Julia McFarlane Diabetes Research Centre
Area of Research -
The focus of Santamaria’s laboratory has been to understand the immunogenetics and immunopathogenesis of autoimmune disorders, with a particular focus on type 1 diabetes, to try to find targets for therapeutic intervention. Early efforts focused on the relationship between genetic susceptibility and resistance to autoimmunity and T-cell tolerance. This work culminated in the discovery of a new therapeutic platform for the treatment of chronic inflammatory disorders based on nanomedicine. This therapeutic approach triggers the formation of extensive antigen- and disease-specific networks of regulatory T and B-cells that efficiently suppress the progression of several different autoimmune disorders without compromising systemic immunity. Current efforts focus on dissecting the mechanisms that sustain and regulate these regulatory cellular networks, the developmental origin(s) of their cellular components and the molecules that control cell-to-cell communication within the networks. Mice humanized with peripheral blood mononuclear cells from patients are used to select candidate nanomedicines for clinical development. Ultimately, Santamaria’s goal is to bring this new technology to the clinic.
Santamaria P, Boyce-Jacino M, Lindstrom A, Barbosa J, Faras A, Rich S. Class II HLA typing: direct sequencing of DRB, DQB and DQA genes. Hum Immunol, 33: 69-81, 1992.
Santamaria P, Lindstrom AL, Boyce-Jacino MT, Myster SH, Barbosa JJ, Faras AJ, Rich SS. HLA class I sequence-based typing. Hum Immunol, 37: 39-50, 1993.
Verdaguer J, Yoon J-W, Anderson B, Averill N, Utsugi T, Park B-J, Santamaria P. Acceleration of spontaneous diabetes in TCR-b-transgenic NOD mice by beta cell-cytotoxic CD8+ T cells expressing identical endogenous TCR-a chains. J Immunol, 157: 4726-4736, 1996.
Schmidt D, Verdaguer J, Averill N, Santamaria P. A mechanism for the MHC-linked resistance to autoimmunity. J Exp Med, 186: 1059-1075, 1997.
Verdaguer J, Schmidt D, Amrani A, Anderson B, Averill N, Santamaria P. Spontaneous autoimmune diabetes in monoclonal T-cell NOD Mice. J Exp Med, 186: 1663-1676, 1997.
Schmidt D, Amrani A, Verdaguer J, Bou S, Santamaria P. Autoantigen-independent deletion of diabetogenic thymocytes by protective MHC class II molecules. J Immunol, 162:4627-4636, 1999.
Anderson B, Park B-J, Amrani A, Verdaguer J, Bou S, Santamaria P. Prevalent CD8+ T-cell response to a single peptide/Kd complex in autoimmune diabetes. Proc Natl Acad Sci USA, 96: 9311-9316, 1999.
Amrani A, Verdaguer J, Thiessen S, Bou S, Santamaria P. IL-1a IL-1b and IFN-γ mark beta cells for Fas-dependent destruction by diabetogenic CD4+ T-lymphocytes. J Clin Invest, 105: 459-468, 2000.
Amrani A, Verdaguer J, Serra P, Tafuro S, Tan R, Santamaria P. Progression of autoimmune diabetes driven by avidity maturation of a T-cell population. Nature, 406: 739-742, 2000.
Liblau RS, Wong FS, Mars LT, Santamaria P. Autoreactive CD8+ T-cells in organ-specific autoimmunity: emerging targets for therapeutic intervention. Immunity, 17: 1-6, 2002.
Amrani A, Serra P, Yamanouchi J, Han B, Thiessen S, Verdaguer J, Santamaria P. CD154-dependent activation of diabetogenic CD4+ T-cells dissociated from APC activation. Immunity, 16: 719-732, 2002.
Winer S, Tsui H, Lau A, Song A, Li X, Cheung RK, Sampson A, Afifiyan F, Elford A, Jackowski G, Becker DJ, Santamaria P, Ohashi P, Dosch HM. Autoimmune islet destruction in spontaneous type 1 diabetes is not beta-cell exclusive. Nat Med, 9: 198-205, 2003.
Serra P, Amrani A, Han B, Yamanouchi J, Thiessen S, Santamaria, P. RAG-dependent peripheral T cell receptor diversification in CD8+ T-lymphocytes. Proc Natl Acad Sci USA, 99: 15566-15571, 2002.
Trudeau JD, Kelly-Smith C, Verchere B, Finegood DT, Santamaria P, Tan R. Autoreactive T cells in peripheral blood predict development of type 1 diabetes. J Clin Invest, 111: 217-223, 2003.
Lieberman SM, Evans AM, Han B, Takaki T, Vinnitskaya Y, Caldwell JA, Serreze DV, Shabanowitz J, Hunt DF, Nathenson SG, Santamaria P, DiLorenzo T. Identification of the novel beta cell antigen targeted by a prevalent population of pathogenic CD8+ T cells in autoimmune diabetes. Proc Natl Acad Sci USA, 100: 8384-8388, 2003.
Serra P, Amrani A, Yamanouchi J, Han B, Thiessen S, Utsugi T, Verdaguer P, Santamaria P. CD40 ligation releases immature DCs from the control of regulatory CD4+CD25+ T-cells. Immunity, 19: 877-889, 2003.
Yamanouchi J, Verdaguer J, Han B-H, Amrani A, Serra P, Santamaria P. Cross-priming of diabetogenic T-cells dissociated from CTL-induced shedding of beta cell autoantigens. J Immunol, 171: 6900-6909, 2003.
Ogasawara K, Hamerman JA, Ehrlich LR, Bour-Jordan H, Santamaria P, Bluestone JA, Lanier LL. NKG2D blockade prevents autoimmune diabetes in NOD mice. Immunity, 20: 757-767, 2004.
