The major problem in the field of cardiac transplantation is the lack of human organs and tissuesfor those who need them. This problem is so severe that by some estimates only 5-15% of theheart transplants needed are carried out; this shortage may worsen as medical advances allowdiseases of aging, such as diabetes and atherosclerosis, to be increasingly prevalent. Oneapproach to overcoming this problem is to use animal organs in lieu of human organs fortransplantation, that is xenotransplantation. However, cardiac xenotransplantation is notpresently feasible because the immune system of the recipient immune reacts severely with thegraft causing vascular diseases such as hyperacute and acute vascular rejection, and possiblychronic rejection. Triggered by the binding of xenoreactive antibodies and the activation ofcomplement, acute vascular rejection destroys organ xenografts over a period of days to weeksand is now the main impediment to clinical application of xenotransplantation. Despite theseverity of this condition, acute vascular rejection is not an invariable outcome of cardiacxenotransplantation. Under some conditions, such as when xenoreactive antibodies aretemporarily depleted, a graft may seemingly acquire resistance to injury by anti-donorantibodies, a condition referred to as accommodation. This application proposes studies that willaddress the problem of acute vascular rejection and test new strategies for understanding andgenerating accommodation. The first objective will be to determine which antigens provokerejection of organs from Gala1-3Gal-deficient pigs. Since rejection of these organs appears alsoto be caused by acute vascular rejection, novel strategies will be tested for abrogating the B cellresponses causing this condition. A second objective will be to induce resistance of cells andorgans to acute vascular rejection, thus determining how accommodation can be more reliablyinduced. New strategies toward this end will be tested. Fulfilling these objectives will yield muchprogress toward the preventing of acute vascular rejection or promoting the occurrence ofaccommodation of cardiac xenografts and allografts.
| Platt, Jeffrey L; Zhou, Xiaofeng; Lefferts, Adam R et al. (2016) Cell Fusion in the War on Cancer: A Perspective on the Inception of Malignancy. Int J Mol Sci 17: |
| Zhou, Xiaofeng; Merchak, Kevin; Lee, Woojin et al. (2015) Cell Fusion Connects Oncogenesis with Tumor Evolution. Am J Pathol 185:2049-60 |
| Platt, Jeffrey L; Cascalho, Marilia (2015) IgM in the kidney: a multiple personality disorder. Kidney Int 88:439-41 |
| Tsuji, Shoichiro; Stein, Lucas; Kamada, Nobuhiko et al. (2014) TACI deficiency enhances antibody avidity and clearance of an intestinal pathogen. J Clin Invest 124:4857-66 |
| Cascalho, Marilia I; Chen, Brian J; Kain, Mandy et al. (2013) The paradoxical functions of B cells and antibodies in transplantation. J Immunol 190:875-9 |
| Lynch, R J; Silva, I A; Chen, B J et al. (2013) Cryptic B cell response to renal transplantation. Am J Transplant 13:1713-23 |
| Platt, Jeffrey L; Tsuji, Shoichiro; Cascalho, Marilia (2011) Novel functions of B cells in transplantation. Curr Opin Organ Transplant 16:61-8 |
| Platt, J L (2011) Accommodation: how you see it, how you don't. Am J Transplant 11:2007-8 |
| McConico, Andrea; Butters, Kim; Lien, Karen et al. (2011) In utero cell transfer between porcine littermates. Reprod Fertil Dev 23:297-302 |
| Tsuji, Shoichiro; Cortesão, Catarina; Bram, Richard J et al. (2011) TACI deficiency impairs sustained Blimp-1 expression in B cells decreasing long-lived plasma cells in the bone marrow. Blood 118:5832-9 |
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