune response when transplanted into a new host—in effect, cloaking it from the immune system. Cells that can evade immune recognition are more likely to be accepted by the recipient.

If successful, these synergistic strategies could not only stem the loss of beta islet cells in patients with Type I diabetes, but they could also improve the success of transplant-based therapies for patients needing new cells. Further, the new “cloaked” stem cells could serve as a universal source of therapeutic cells for all patients, making these immunotherapies cheaper, faster and easier to access.

The Medicine by Design initiative at U of T brings together more than 90 world-class researchers using the latest technological, experimental and computational approaches to advance regenerative medicine and cell therapy. It received $114 million from the federal government last summer as the first grant awarded under the Canada First Research Excellence Fund. The $27 million funding announcement is the initiative’s first investment in collaborative team projects.