Additive efficacy of CTLA4Ig and OX40Ig secreted by genetically modified grafts.
BACKGROUND
The use of systemic immunosuppressive drugs have been paramount in the success in transplantation, but there are serious deleterious effects. Genetic modification of grafts to secrete immunomodulators locally may be a way to reduce the need for systemic immunosuppression.


RESULTS
An insulinoma cell line, NIT, having the nonobese diabetic (NOD) genotype but also expressing the SV40 large T Ag, was transfected with CTLA4Ig or OX40Ig in an attempt to block signals in the costimulatory/adhesion pathways. The extracellular domains of these molecules have been fused to the Fc of IgG2c derived from the NOD mouse strain. This resulted in secreted and dimerized proteins. SV40 T Ag is potent at inducing graft rejection. Test and control transfectants were transplanted subcutaneously into young NOD mice to determine whether secretion of CTLA4Ig and OX40Ig would promote survival of the insulinoma graft. 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 controls. By combining test transfectants, we found that graft survival was enhanced in an additive and significant fashion. In vitro, there was a significant reduction in immune responses-compared with control-when purified fusion proteins were added to mixed leukocyte reaction cultures.


CONCLUSIONS
We conclude that blockade of individual costimulatory/adhesion signals by graft manipulation can contribute to transplantation success and that blockade of combinations of signals in these pathways enhances this success. Successful immunomodulation by the graft itself can be achieved.
Brady
J L
JL
Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville, Australia.
Lew
A M
AM
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D060908:CTLA-4 Antigen; D002455:Cell Division / Q000187:drug effects; D005821:Genetic Techniques; D007121:Immunocompetence; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D007328:Insulin / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016381:Islets of Langerhans Transplantation; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008808:Mice, Inbred CBA; D016688:Mice, Inbred NOD / Q000502:physiology; D016513:Mice, SCID; D011956:Receptors, Cell Surface / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000637:transplantation
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; C406563:IgG2c receptor; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments; D007328:Insulin; C406562:OX40Ig; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D000069594:Abatacept