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.
BohmigG. A.KovarikJ.HolterW.PohankaE.ZlabingerG. J.Specific down-regulation of proliferative T cell alloresponsiveness by interference with CD2/LFA-3 and LFA-1/ICAM-1 in vitro.J. Immunol.152: 3720-3728; 1994.
2.
BoyleJ. S.BradyJ. L.LewA. M.Enhanced responses to a DNA vaccine encoding a fusion antigen that is directed to sites of immune induction.Nature392: 408-411; 1998.
3.
ChahineA. A.YuM.McKernanM. M.StoeckertC.LauH. T.Immunomodulation of pancreatic islet allografts in mice with CTLA4Ig secreting muscle cells.Transplantation59: 1313-1318; 1995.
4.
ChavinK. D.LauH. T.BrombergJ. S.Prolongation of allograft and xenograft survival in mice by anti-CD2 monoclonal antibodies.Transplantation54: 286-291; 1992.
5.
ChavinK. D.QinL.LinJ.KaplanA. J.BrombergJ. S.Anti-CD2 and anti-CD3 monoclonal antibodies synergize to prolong allograft survival with decreased side effects.Transplantation55: 901-908; 1993.
6.
ChisholmP. L.WilliamsC. A.JonesW. E.MajeauG. R.OlesonF. B.Burrus-FischerB.MeierW.HochmanP. S.The effects of an immunomodulatory LFA3–IgG1 fusion protein on nonhuman primates.Ther. Immunol.1: 205-216; 1994.
7.
DavisS. J.van der MerweP. A.The structure and ligand interactions of CD2: Implications for T-cell function.Immunol. Today17: 177-187; 1996.
8.
DingY.QinL.YangQ.PunchJ. D.FoxD. A.HochmanP. S.BrombergJ. S.A novel murine model for the assessment of human CD2-related reagents in vivo.J. Immunol.157: 1863-1869; 1996.
9.
DubeyC.CroftM.SwainS. L.Co-stimulatory requirements of naive CD4+ T cells.ICAM-1 or B7–1 can costimulate naive CD4 T cell activation but both are required for optimum response. J. Immunol.155: 45-57; 1995.
10.
FengS.QuickelR. R.Hollister-LockJ.McLeodM.Bonner-WeirS.MulliganR. C.WeirG. C.Prolonged xenograft survival of islets infected with small doses of adenovirus expressing CTLA4Ig.Transplantation67: 1607-1613; 1999.
11.
GainerA. L.Suarez-PinzonW. L.MinW. P.SwistonJ. R.Hancock-FriesenC.KorbuttG. S.RajotteR. V.WarnockG. L.ElliottJ. F.Improved survival of biolistically transfected mouse islet allografts expressing CTLA4-Ig or soluble Fas ligand.Transplantation66: 194-199; 1998.
12.
GotohM.FukuzakiT.MondenM.DonoK.KanaiT.YagitaH.OkumuraK.MoriT.A potential immunosuppressive effect of anti-lymphocyte function-associated antigen-1 monoclonal antibody on islet transplantation.Transplantation57: 123-126; 1994.
13.
HamaguchiK.GaskinsH. R.LeiterE. H.NIT-1, a pancreatic beta-cell line established from a transgenic NOD/Lt mouse.Diabetes40: 842-849; 1991.
14.
HargreavesR.LogiouV.LechlerR.The primary allo-response of human CD4+ T cells is dependent on B7 (CD80), augmented by CD58, but relatively uninfluenced by CD54 expression.Int. Immunol.7: 1505-1513; 1995.
15.
IsobeM.YagitaH.OkumuraK.IharaA.Specific acceptance of cardiac allograft after treatment with antibodies to ICAM-1 and LFA-1.Science255: 1125-1127; 1992.
16.
KaplonR. J.HochmanP. S.MichlerR. E.KwiatkowskiP. A.EdwardsN. M.BergerC. L.XuH.MeierW.WallnerB. P.ChisholmP.MarboeC. C.Short course single agent therapy with an LFA-3-IgG1 fusion protein prolongs primate cardiac allograft survival.Transplantation61: 356-363; 1996.
17.
LehnertA. M.YiS.BurgessJ. S.O'ConnellP. J.Pancreatic islet xenograft tolerance after short-term co-stimulation blockade is associated with increased CD4+ T cell apoptosis but not immune deviation.Transplantation69: 1176-1185; 2000.
