IL-33 Vesicle-Activated Regulatory T Cells: A Reparative Cell Therapy for Inflammation, Tissue Injury and Graft Rejection

This invention is a cell therapy in which a patient’s regulatory T cells are expanded outside the body and activated by co-culture with IL-33-bearing matrix-bound vesicles, so that they produce the reparative cytokine IL-13. The activated cells can be delivered to patients with injury or inflammatory conditions, including graft rejection, systemic inflammatory response and myocardial infarction, to reduce inflammation and support tissue repair.

Description

Unmet Need - Regulatory T cell therapies depend on scarce reparative cell subsets and have shown limited clinical impact, whereas this approach produces large numbers of IL-13-secreting, repair-oriented Tregs for use in inflammatory and injury settings.

Regulatory T cells are immune cells that restrain excessive inflammation. A rare subset carries the IL-33 receptor ST2 and secretes IL-13. IL-13 directs macrophages toward a repair-promoting state rather than a pro-inflammatory one. This subset is hard to obtain in meaningful numbers from the body.

The invention addresses this by co-culturing Treg cells outside the body with IL-33-containing matrix-bound vesicles. These are nano-sized, lipid-enclosed particles that come from the extracellular matrix. The co-culture activates the Tregs to produce IL-13. The activated cells are then given parenterally to the patient, and options include local delivery, intravenous delivery, or intraperitoneal delivery. The cells can be taken from the patient (autologous), and the vesicles can come from the patient’s own species, a donor, or another species.

Applications

- Cell therapy to reduce rejection and inflammation after solid organ or tissue transplantation, including perfusion of the graft with the cells
- Treatment of ischemic injury, such as myocardial infarction
- Treatment of systemic inflammatory response syndrome, including infection-driven hyperinflammation such as SARS-CoV-2 infection
- Reparative therapy for tissue injury and fibrosis in organs such as the heart, lung and skeletal muscle
- Manufacturing platform and kits for expanding patient-specific, IL-13-producing Treg products

Advantages

- Activates Tregs to produce IL-13, a cytokine linked to reparative macrophage function and reduced inflammation
- Activation by ex vivo co-culture before administration, so the cells are conditioned before they reach the patient
- Autologous Tregs can be used, which supports a patient-specific therapy
- Flexible delivery, including local, intravenous and intraperitoneal routes
- Applicable across several conditions, including graft rejection, systemic inflammatory response syndrome, and myocardial infarction

Invention Readiness

The technology is at an early proof-of-concept stage. Human Treg expansion and activation with IL-33 in co-culture with dendritic cells or artificial antigen-presenting cells has been demonstrated in vitro. The data show higher cell yields, higher IL-13 secretion, and a higher fraction of IL-13-positive Foxp3-positive Tregs. In mouse models, IL-33-bearing vesicles improved graft survival, improved muscle function after injury, and increased the frequency of reparative ST2-positive Tregs during influenza infection.

IP Status

US12,741,026

Related Publication(s)

Hussey, G. S., Dziki, J. L., Lee, Y. C., Bartolacci, J. G., Behun, M., Turnquist, H. R., & Badylak, S. F. (2019). Matrix bound nanovesicle-associated IL-33 activates a pro-remodeling macrophage phenotype via a non-canonical, ST2-independent pathway. Journal of Immunology and Regenerative Medicine, 3, 26–35. https://doi.org/10.1016/j.regen.2019.01.001

Liu, Q., Dwyer, G. K., Zhao, Y., Li, H., Mathews, L. R., Chakka, A. B., et al. (2019). IL-33-mediated IL-13 secretion by ST2+ Tregs controls inflammation after lung injury. JCI Insight, 4(6). https://doi.org/10.1172/jci.insight.123919