The TregTherapeutics tolerogenic approach has been developed over the past fifteen years, primarily using various models of experimental autoimmune encephalopathy (EAE) in laboratory animals.
This work culminated with the discovery that when a tolerogenic cytokine is linked with a neuro-antigen, derived from the protein targeted in the pathogenic response, it is possible to elicit a tolerogenic cascade that results is restored autoimmunity. This research is consistent with known tolerogenic principles, and based on the diversity of experimental models and designs, is extremely compelling. A humanized version of the vaccine offers hope for a similar response in humans with multiple sclerosis.
Mechanism of Action:
The target for the TregTherapeutics tolerogenic vaccine is an antigen presenting cell (APC) located in the peripheral tissues; specifically, it targets an APC known as the dendritic cell (DC). The vaccine causes this DC to play a fundamental role in inducing sustainable self-tolerance. The underlying principle is that the cytokine domain of the vaccine will interact with cytokine receptors on the DC. As a result, this DC is now a tolerogenic DC that will induce a regulatory phenotype downstream. Concurrently, the vaccine-linked neuro-antigen domain is phagocytosed by the DC and undergoes processing to provide epitopes that are presented on the DC’s surface MHC class II molecules. The activated DC migrates to the draining lymph node where it comes into contact with the body’s repertoire of antigen-specific naïve CD4 T cells. Once the DC locates its cognate T cell receptor (TCR) that T cell becomes polarized to express a tolerogenic Treg phenotype marked by FOXP3. This clone is expanded to dominate the immune response to this specific neuroantigen and to other similar epitopes. This latter point, concerning other epitopes, is due to infectious tolerance, the response that is elicited by the vaccine to epitope spreading.
To summarize, there are several expected outcomes from the vaccine:
- Pathogenic effector T cells are eliminated via anergy and apoptosis.
- Regulatory T (Treg) cells are clonally expanded and stimulated to down-regulate the immunologic response, and
- Long-term antigen-specific memory is developed to prevent the disease in the future.
Foundationally, the science is compelling and the experimental design is systematic and elegant, building the case, accumulating the evidence, creating clear and imperative conclusions. The research string encompasses a series of discoveries, derived from experiments with various murine EAE models, which progress logically and methodically. The outcome in animals is striking – restoration with no signs of disease. The implications for treating multiple sclerosis, as well as other autoimmune conditions, in humans are equally as profound.