Secretion of CTLA4Ig by an SV40 T antigen-transformed islet cell line inhibits graft rejection against the neoantigen.
In a model of transplantation rejection, we tested whether a graft manipulated to secrete an immunomodulator could protect itself from immune destruction, thus waiving the need for administration of exogenous immunosuppressants to the recipient. An insulinoma cell line, NIT, having the nonobese diabetic (NOD) genotype but also expressing the SV40 large T antigen, was transfected with CTLA4Ig in an attempt to block the CD28/B7 costimulatory pathway between antigen-presenting calls and T lymphocytes near the site of the graft. The SV40 T antigen is potent at inducing graft rejection. NIT.CTLA4Ig and control transfectants were transplanted subcutaneously into young NOD mice to determine whether CTLA4Ig secretion would abet the survival of the insulinoma graft. CTLA4Ig protein was secreted abundantly in vitro (3-5 microg/ml) and this phenotype was maintained in vivo. Tumor growth was monitored visibly, by palpation, by measuring blood glucose levels, and by death of the host from hypoglycemia caused by unregulated insulin production of the growing insulinoma. Cell growth was similar for NIT.CTLA4Ig7 and control transfectants in immunodeficient mice (nude, irradiated, or SCID mice), indicating that there was no intrinsic growth advantage of the NIT.CTLA4Ig cells. In immunocompetent NOD mice however, the survival/growth of the NIT.CTLA4Ig graft was significantly better than that of the controls. Histopathology was consistent with this finding. Donor-specific second-set grafts were acutely rejected, indicating that tolerance was not induced. CTLs were generated even when the graft secreted CTLA4Ig; there was no clear difference in in vitro immune responses generated by NIT.CTLA4Ig and control cells. We conclude that blockade of the B7 costimulation pathway by graft manipulation can contribute to transplantation success.
Lew
A M
AM
Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Australia.
Brady
J L
JL
Silva
A
A
Coligan
J E
JE
Georgiou
H M
HM
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000008:administration & dosage* / Q000276:immunology; D001483:Base Sequence; D060908:CTLA-4 Antigen; D017931:DNA Primers / Q000737:chemistry; D018796:Immunoconjugates; D007165:Immunosuppression Therapy / Q000379:methods*; D007515:Islets of Langerhans / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000379:methods; D008213:Lymphocyte Activation; D051379:Mice; D008808:Mice, Inbred CBA; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008969:Molecular Sequence Data; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology; D014162:Transfection
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D017931:DNA Primers; D018796:Immunoconjugates; D000069594:Abatacept