such as organ toxicity, risk of infection, and cancer. Due to the adverse risks associated with immunosuppressive drugs, it became apparent that the ideal strategy would be antigen-specific: a therapy that was able to inhibit the antigen-specific T-cell response, but would still leave the remainder of the immune system intact to defend against infection. These strategies employed the use of soluble peptide tolerance and oral peptide tolerance to great efficacy in experimental settings, however, all have failed to translate into the clinic. One reason for the failure of these strategies is that T-cell mediated organ destruction is now understood to be a complex event involving epitope spreading to multiple tissue-specific antigens and cryptic epitopes. Thus, at any given stage of disease or rejection, the T-cell response is likely to be heterogenic, involving multiple TCR specificities, leading to difficulties in prescribing the antigen, dosing, and timing of administration required to induce tolerance. While antigen-specific tolerance induction is an attractive strategy, it's limited by a lack of knowledge, and because of its stringent requirements, a slightly broader approach is more practical. SCIIT attempts to occupy the middle ground of immuno-therapeutics by avoiding the dangerous side effects of general immunosuppressive therapy, while alleviating the stringent demands of antigen-specific tolerance induction. SCIIT aims to achieve this by targeting receptor-ligand interactions that provide signals that are critical for the survival, activation, and function of T-cells in the periphery. T-Cell Receptor Targeting T-cell receptor stimulation is the primary signal required for the activation and differentiation of T-cells. Recognition of specific antigen through the interaction of the TCR with its cognate antigen/MHC complex leads to a cascade of effects ultimately leading to T cell-mediated immunity. It is with good reason that some of the most promising tolerance inducing therapies have targeted the TCR and its co-receptors. αCD3 antibody treatment The most promising therapy to make use of targeting the T-cell through its receptor is the class of monoclonal antibodies specific for CD3. The CD3 chains compose the signaling arm of the TCR, translating the strength of binding affinity of the TCR/peptide-MHC complex to downstream cytoplasmic signals. Initial studies involving αCD3 as a therapy used Fc receptor(FCR)-binding monoclonal antibodies, which proved to be very efficacious. A short, 5-day course of FcR-binding, anti-CD3 antibody treatment was able to re-establish peripheral tolerance in animal models of autoimmune disease, thereby completely reversing disease. The mechanism of action caused systemic depletion of