Treating inflammatory or autoimmune disorders in which the immune system overreacts and starts attacking the body can involve shutting down the whole immune system, and this may increase the risk of developing infections or cancer. Scientists at the University of California, San Francisco (UCSF), have now identified a potentially more precise way to dial the immune system down locally, in targeted tissues or transplants, without the need for systemic immunosuppression.
Their approach uses engineered T cells that act as immune “referees” to soothe overactive immune responses, and also mop up inflammatory molecules. The team tested the ability of these synthetic suppressor T cells to protect specific tissues from unwanted chimeric antigen receptor (CAR) T cell cross-reactivity, and also to protect transplants against immune system attack in a mouse model of pancreatic islet transplantation. They suggest their approach could be used to stop the body from rejecting transplanted organs and tissues, including pancreatic islet cells, which are sometimes used to treat type 1 diabetes, so transplant recipients would not need to take harsh immunosuppressant drugs.
“This technology can put the immune system back into balance,” said Wendell Lim, PhD, UCSF professor of cellular and molecular pharmacology. “We see it as a potential platform for tackling all kinds of immune dysfunction.” Lim is co-senior author of the team’s published paper in Science, titled, “Engineering synthetic suppressor T cells that execute locally targeted immunoprotective programs,” in which they concluded, “Synthetic suppressor T cells are a customizable platform to potentially treat autoimmune diseases, organ rejection, and CAR T cell toxicities with spatial precision.”
Many treatments for inflammatory or autoimmune disorders cause systemic immunosuppression, and this can lead to severe and chronic toxicities, the authors noted in their research article summary. “If immunity could be suppressed locally, only in targeted tissues or transplants, this could provide a way to overcome these systemic toxicities to treat diverse inflammatory diseases.” Feasibly, they suggest, this could be achieved by programming cell-based therapies to locally protect tissues from immune attack without requiring systemic immunosuppression.
For their newly reported study, Lim and colleagues were inspired by suppressor T cells, which are the immune system’s natural brakes. They wanted to take advantage of these suppressor cells’ power to temper immune responses, such as inflammation.
However, suppressor cells can’t always stop a dangerous immune response. In type 1 diabetes, for example, the immune system destroys pancreatic islet cells, while these suppressor cells just stand by.
To create a cell-based approach to achieving local immunosuppression the team adapted the suppressor cells’ anti-inflammatory abilities to work in CD4 immune cells. “… we took a reconstitution approach of engineering conventional CD4+ T cells to function as synthetic suppressor cells, allowing us to systematically explore the fundamental requirements for immune suppression,” they wrote. These are the same cells that are used to make cancer-killing CAR T cells. They also gave the cells a molecular sensor to guide them to their target tissue in the body. “To design cells potentially useful for local immune suppression, we engineered conventional CD4+ T cells with synthetic Notch (synNotch) receptors driving antigen-triggered production of anti-inflammatory payloads.”
To test their approach the scientists tailored a batch of immune referees to search for human pancreatic islet cells and then produce TGF-β and CD25, molecules that can muzzle killer T cells. They introduced the engineered referee cells into mice that had received a transplant of human islet cells, modeling the treatment for type 1 diabetes.
The investigators found that these referee cells stopped the killer T cells from attacking the vulnerable islet cells. “Synthetic suppressor T cells also locally protected transplants from cytotoxic T cell rejection in a mouse model of pancreatic islet transplantation, maintaining endocrine activity of the transplants without systemic immunosuppression,” they wrote in their research article summary.
“It would be life-changing for people with type 1 diabetes if they could get new islet cells without needing to take immunosuppressants, and stop having to take insulin every day,” said co-senior author Audrey Parent, PhD, associate professor in the UCSF Diabetes Center.
The team also designed and tested synthetic suppressor cells that protected specific tissues from CAR T cell cross-reaction, without compromising CAR T cell tumor-killing effectiveness. The combined results of their studies, they reported, “…demonstrate the potential of synthetic suppressor T cells as a therapeutic platform treating autoimmunity, preventing transplant rejection, or preventing CAR T cell toxicity.”
Lim envisions a future in which organ transplant patients, or those with autoimmune diseases, receive therapies that only treat the specific regions of the body where the immune system is misbehaving.
This could prevent the significant side effects from general immunosuppressants as well as the infections and cancers that arise when the immune system is disabled completely. The new technology also could be used to finetune CAR T cell therapies for cancer, so these CAR T cells only attack tumors, and not healthy tissue. “This puts so many more options on the table for dealing with some of the biggest challenges in medicine,” said Lim, who directs the UCSF Cell Design Institute. “We hope this can benefit patients in the not-so-distant future.”
In their paper, the team suggested that synthetic suppressor T cells could be tailored to sculpt immune environments in a range of therapeutic applications, and noted that the cells can also be directed to specific organs, such as the brain, using synNotch receptors that recognize a tissue-specific antigen to drive local immune suppression. “In all cases, suppressor T cells could act locally without systemic immune suppression and its associated toxicities,” they stated, also acknowledging that “future studies will need to determine the optimal balance between local suppression and immune privilege in the targeted tissues or transplants.”
