CD86 blockade in genetically modified porcine cells delays xenograft rejection by inhibiting T-cell and NK-cell activation.
Porcine xenografts transplanted into primates are rejected in spite of immunosuppression. Identification of the triggering mechanisms and the strategies to overcome them is crucial to achieve long-term graft survival. We hypothesized that porcine CD86 (pCD86) contributes to xenograft rejection by direct activation of host T cells and NK cells. Formerly, we designed the human chimeric molecule hCD152-hCD59 to block pCD86 in cis. To test the efficacy in vivo, we have utilized a pig-to-mouse xenotransplant model. First, we showed that hCD152-hCD59 expression prevents the binding of murine CD28Ig to pCD86 on porcine aortic endothelial cells (PAEC) and dramatically reduces IL-2 secretion by Con A-stimulated mouse splenocytes in coculture. Moreover, IFN-gamma secretion by IL-12-stimulated mouse NK cells was averted after coculture with hCD152-hCD59 PAEC. In vivo, control PAEC implanted under the kidney capsule were rapidly rejected (2-4 weeks) in BALB/c and BALB/c SCID mice. Rejection of hCD152-hCD59 PAEC was significantly delayed in both cases. Signs of immune modulation in the hCD152-hCD59-PAEC BALB/c recipients were identified such as early hyporesponsiveness and diminished antibody response. Thus, simply modifying the donor xenogeneic cell can diminish both T cell and NK cell immune responses. We specifically demonstrate that pCD86 contributes to rejection of porcine xenografts.
Costa
Cristina
C
Department of Molecular Science, Alexion Pharmaceuticals Inc., 352 Knotter Drive, Cheshire, CT 06410, USA. costac@alxn.com
Pizzolato
Maryellen C
MC
Shen
Yamin
Y
Wang
Yi
Y
Fodor
William L
WL
D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000097:blood* / Q000276:immunology; D000943:Antigens, Differentiation / Q000032:analysis; D001011:Aorta; D051940:B7-2 Antigen; D018957:CD59 Antigens / Q000032:analysis; D060908:CTLA-4 Antigen; D018920:Coculture Techniques; D003208:Concanavalin A; D004730:Endothelium, Vascular / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000097:blood* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D013552:Swine; D013601:T-Lymphocytes / Q000276:immunology*; D014183:Transplantation, Heterologous / Q000276:immunology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D051940:B7-2 Antigen; D018957:CD59 Antigens; C497964:CD86 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D003208:Concanavalin A