Summary of the probe development effort to identify inhibitors of T-cell receptor (TCR)-CD3 interaction using a TAMRA-labeled TCR probe
Name: Summary of the probe development effort to identify inhibitors of T-cell receptor (TCR)-CD3 interaction using a TAMRA-labeled TCR probe. ..more
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center
Affiliation: The Scripps Research Institute, TSRI
Assay Provider: Luc Teyton, TSRI
Network: Molecular Library Probe Production Centers Network (MLPCN)
Grant Proposal Number: 1 R01 AI095511-01
Grant Proposal PI: Luc Teyton, TSRI
External Assay ID: TCR_INH_SUMMARY
Name: Summary of the probe development effort to identify inhibitors of T-cell receptor (TCR)-CD3 interaction using a TAMRA-labeled TCR probe.
Immunosuppressive drugs are critical for organ transplantation and the control of autoimmunity. The current arsenal of usable drugs is limited to small molecules targeting intracellular signaling pathways, e.g. cyclosporine A (1, 2), or antibodies with poorly known mode of action, e.g. OKT3 (3-5). Both categories are endowed with short and long-term life-threatening side effects (1, 2, 3, 4, 6). In most rejection of transplantation situations and in most autoimmune-mediated diseases, T-cell-mediated immunity dominates the adaptive immune response (7-10). Small compounds have focused on T-cell-specific signaling components; however, expression of most of these switches is not exclusive to T cells, explaining many of the adverse effects (3). The targeting of cell surface receptors involved in trafficking, proliferation, and co-stimulation by antibodies does work (11) but does not provide a tunable system easily usable for the long-term. For the same reasons, the T-cell receptor (TCR) complex itself has only been targeted by polyclonal and monoclonal antibodies in the induction setting of transplantation (3, 4) and in very limited studies of type 1 diabetes (12). Based on this background, we hypothesized that the ideal molecular target for small molecule therapeutics should be the two components of the TCR complex itself, the idiotypic alpha-Beta TCR and the associated CD3 signaling dimers. Indeed, the exclusive expression of TCR by T cells will provide absolute specificity whereas the disruption of CD3 engagement will modulate the very first signaling step in T-cell activation. We have now established that proof of principle. This project has the potential of identifying new classes of immunosuppressive drugs, an important concern in clinical medicine today.
Summary of Probe Development Effort:
This probe development effort is focused on the identification of inhibitors of T-cell receptor (TCR)-CD3 interaction using a TAMRA-labeled TCR probe. All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.
1. Penninga L, Moller CH, Gustafsson F, Steinbruchel DA, Gluud C. Tacrolimus versus cyclosporine as primary immunosuppression after heart transplantation: systematic review with meta-analyses and trial sequential analyses of randomised trials. Eur J Clin Pharmacol. 2010 Dec;66(12):1177-1187.
2. Pillai AA, Levitsky J. Overview of immunosuppression in liver transplantation. World J Gastroenterol. 2009 Sep 14;15(34):4225-4233.
3. Getts DR, Shankar S, Chastain EM, Martin A, Getts MT, Wood K, Miller SD. Current landscape for T-cell targeting in autoimmunity and transplantation. Immunotherapy. 2011 Jul;3(7):853-870.
4. Ippoliti G, Pellegrini C, Nieswandt V. Controversies about induction therapy. Transplant Proc. 2011 Jul-Aug;43(6):2450-2452.
5. Klipa D, Mahmud N, Ahsan N. Antibody immunosuppressive therapy in solid organ transplant: Part II. MAbs. 2010 Nov-Dec;2(6):607-612.
6. Delgado JF, Vaqueriza D, Sanchez V, Escribano P, Ruiz-Cano MJ, Renes E, Gomez-Sanchez MA, Cortina JM, de la Calzada CS. Induction treatment with monoclonal antibodies for heart transplantation. Transplant Rev (Orlando). 2011 Jan;25(1):21-26.
7. Gras S, Kjer-Nielsen L, Chen Z, Rossjohn J, McCluskey J. The structural bases of direct T-cell allorecognition: implications for T-cell-mediated transplant rejection. Immunol Cell Biol. 2011 Mar;89(3):388-395.
8. Sanchez-Fueyo A, Strom TB. Immunologic basis of graft rejection and tolerance following transplantation of liver or other solid organs. Gastroenterology. 2011 Jan;140(1):51-64.
9. Long SA, Buckner JH. CD4+FOXP3+ T regulatory cells in human autoimmunity: more than a numbers game. J Immunol. 2011 Sep 1;187(5):2061-2066.
10. Strioga M, Pasukoniene V, Characiejus D. CD8+ CD28- and CD8+ CD57+ T cells and their role in health and disease. Immunology. 2011 Sep;134(1):17-32.
11. Savinov AY, Burn P. Interference with islet-specific homing of autoreactive T cells: an emerging therapeutic strategy for type 1 diabetes. Drug Discov Today. 2010 Jul;15(13-14):531-539.
12. Savinov AY, Rozanov DV, Strongin AY. Specific inhibition of autoimmune T cell transmigration contributes to beta cell functionality and insulin synthesis in non-obese diabetic (NOD) mice. J Biol Chem. 2007 Nov 2;282(44):32106-32111.
Summary, Summary AID, T-cell receptor, TCR, TCR alpha, cluster of differentiation 3, CD3, CD3 epsilon, TAMRA, fluorescence polarization, inhibitor, inhibition, protein-protein interaction, primary, immunosuppression, immunosuppressive therapy, autoimmunity, organ transplantation, HTS, 1536, Scripps, Scripps Florida, Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN