Enhanced survival of grafts genetically endowed with the ability to block CD2 and B7.
In a model of transplantation rejection, we have tested whether a graft manipulated to secrete immunomodulators could protect itself from immune destruction. An insulinoma cell line having the NOD genotype but also expressing the neoantigen, SV40 T antigen, was transfected with CTLA4Ig or LFA3Ig to block signals in the co-stimulatory/adhesion pathways. This neoantigen is potent at inducing graft rejection. Secretion of CTLA4Ig and LFA3Ig by transfectants promoted survival of the insulinoma graft in young NOD mice. In immunodeficient mice, cell growth was similar for all transfectants. However, in immunocompetent NOD mice the survival/growth of test grafts was significantly better than that of the controls. Graft survival was enhanced additively, when the two test transfectants were cotransplanted. Endowing the graft the ability to secrete immunomodulators that block individual co-stimulatory/adhesion signals can contribute to transplantation success. Blockade of two signals (CD2 and CD28) in these pathways enhances this success.
Brady
J L
JL
Walter and Eliza Hall Institute of Medical Research, PO Royal Melbourne Hospital, Parkville, Australia.
Yamashita
K
K
Lew
A M
AM
D000069594:Abatacept; D000077944:Alefacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D018122:B7-1 Antigen / Q000276:immunology*; D018801:CD2 Antigens / Q000276:immunology*; D060908:CTLA-4 Antigen; D006085:Graft Survival / Q000502:physiology*; D018796:Immunoconjugates; D007165:Immunosuppression Therapy / Q000379:methods; D007166:Immunosuppressive Agents; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007340:Insulinoma / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D009368:Neoplasm Transplantation / Q000473:pathology / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D014162:Transfection; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D000943:Antigens, Differentiation; D000952:Antigens, Polyomavirus Transforming; D018122:B7-1 Antigen; D018801:CD2 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D007328:Insulin; D011993:Recombinant Fusion Proteins; D000069594:Abatacept; D000077944:Alefacept