Re-educating T cells for combat

C&I Issue 3, 2017

Researchers have restored the power of movement to paralysed mice, they reported at the ACS meeting in San Francisco in April – by re-educating wayward immune cells to stop attacking the protective sheath that insulates nerve cells in the brain. The approach may one day help to combat MS and other autoimmune diseases such as Type 1 diabetes.

Autoimmune diseases occur when our immune system mistakenly recognises antigens on the surface of our own body’s cells as foreign. This results in development of inflammatory T cells that attack these self-cells. In the case of MS, for example, T cells are malfunction and attack the myelin sheath surrounding neurons in the brain.

Christopher Jewell and coworkers at the University of Maryland set out to intercept this process in the lymph nodes, where suspect antigens are deposited after being detected by other roving immune cells in the bloodstream. By injecting an ‘immune system modifying agent’ directly into the lymph nodes of paralysed mice exhibiting a mouse model of MS, they were able to reprogramme the environment in the nodes to generate regulatory T cells that migrated to the brain to stop the attack.

‘The T cells that learn not to attack myelin are able to inactivate inflammatory cells and secrete anti-inflammatory molecules,’ said Jewell. ‘In our disease reversal/paralysis studies, 75% of mice exhibit complete or near-complete recovery [including the ability to walk again], while the majority of the other 25% improve.’

A single injection sustained these effects for several months, the duration of the study, ‘which is a long time for mice that only live one to two years,’ Jewell said; ‘However, humans are a much more complicated.’

To make the immune modifying agent, the researchers combined molecules of myelin antigen along with different immunosuppressant drugs, such as rapamycin, and loaded them onto an FDA-approved polymer carrier, poly(lactide)-co-glycolide).

Two mechanisms are believed to account for the resulting effects, Jewell explained. ‘One is a change in how the myelin is processed by the immune system when in the polymer depots we designed, and the second is the effects of the rapamycin. Together, these effects help push developing T cells – which are already specific for myelin – away from inflammatory functions that drive disease and towards regulatory functions that control disease.’

Targeting the lymph nodes could offer a more specific and safer approach to conventional immunotherapies. ‘What is novel is that we are combining the components with degradable polymer particles and injecting these directly in to the lymph node,’ Jewell explained. ‘We are not exposing the entire patient to the strong immunosuppressive agents typical of existing therapies, just the lymph node where the cells differentiate.’

The researchers have been testing the idea in other mouse models, including organ transplant models and models of Type 1 diabetes. Later this year they will begin collaborations with researchers at the University of Maryland Medical School to begin tests in macaque monkeys, a species more closely related to humans.

‘We hope what we work on will eventually contribute to better options for patients with autoimmune diseases or organ transplant recipients,’ Jewell said. ‘However, right now there are many questions that need answered regarding the mechanism of action, how long-lasting the effects are, and if there are side-effects.’

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