Moore A, Grimm J, Han B, Santamaria P. Tracking the recruitment of diabetogenic CD8+ T-cells to the pancreas in real time. Diabetes 53: 1459-1466, 2004.
Han B, Serra P, Amrani A, Yamanouchi J, Marée AF, Edelstein-Keshet L, Santamaria P. Prevention of diabetes by manipulation of anti-IGRP autoimmunity: high efficiency of a low affinity APL. Nat Med, 11: 645-652, 2005.
Han B, Serra P, Yamanouchi J, Amrani A, Elliott JF, Dickie P, Dilorenzo TP, Santamaria P. Developmental control of CD8+ T-cell avidity maturation in autoimmune diabetes. J Clin Invest, 115: 1879-1887, 2005.
Tang Q, Adams JY, Tooley AJ, Bi M, Fife BT, Serra P, Santamaria P, Locksley RM, Krummel MF, Bluestone JA. Visualizing regulatory T cell control of autoimmune response in non-obese diabetic mice. Nat Immunol, 7: 83-92, 2006.
Razavi R, Chan Y, Afifiyan FN, Liu X-J, Wan X, Yantha J, Tsui H, Tang L, Tsai S, Santamaria P, Driver JP, Serreze D, Salter MW, Dosch H-M. TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes. Cell, 127: 1123-35, 2006.
Walter U, and Santamaria P. CD8+ T-cells in autoimmunity. Curr Opin Immunol, 17: 624-631, 2006.
Yamanouchi J, Rainbow D, Serra P, Howlett S, Hunter K, Garner VE, Gonzalez-Munoz A, Clark J, Veijola R, Cubbon R, Chen SL, Rosa R, Cumiskey AM, Serreze DV, Gregory S, Rogers J, Lyons PA, Healy B, Smink LJ, Todd JA, Peterson LB, Wicker LS, Santamaria P. Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nat Genet, 39: 329-337, 2007.
Lennon GP, Bettini M, Burton AR, Vincent E, Arnold PY, Santamaria P, Vignali DA. T cell islet accumulation in type 1 diabetes is a tightly regulated, cell-autonomous event. Immunity, 31: 643-653, 2009.
Tailor P, Tsai S, Shameli A, Serra P, Wang J, Robbins S, Nagata M, Szymczak-Workman A-L, Vignali DAA, Santamaria P. The proline-rich sequence of CD3epsilon as an amplifier of low-avidity TCR signaling. J Immunol, 181: 243-255, 2008.
Tsai S, Shameli A, Santamaria P. CD8+ T-cells in autoimmune diabetes. Adv Immunol, 100: 79-124, 2008.
Tsai S, Shameli A, Yamanouchi J, Clemente-Casares X, Wang J, Serra P, Yang Y, Medarova Z, Moore A, Santamaria P. Reversal of autoimmunity by boosting memory-like autoregulatory T-cells. Immunity, 32: 568-580, 2010.
Santamaria, P. The long and winding road to understanding and conquering T1D. Immunity, 32: 437-445, 2010.
Wang J, Tsai S, Shameli A, Yamanouchi J, Alkemade G, Santamaria P. In situ recognition of autoantigen as an essential gatekeeper in autoimmune CD8+ T cell inflammation. Proc Natl Acad Sci USA, 107: 9317-22, 2010.
Shameli A, Clemente-Casares X, Wang J, Santamaria P. Development of memory-like autoregulatory CD8+ T cells is CD4+ T cell-dependent. J Immunol, 187: 2859-2866, 2011
Wang J, Tsai S, Tailor P, Santamaria P. Autoantigen recognition is required for recruitment of IGRP206-214-autoreactive CD8+ T-cells but is dispensable for tolerance. J Immunol, 189: 2975-2984, 2012.
Alkemade G, Clementer-Casares X, Yu Z, Xu B-Y, Wang J, Tsai S, Wright J, Roep BO, Santamaria P. Local autoantigen expression as an essential gatekeeper of T-cell recruitment to islet grafts in diabetic mice. Diabetes, 62: 905-911, 2012
Tsai S, Serra-Devecchi P, Clemente-Casares X, Yamanouchi J, Thiessen S, Slattery RM, Elliott JF, Santamaria P. Anti-diabetogenic MHC class II promotes the differentiation of MHC-promiscuous autoreactive T-cells into FoxP3+ Tregs. Proc Natl Acad Sci USA, 110: 3471-3476, 2013.
Tsai S and Santamaria P. MHC class II polymorphisms, autoreactive T-cells, and autoimmunity. Front Immunol, 4: 321-326, 2013.
Wang J, Nanjundappa R, Shameli A, Clemente-Casares X, Yamanouchi J, Elliott J, Slattery R, Serra P, Santamaria P. The cross-priming capacity and direct presentation potential of an autoantigen are separable and inversely related properties. J Immunol, 193: 3296-3307, 2014.
Clemente-Casares X and Santamaria P. Nanomedicines for the treatment of autoimmune disease. Immunol Lett, 158: 167-174, 2014.
Singha S, Shao K, Clemente-Casares X, Tsai S, Yang Y, Santamaria P. Nanoparticle-based immunotherapy for cancer. ACS Nano, 9: 16-30, 2015.
Clemente-Casares X, Blanco J, Ambalavalan P, Singha S, Yamanouchi J, Fandos C, Tsai S, Wang J, Garabatos N, Izquierdo C, Agrawal S, Keough MB, Yong VW, James E, Moore A, Yang Y, Stratmann T, Serra P, Santamaria P. (2015) Expanding antigen-specific regulatory networks to treat autoimmunity. Nature, in press