The Immunobiology of Transplantation
Dr. Platt's research focuses on the immunobiology of transplantation and related fields. The research poses such questions as how does the immune system become activated by foreign cells and how does the activated immune system injure transplants. This research explores the mechanisms by which T cells and B cells recognize allogeneic cells and how the products of the immune system, particularly antibodies, injure tissues and organs. As one example, Dr. Platt investigates how activation of complement modifies the functions of blood vessels to promote coagulation and inflammation via regulation of transcription of IL-1 alpha.
As another example, Dr. Platt investigates how complement and other products of the immune system impart on tissues a resistance to immune-mediated injury, a phenomenon Dr. Platt originally described and named "accommodation." Accommodation may be vital to the survival and function of organ transplants. Accommodation may also be a key component of host defense, allowing effector cells and cytokines to eradicate infectious organisms without causing unwanted destruction of tissue.
Because therapies used to suppress immunity to transplantation and to treat various types of cancer, as well as primary and acquired immunodeficiencies impair the function of or destroy immune cells, Dr. Platt has directed a line of research toward the devising of new approaches to rebuilding immunity. Key questions addressed in this line of research include how diverse repertoires of B cells and T cells develop and are maintained, and what physiological functions of immunity depend on this diversity.
Dr. Platt originally reported that toll-like receptors are not only activated by microbial products but can be activated by endogenous substances. This line of research now focuses on mechanisms that control toll like receptor function in health and disease, preventing inadvertent activation.
Dr. Platt also directs lines of research that would lead to development of novel approaches to augmentation and replacement of organs. This research includes the immunology of xenotransplantation, the interaction of stem cells and engineered tissues with the immune system and the mechanisms and implications of cell fusion.
Saadi S, Platt JL. Transient perturbation of endothelial integrity induced by antibodies and complement. J Exp Med 181:21, 1995.
Holzknecht Z, Platt JL. Identification of porcine endothelial cell membrane antigens recognized by human xenoreactive natural antibodies. J Immunol 154:4565, 1995.
McCurry KR, Kooyman DL, Alvarado CG, Cotterell AH, Martin MJ, Logan JS, Platt JL. Human complement regulatory proteins protect swine-to-primate cardiac xenografts from humoral injury. Nat Med 1:423, 1995.
Kooyman DL, Byrne GW, McClellan S, Nielsen D, Tone M, McCurry KR, Coffman TM, Waldmann H, Platt JL, Logan JS. In vivo transfer of GPI-linked complement restriction factors from erythrocytes to the endothelium. Science 269: 89, 1995.
Collins BH, Cotterell AH, McCurry KR, Alvarado CG, Magee JC, Parker W, Platt JL. Cardiac xenografts between primate species provide evidence for the importance of the a-galactosyl determinant in hyperacute rejection. J Immunol 154:5500, 1995.
Magee JC, Collins, Harland RC, Lindman BJ, Bollinger RR, Frank MM, Platt JL. Immunoglobulin prevents com- plement-mediated hyperacute rejection in swine-to-primate xenotransplantation. J Clin Invest 96:2404, 1995.
Saadi S, Holzknecht RA, Patte CP, Stern DM, Platt JL. Complement-mediated regulation of the tissue factor in endothelium. J Exp Med 182:1807, 1995.
Parker W, Saadi S, Lin SS, Holzknecht ZE, Bustos M, Platt JL. Transplantation of discordant xenografts: a challenge revisited. Immunol Today 17:373, 1996.
Platt JL, Parker W. Another step toward clinical xenotransplantation. Nat Med 1:1248, 1995.
Sharma A, Okabe JF, Birch P, Martin MJ, Platt JL, Logan JS. Reduction in the level of Gal(a1,3)Gal in trans-genic mice and pigs by the expression of an a(1,2)fucosyltransferase. Proc Natl Acad Sci USA 93:7190, 1996.
Ihrcke NS, Platt JL. Shedding of heparan sulfate proteoglycan by stimulated endothelial cells: evidence for proteolysis of cell surface molecules. J Cell Physiol 168:6225, 1996.
Platt JL. Islet xenotransplantation: how sweet it is. J Clin Invest 98:1273, 1996.
Yu PB, Holzknecht ZE, Bruno D, Parker W, Platt JL. Modulation of natural IgM binding and complement activation by Natural IgG antibodies. J Immunol 157:5163, 1996.
Platt JL. Xenotransplantation of hepatocytes: the triumph of a cup half full. Nat Med 3:26, 1997.
Bustos M, Coffman TM, Saadi S, Platt JL. Modulation of eicosanoid metabolism in endothelial cells in a xenograft model: role of cycloosygenase-2. J Clin Invest 100:1, 1997.
Selvan RS, Kapadia HB, Platt JL. Complement-induced expression of chemokine genes in endothelium: Regulation by IL-1-dependent and -independent mechanisms. J Immunol 161:4388, 1998.
Platt JL. New directions for organ transplantation. Nature 392 (Suppl 6679):11, 1998.
Lin SS, Weidner BC, Byrne GW, Diamond LE, Lawson JH, Hoopes CW, Daniels LJ, Daggett CW, Parker W, Harland RC, Davis RD, Bollinger RR, Logan JS, Platt JL. The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants. J Clin Invest 101:1745, 1998.
Platt JL, Nath KA. Heme oxygenase: protective gene or trojan horse. Nat Med 4:1364, 1998.
Dempsey LA, Plummer TB, Coombes SL, Platt JL. Heparanase expression in invasive trophoblasts and acute vascular damage. Glycobiology 10:467, 2000.
Platt JL. Tolerance by transplantation: how much is enough, how much is too much. J Clin Invest 104:227, 1999.
Wrenshall L, Platt JL. Regulation of T cell homeostasis by heparan sulfate-bound IL‑2. J Immunol 163:3793, 1999.
Kodaira Y, Nair SK, Wrenshall LE, Gilboa E, Platt JL. Phenotypic and functional maturation of dendritic cells modulated by heparan sulfate. J Immunol 165:1599, 2000.
Dempsey LA, Brunn GJ, Platt JL. Heparanase, a potential regulator of cell-matrix interactions. Trends Biochem Sci 25:349, 2000.
Saadi S, Holzknecht RA, Patte CP, Platt JL. Endothelial cell activation by pore-forming structures: pivotal role for IL-1a. Circulation 101:1867, 2000.
Holzknecht ZE, Platt JL.The fine cytokine line between graft acceptance and rejection. Nat Med 6: 497, 2000.
Platt JL. Xenotransplantation: new risks and new gains. Nature 407:27, 2000.
Cascalho M, Platt JL. The immunological barrier to xenotransplantation. Immunity 14:437, 2001.
Cascalho M, Platt JL. Xenotransplantation and other means of organ replacement. Nat Rev Immunol 1:154, 2001.
Platt JL. Knocking out xenograft rejection. Nat Biotechnol 20:231, 2002.
Johnson GB, Brunn GJ, Kodaira Y, Platt JL. Receptor-mediated monitoring of tissue well being via detection of soluble heparan sulfate by toll-like receptor 4. J Immunol 277: 8989, 2002.
Holzknecht ZE, Kuypers KL, Plummer TB, Williams J, Bustos M, Gores GJ, Brunn GJ, Platt JL. Apoptosis and cellular activation in the pathogenesis of acute vascular rejection. Circ Res 91:1135, 2002.
Johnson GB, Brunn GJ, Tang AH, Platt JL. Evolutionary clues to the functions of the toll-like family as surveillance receptors. Trends Immunol 24:19, 2003.
Ogle BM, Cascalho M, Joao CM, Taylor W, West LJ, Platt JL. Direct measurement of lymphocyte receptor diversity. Nucleic Acids Res 31:e139, 2003.
Ogle BM, Butters KA, Cascalho M, Plummer TB, Ring KR, Knudsen B, Litzow MR, Platt JL. Spontaneous fusion of cells between species yields transdifferentiation and retroviral transfer in vivo. FASEB J 18:548, 2004.
Johnson GB, Brunn GJ, Platt JL. An endogenous pathway to systemic inflammatory response syndrome (SIRS)-like responses through toll-like receptor 4. J Immunol (Cutting Edge) 172:20, 2004.
João CM, Ogle BM, Gay-Rubenstein C, Platt JL, Cascalho M. B cell-dependent TCR diversification. J Immunol 172:4709, 2004.
Johnson GB, Riggs BL, Platt JL. A genetic basis for the Adonis phenotype of low adiposity and strong bones. FASEB J 18:1282, 2004.
Koch CA, Khalpey ZI, Platt JL. Accommodation: preventing injury in transplantation and disease. J Immunol 172:5143, 2004.
Fan X, Ang A, Pollock-BarZiv SM, Dipchand AI, Ruiz P, Wilson G, Platt JL, West LJ. Donor-specific B-cell tolerance after ABO-incompatible infant heart transplantation. Nat Med 10:1227, 2004.
Brunn GB, Bungum MK, Johnson GB, Platt JL. Conditional signaling by Toll-like receptor 4. FASEB J 19:872, 2005.
Kishore SP, Bungam MK, Platt JL, Brunn GJ. Selective suppression of toll-like receptor 4 activation by chemokine receptor 4. FEBS Letters 579:699, 2005.
