Technology Platform

AUTOIMMUNE DISEASE

The immune system comprises a shield to protect us, but under certain conditions it can attack the very cells it is meant to protect. This can lead to a variety of autoimmune diseases.

There are in excess of a hundred known autoimmune diseases affecting every organ and organ system of the body. The immune system is responsible for providing the essential function of protecting the human organism from invasion of pathogens. The biological world is a harsh environment, and without the immune system, we would not be able to survive. The immune system functions to recognize antigenic elements in its environment and to mount an appropriate response to those elements. The mechanisms involved are complex, interactive, redundant, and normally highly effective. Even so, there are issues. People do get sick from pathogens that slip through the intense surveillance systems mounted by the immune system. In addition, the immune system can erroneously interpret a completely benign tissue or other physiologic component as dangerous, and then mount an attack upon that substance. That circumstance is known as an autoimmune disease. Typically, the immune cells undergo an educational process to condition the cells for appropriate responses to stimuli, but in autoimmune disease, this ability becomes compromised. The immune system turns on its own healthy tissues to destroy the fabric of its own existence. The results of this can be devastating. According to the American Autoimmune Related Diseases Association (AARDA) there are over 50 million Americans suffering with some kind of autoimmune disease. CLICK HERE (AARDA) for a list of autoimmune diseases.

TECHNOLOGY OVERVIEW

Vaccine approaches using disease associated antigens have been studied for the past 10-15 years.

Although vaccines do not generate the global immune suppression seen with other DMTs, nor are these approaches associated with accompanying serious side effects of other MS therapies on the market, success with these vaccines has been limited. Examples of previous attempts to induce tolerance are: DNA vaccination of myelin protein, peptide(s) administered in skin patches, altered peptide ligands (APL), autologous myelin¬ reactive T cells, HLA/MOG recombinant constructs, autologous PBMCs or other blood cells or liposomes coupled with myelin¬ peptides, and tolerogenic dendritic cells.

SYNOPSIS OF RESEARCH

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.

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