Tolerizing Agonist/Immunomodulator Loaded Liposomes for Long-Lived Immune Tolerance
SUMMARY
More selective suppression of disease-related immune responses may reduce reliance on broad immunosuppression; this preclinical approach co-delivers a disease antigen, immunomodulatory drugs, and TLR agonists in liposomes to promote antigen-specific immune tolerance.
The Unmet Need: Broad immunosuppression can suppress protective immunity alongside disease-related responses
- Current broad immunosuppressive approaches may cause side effects and do not selectively target responses to disease-related antigens. This can leave protective immune responses affected while failing to focus treatment on the immune response driving disease.
- Advances in targeted delivery and immunomodulation are creating opportunities to shape immune responses with greater specificity. Combining antigen delivery with signals that guide dendritic-cell behavior reflects a broader move toward precision approaches for autoimmune disease, particularly when the relevant disease antigen is known.
The Proposed Solution: Liposomes co-deliver disease antigen, immunomodulatory drugs, and TLR agonists to promote antigen-specific tolerance
-
The faculty inventor developed a novel approach including a liposome loaded with immunosuppressive drugs, toll-like-receptor (TLR) agonists, and any antigen of interest. The push/pull mechanism combines activating signals that support antigen uptake and presentation with inhibitory drug signals that restrain inflammatory activity and encourage tolerogenic dendritic cells and regulatory T cells.
-
In cell studies, the formulation increased tolerogenic features, including PD-L1 and IL-10, while reducing inflammatory or co-stimulatory markers; TLR agonists also improved dendritic-cell viability and prolonged tolerogenic activity compared with the drug combination alone. In mice, treatment generated antigen-specific Tregs and reduced matching effector T-cell and antibody responses without broadly changing overall T-cell populations. MOG-loaded liposomes limited symptoms in experimental autoimmune encephalomyelitis, including when treatment began after early symptoms, and the combined formulation provided more durable protection than inhibitor-only liposomes.
FIGURE
Tolerogenic Liposomes Prevent EAE Disease Progression via Antigen Specific Bystander Tolerance.
(A) Mice were treated on day 4 and 5 (following EAE induction), allowed to rest for 48 hrs then treated again on day 7 and 8. After final treatment, mice were monitored for 37 days. (B) Mice were treated similarly, but sacrificed on day 14 following EAE induction. Serum was taken and analyzed for EAE peptide specific IgG levels via ELISA. UT denotes an “untreated” mouse without MOG exposure.
ADVANTAGES
ADVANTAGES
-
Antigen-specific immune suppression
-
Preserved overall T-cell populations
-
Reduced matching effector T cells
-
Long-lived immune tolerance
-
Easy manufacturing and storage
APPLICATIONS
- Autoimmune diseases
- Transplant medicine