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By Anne De Groot

Anne De Groot-finalIt begins in the thymus, where T cells are programmed to recognize “self” and “not self”. In the peripheral blood, T cells seek out and destroy infections. How do T cells differentiate “self” versus “pathogen”? They recognize T cell epitopes—short, linear strings of amino acids. Some T cell epitopes activate killer T cells, others activate regulatory T cells (Tregs). Both types of epitopes are now rapidly discovered by cutting edge computer algorithms. Most biologics and vaccine developers are well aware of tools for computational modeling of T cell epitopes, but new tools may be able to discern special patterns that define which sequences are Treg epitopes and which are not.

In 2008, researchers screened thousands of monoclonal antibodies and uncovered highly conserved patterns in the framework regions of immunoglobulin G which appeared to trigger T cell response. Further analysis suggested these sequences were not epitopes for triggering effector T cells, but rather they were epitopes for triggering regulatory T cells. Enter Tregitope (t•rej•i•tope). Tregitopes are peptide sequences that drive regulatory T cell response.

Tregitope-Illustration-2012_Page_5-1024x662The most well-known Tregitope peptides are found in immunoglobulin G. Evidence suggests that Tregitopes cause the stimulation and expansion of regulatory T cells following intravenous immunoglobulin therapy. Tregitope technology has been validated both in vitro and in vivo. It goes without saying that when modifying monoclonal antibody sequences, leaving Tregitopes in place is of paramount importance (FDA Guidelines [PDF]). That is why Tregitopes are important to biologics developers.

Why are Tregitopes important to vaccine developers? Researchers have recently observed Tregitopes contained in pathogens that have co-evolved with humans. “Commensal” viruses (e.g., Epstein Barr) carry significantly more of Tregitopes than “hit and run” viruses (e.g., Ebola, SARS). Tregitopes are different from “attack” epitopes because they contain extensive networks of cross-conservation with human proteins on their T cell receptor face (TCR). Epitopes with less TCR face cross-conservation are associated with autoimmune disease.

The discovery of T cell receptor networks leads to two important questions: (1) Do autologous Tregitopes play a key role in tolerance to self? And, (2) Do epitopes in pathogens with less TCR-face cross-conservation trigger post-infection autoimmune disease? These fundamental questions are critical to developing better solutions for unmet medical needs. This research, Wonderbumin: A Fully Synthetic Alternative to IgT for Autoimmune Disease?, will be presented at the 2015 AAPS National Biotechnology Conference on Tuesday, June 9.

Anne De Groot, M.D., is internationally known for her research on the human immune system’s response to vaccines and biologic therapeutics.