 Technology 
Beyond the mechanism of central tolerance that takes place in the thymus, peripheral tolerance appears to be a crucial component of the immune system to recognize as non harmful a vast array of antigen species such as self-antigens and environmental (ingested, inhaled, contact and bacterial flora derived) antigens.
Three main mechanisms of peripheral tolerance are described in the literature; clonal deletion, anergy induction in responsive T cells and active immune suppression mediated by regulatory cells (Treg cells). Tr1 cells and natural CD4+CD25+ Treg cells are the most described Treg populations known as regulating inflammatory responses.
Tr1 cell discovery
Tr1 cells were firstly described in 1997 by the team of MG. Roncarolo at DNAX, Palo Alto. Naïve CD4+ T cells were stimulated during four weeks with their specific antigen in the presence of Interleukin-10 (IL-10).
In 2003, the first demonstration of the curative activity of Tr1 cells in inflammatory diseases was obtained in an experimental colitis model. Tr1 cells mechanism of action
One singular property of Tr1 cells resides in their highly specific tropism for inflamed tissues. When administered in animals displaying inflammation, Tr1 cells homed within 24 hours in the lesional sites.
If the specific antigen is locally present, its presentation to the Tr1 lymphocytes by antigen presenting cells induces Tr1 cell activation and the secretion of immunosuppressive cytokines. These cytokines, in turn, dampen the inflammatory process by an action directed on both bystander activated effector T cells and antigen presenting cells. Importantly, recent research data at TxCell suggest that Tr1 cells may also bear membrane bound suppressive molecules that could also have an inhibitory effect on activated T cells by a cell contact dependent mechanism. 1. Specific migration of Tr1 cells within inflamed tissues after intravenous administration.
2. Activation of Tr1 cell by the specific antigen presented by dendritic cells within the inflamed tissue.
3. Release of anti-inflammatory cytokines IL-10 and TGF-beta.
4. Inhibition of chronic inflammation by the bystander action of cytokines on effector T cells and antigen presenting cells.
Potential key advantages of Tr1 cell therapy
Firstly, TxCell’s proposed treatment is inflammation and tissue-targeted and thus the risk of systemic suppression or activation of Tr1 cells in other parts of the organisms than in the inflammatory targeted tissue is lowered.
In consequence, Tr1 cell administration allows a local delivery of high concentrations of natural highly potent immunosuppressive agents that have shown in early studies low potential of action and high risks of adverse events when administered systemically.
Tr1 cell treatment will reflect a more physiologic mechanism of action against inflammation compared to pharmaceutical compounds due to a more physiologic migration, activation and effector functions.
Importantly, Tr1 cells activity will dampen the inflammatory immune response and re-equilibrate the tissue microenvironment in a tolerogenic state, leading to a restoration of the tissue homeostasis.
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