An article reporting their findings, “Selective IL-2 Responsiveness of Regulatory T Cells through Multiple Intrinsic Mechanisms Supports the Use of Low-Dose IL-2 Therapy in Type 1 Diabetes,” has been published in the journal Diabetes. The journal’s editors judged the article important enough that it was accompanied by a two-page commentary and highlighted in the “In This Issue” section.
“IL-2 is a major regulator of the immune system,” said Thomas R. Malek, Ph.D., Professor and Vice Chair of the Department of Microbiology and Immunology, and one of the authors. “It is an essential molecule for the production and maintenance of regulatory T cells, also known as Tregs, which function as a gatekeeper of the immune system. Impaired Tregs have been linked to many autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis, and there is considerable clinical interest in boosting Tregs in patients with these diseases.”
The use of IL-2 to do so, however, has historically been problematic for researchers.
“That is because of the dual activity of IL-2 to promote immune responses to infectious agents while also suppressing autoreactivity through action on Tregs,” said Malek. “The worry has been that the use of IL-2 to increase suppressive Tregs in autoimmune patients might instead lead to an unwanted increase of the disease-related responses by autoreactive T effector cells.”
The first indication that IL-2 might be used in a way to selectively act on Tregs came from Malek’s lab, where it was shown that low IL-2 signaling effectively worked for Tregs but not T effector cells. Preclinical studies by others then showed that low-dose IL-2 prevented autoimmunity in mice. More recently there have been several small-scale safety trials of low-dose IL-2 in patients with severe unwanted immune responses. So far the results look promising. Tregs increased in the patients, there was no adverse increase in the unwanted immune response, and some patients even showed clinical benefit.
“Although low-dose IL-2 appears promising by selectively boosting Tregs, there still remains the general worry that it has the potential to make autoimmune disease worse,” said Malek. “Defining the exact window of selectivity of IL-2 for human Tregs would solidify the utility of this approach and support clinical testing of low dose IL-2 in many autoimmune diseases. For this reason, we quantified the range by which IL-2 acts on Tregs vs. other cells in the immune system. We did this for both normal subjects and patients with type 1 diabetes to determine whether autoimmunity might disrupt this balance.”
Malek worked in close collaboration with co-author Alberto Pugliese, M.D., professor of medicine, microbiology and immunology, and Head of the Immunogenetics Program at the Diabetes Research Institute, and they found that Tregs responded to 10x lower levels of IL-2 than T effector cells, the cells which promote autoimmunity, when studying initial signaling of IL-2 through its receptor. Moreover, the selectivity increased to over 100-fold when they assessed IL-2-dependent gene activation in these cells.
“This window of selectivity of Tregs to low-dose IL-2 was maintained in patients with type 1 diabetes,” said Malek. “We also collaborated with David Klatzmann at Pierre and Marie Curie University in Paris, who is pioneering the use of low-dose IL-2 therapy in autoimmunity. In those studies, we found that patients with type 1 diabetes who were undergoing a short course of low-dose IL-2 therapy in a safety study had their Tregs maintain selective response to IL-2 after the treatment. In addition, we were able to establish some of the features of Tregs that account for their selective response to low levels of IL-2.”
Malek’s study provides strong support for the use of low-dose IL-2 as a therapy to boost Tregs in patients with type 1 diabetes and other autoimmune diseases.
“Most current therapies use agents that generally suppress the immune system, which inhibits the unwanted autoimmune responses but also generally weakens beneficial responses by the immune system, making the patient more susceptible to infection,” he said. “Many of those agents show other non-specific toxicities, as well. Increasing Tregs with low-dose IL-2 represents an entirely new approach to help patients with autoimmune diseases where normal mechanisms are restored to selectively suppress self-reactive responses.”
The next step is further study by Malek, Pugliese and colleagues at the Diabetes Research Institute.
“We are planning a low-dose IL-2 trial in patients with established type 1 diabetes,” Malek said. “We are further working to understand the mechanism in Tregs that allows selective responses to IL-2. We also want to determine whether there are individuals whose Tregs might be classified as high and low responders to low-dose IL-2, as this information may help to refine and improve this therapy.”
Additional Miller School authors are Aixin Yu, M.D., Assistant Scientist in the Department of Microbiology and Immunology, Isaac Snowhite, Ph.D., Associate Scientist at the Diabetes Research Institute, and Francesco Vendrame, M.D., Ph.D., Scientist at the Diabetes Research Institute.
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