18.
LenschowD. J.ZengY.ThistlethwaiteJ. R.Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg.Science257: 789-792; 1992.
19.
LenschowD. J.WalunasT. L.BluestoneJ. A.CD28/B7 system of T cell costimulation.Annu. Rev. Immunol.14: 233-258; 1996.
20.
LewA. M.BradyJ. L.SilvaA.ColiganJ. E.GeorgiouH. M.Secretion of CTLA4Ig by an SV40 T antigen-transformed islet cell line inhibits graft rejection against the neoantigen.Transplantation62: 83-89; 1996.
21.
LinH.BollingS. F.LinsleyP. S.WeiR. Q.GordonD.ThompsonC. B.TurkaL. A.Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific trans-fusion.J. Exp. Med.178: 1801-1806; 1993.
22.
MajeauG. R.MeierW.JimmoB.KioussisD.HochmanP. S.Mechanism of lymphocyte function-associated molecule 3-Ig fusion proteins inhibition of T cell responses.Structure/function analysis in vitro and in human CD2 transgenic mice. J. Immunol.152: 2753-2767; 1994.
23.
MartinR. M.SilvaA.LewA. M.The Igh-1 sequence of the non-obese diabetic (NOD) mouse assigns it to the IgG2c isotype.Immunogenetics46: 167-168; 1997.
24.
MartinR. M.BradyJ. L.LewA. M.The need for IgG2c specific antiserum when isotyping antibodies from C57Bl/6 and NOD mice.J. Immunol. Methods212: 187-192; 1998.
25.
MillerG. T.HochmanP. S.MeierW.TizardR.BixlerS. A.RosaM. D.WallnerB. P.Specific interaction of lymphocyte function-associated antigen 3 with CD2 can inhibit T cell responses.J. Exp. Med.178: 211-222; 1993.
26.
NikolicB.SykesM.Mixed hematopoietic chimerism and transplantation tolerance.Immunol. Res.16: 217-228; 1997.
27.
OlthoffK. M.JudgeT. A.GelmanA. E.da ShenX.HancockW. W.TurkaL. A.ShakedA.Adenovirus-mediated gene transfer into cold-preserved liver allografts: Survival pattern and unresponsiveness following transduction with CTLA4Ig.Nat. Med.4: 194-200; 1998.
28.
O'RourkeR. W.KangS. M.LowerJ. A.FengS.AscherN. L.BaekkeskovS.StockP. G.A dendritic cell line genetically modified to express CTLA4-IG as a means to prolong islet allograft survival.Transplantation69: 1440-1446; 2000.
29.
ParraE.WingrenA. G.HedlundG.KallandT.DohlstenM.The role of B7–1 and LFA-3 in costimulation of CD8+ T cells.J. Immunol.158: 637-642; 1997.
SteurerW.NickersonP. W.SteeleA. W.SteigerJ.ZhengX. X.StromT. B.Ex vivo coating of islet cell allografts with murine CTLA4/Fc promotes graft tolerance.J. Immunol.155: 1165-1174; 1995.
32.
SultanP.SchechnerJ. S.McNiffJ. M.HochmanP. S.HughesC. C.LorberM. I.AskenaseP. W.PoberJ. S.Blockade of CD2-LFA-3 interactions protects human skin allografts in immunodeficient mouse/human chimeras.Nat. Biotechnol.15: 759-762; 1997.
33.
WallaceP. M.JohnsonJ. S.MacMasterJ. F.KennedyK. A.GladstoneP.LinsleyP. S.CTLA4Ig treatment ameliorates the lethality of murine graft-versus-host disease across major histocompatibility complex barriers.Transplantation58: 602-610; 1994.
34.
WeinbergA. D.WegmannK. W.FunatakeC.WhithamR. H.Blocking OX-40/OX-40 ligand interaction in vitro and in vivo leads to decreased T cell function and amelioration of experimental allergic encephalomyelitis.J. Immunol.162: 1818-1826; 1999.
35.
YoungJ. W.KoulovaL.SoergelS. A.ClarkE. A.SteinmanR. M.DupontB.The B7/BB1 antigen provides one of several co-stimulatory signals for the activation of CD4+ T lymphocytes by human blood dendritic cells in vitro.J. Clin. Invest.90: 229-237; 1992.
