TIB: Tolerance Inducing Biomaterials for Regulatory T Cells

The Problem

Tissue regeneration following injuries and degenerative processes benefits greatly from the activity of regulatory T cells (T_regs) that help balance the immune system, which senses, regulates, and helps restore tissue environments following injury and in disease. In fact, immune therapies using Tregs have shown first promise in treating a wider variety of diseases. However, they still face limitations due to difficulties in targeting specific tissues with T_regs, keeping T_regs sufficiently active in the longer term.

Our Solution

Wyss researchers have developed TIBs, short for “Tolerance-Inducing Biomaterials,” an injectable biomaterial technology that is able to deliver T_regs to specific tissues and create niches that maintain their pro-regenerative state and functions over extended periods of time. An additional advantage of TIBs is their ability to transform host immune effector cells (T_effs) into Tregs at injury sites, which further enlarges the pool of local T_regs and reduces the risk of unwanted autoimmune activities that T_effs may exhibit in indications beyond tissue regeneration.

Product Journey

Inspired by previously developed injectable immunomaterials developed in Wyss Core Faculty member David Mooney’s group to reprogram dendritic cells (Cancer Vaccine) in cancer patients, a Wyss team led by Mooney and spearheaded by Kwasi Adu-Berchie and Tania To hypothesized that biomaterial scaffolds could also be used to enable or improve tissue regeneration in a variety of diseases. By delivering and regulating T_regs deeper inside tissues and providing the right type and amounts of factors for their stimulation, biomaterial scaffolds could shift the immune system into a pro-regenerative state. This new concept and first promising insights led their “TIB project” to be named to two consecutive classes of Wyss Validation Projects, which provided critical funding. To enable the desired biomaterial capabilities of TIBs, they developed a new gelatin-based hydrogel that is injectable through significantly thinner needles in order to reach deeper into tissues, and that slow-releases optimized doses of the cytokine IL-2, which is known to be indispensable for the survival, engagement, and migration of differentiated T_regs. With other specific small molecules, they were able to show that TIBs can also be used to induce T_regs from naïve to effector/memory T cells, further strengthening their approach.

When injected deep into tissues of mice, TIBs with encapsulated T_regs significantly increased the persistence of regenerative T_reg functions, compared to T_regs that were injected without any biomaterial enhancement. The team found that T_regs could effectively leave the TIB scaffold and populate the nearby tissue environment. T_reg-inducing hydrogels reduced pro-inflammatory macrophage responses and enhanced bone regeneration.

From implant sites, the reprogrammed T_regs also reached nearby lymph nodes where broader immune responses are coordinated and which, via the larger lymphatic system, help feed immune cells back into the blood circulation so they can become available to other parts of the body. This suggested to the team that TIBs could also have utility for fighting autoimmune disorders that affect tissues other than the one they are injected into.

To further validate TIBs for human applications, the Wyss Institute team is collaborating with the group of Wyss Associate Faculty member Georg Duda at Charité – University Medicine Berlin, Germany, using T_regs manufactured at their GMP facility and benchmarking TIBs in preparation for clinical studies. Duda, who is the Vice-Director of the Berlin-Brandenburg Center for Regenerative Therapies (BCRT) and Director of the Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration at Charité, shares with Mooney’s team a deep interest in developing technological innovations that can stimulate the body’s own regenerative powers. To differentiate TIBs from clinical developments around other T_regs therapies, which have focused on treating autoimmune diseases, transplant rejection and inflammatory conditions, the collaboration homes in on musculoskeletal diseases and injuries as a high-value clinical application with unmet clinical needs.