Koch CA, Kanazawa A, Nishitai R, Knudsen BE, Ogata K, Plummer TB, Butters K, Platt JL. Intrinsic resistance of hepatocytes to complement-mediated injury. J Immunol 174:7302, 2005.
Ogle BM, Cascalho M, Platt JL. Biological implications of cell fusion. Nat Rev Mol Cell Biol 6:567, 2005.
Bischof D, Elsawa SF, Mantchev G, Yoon J, Michels GE, Nilson A, Sutor SL, Platt JL, Ansell SM, von Bulow G, Bram RJ. Selective activation of TACI by syndecan-2. Blood 107:3235, 2006.
Brunn GJ, Saadi S, Platt JL. Differential regulation of endothelial cell activation by complement and interleukin-1α. Circ Res 98:793, 2006.
Koch CA, Jordan CE, Platt JL. Complement-dependent control of teratoma formation by embryonic stem cells. J Immunol 177:4803-4809, 2006.
Brunn GJ, Platt JL. The etiology of sepsis: turned inside out. Trends Mol Med 12:10, 2006.
Ogle BM, West LJ, Driscoll DJ, Strome SE, Razonable RR, Paya CV, Cascalho M, Platt JL. Effacing of the T cell compartment by cardiac transplantation in infancy. J Immunol 176:1962, 2006.
Quiros RM, Rao G, Plate J, Harris JI, Brunnn GB, Platt JL, Gattuso P, Prinz RA, Xu X. Elevated serum heparanase-1 levels in patients with pancreatic carcinoma are associated with poor survival. Cancer 106:532, 2006.
Brunn GJ, Wijdicks MF, Platt JL. Toward a modern concept of sepsis: New answers to ancient questions. Discov Med 6:11, 2006.
Nagata H, Nishitai R, Shirota C, Zhang J-L, Koch CA, Cai J, Awwad M, Schuurman H-J, Christians U, Abe M, Baranowska-Kortylewicz J, Platt JL, Fox IJ. Prolonged survival of porcine hepatocytes in cynomolgus monkeys. Gastroenterology 132:321, 2007.
Xu X, Rao G, Quiros RM, Kim AW, Miao H-Q, Brunn GJ, Platt JL, Gattuso P, Prinz RA. In vivo and in vitro degradation of heparan sulfate (HS) proteoglycans by HPR1 in pancreatic adenocarcinomas: Loss of cell surface HS suppresses fibroblast growth factor 2-mediated cell signaling and proliferation. J Biol Chem 282:2363, 2007.
Platt JL. Allophenic mice: A pillar awaiting its superstructure. J Immunol 178:4005, 2007.
AbuAttieh M, Rebrovich M, Wettstein PJ, Vuk-Pavlovic Z, Limper AH, Platt JL, Cascalho M. Fitness of cell-mediated immunity independent of repertoire diversity. J Immunol 178:2950, 2007.
Tang AH, Brunn GJ, Cascalho M, Platt JL. Endogenous pathway to SIRS, sepsis and related conditions. J Leukocyte Biol 82:282, 2007.
Koch CA, Geraldes P, Platt JL. Immunosuppression by embryonic stem cells. Stem Cells 26: 89-98, 2008.
Schmidt RL, Trejo TR, Plummer TB, Platt JL, Tang AH. The infection-induced proteolysis of PGRP-LC controls the IM.D. activation and melanization cascades in Drosophila. FASEB J 22:918-929, 2008.
Balin SJ, Ross TM, Platt JL, Cascalho M. HIV genes diversify in B cells. Curr HIV Res 6:10-18, 2008.
Brunn GJ, Saadi S, Platt JL. Constitutive repression of IL-1α in endothelial cells. Circ Res 102:823-830, 2008.
Kushwaha SS, Raichlin E, Sheinin Y, Kremers WK, Chandrasekaran K, Brunn GJ, Platt JL. Sirolimus affects cardiomyocytes to reduce left ventricular mass in heart transplant recipients. Eur Heart J 29:2742-2750, 2008.
Yamanouchi K, Zhou H, Roy-Chowdhury N, Mancuso F, Liu L, Yamamoto T, Yannam GR, Enke C, Solberg TD, Adelson AB, Platt JL, Fox IJ, Roy-Chowdhury J, Guha C. Hepatic irradiation augments engraftment of donor cells following hepatocyte transplantation. Hepatology, 49(1):258-267, 2009.
Basma H, Soto-Gutiérrez A, Yannam G, Liu L, Ito R, Yamamoto T, Ellis E, Carson S, Sato SD, Muirhead D, Navarro-Álvarez N, Wong R, Platt JL, Mercer DF, Miller JD, Strom SC, Kobayashi N, Fox IJ. Differentiation, Enrichment and Transplantation of Human ES Cell-Derived Hepatocytes. Gastroenterology, 136:990-999, 2009.