Goal -
Develop a system that can "turn off" or at least suppress the body's immune response against a specifiable antigen (or set of antigens). This kind of system could be useful as a therapy for patients with autoimmune diseases, as a method of combating transplant rejection, or as a protective measure when introducing a viral vector or other synthetic biological system into the body.
Current State of the Art -
Current therapies for selective immune suppression involve the use of Treg cells. Tregs found naturally in the body tend to have T Cell Receptors (TCRs) specific to one of many possible self antigens - if they bind to a cell presenting that self antigen, they will suppress the activity of any other T Cells that also bind that cell. By engineering Tregs with TCRs specific to an antigen know to be attacked in a certain autoimmune disease, growing them, then reintroducing them into the patient's body, the autoimmune response can be suppressed.
Where a Synbio Approach could do Better -
T Cell Receptors a really specific - each TCR can generally only bind one antigen (although there are multiple ways to make a TCR that binds a given antigen) - and the antigens themselves are very small fragments of foreign peptides which have been broken down by the proteosome. If you aren't sure exactly what antigens may be displayed and acted against when your system is entered into the body, it is difficult to engineer Tregs with appropriate TCRs for the task. Furthermore, it would be nice to have a system that does not require re engineering at the genetic level each time it is to be used to suppress activity against a different antigen.
Engineering antigen presenting cells (APCs) to express Treg-like suppressive behavior when their MHCs are bound could address those goals. Since certain kinds of APCs (eg. dendritic cells) are phagocytes - we could engineer a system in which we simply grow our APCs in the presence of whatever it is that we want the immune system to not attack, then introduce them into the body to suppress that particular immune response. In theory, the APCs would take in proteins from the thing we are trying to protect from the immune system, break them down and display them on their surface bound to MHC - allowing us to determine their specificity at a protein rather than genetic level, and abstracting away from specific antigens. We would also need to engineer the cytoplasmic domain of MHC (normally just an anchor domain) to somehow signal the release of whatever proteins/other chemicals Tregs normally release when they are bound - something similar to the Tango System may work. Aside from that, we would want to have the ability to regulate the APC's ability to produce MHC. If we plan to use the binding of MHC as a signal to start repressing the immune system, we don't want our cells to get infected while in the body then present the corresponding antigens and tell the body to ignore them. To accomplish this, we could introduce microRNAs to knock down production of MHC, and have them regulated by a repressible promoter whose repressor is controlled by an inducible promoter - that way MHC is only produced in the presence of the inducer.
Questions For Next Time -