RRC ID 1588
Author Miao G, Ito T, Uchikoshi F, Akamaru Y, Kiyomoto T, Komodo H, Song J, Nozawa M, Matsuda H.
Title Development of donor-specific immunoregulatory T-cells after local CTLA4Ig gene transfer to pancreatic allograft.
Journal Transplantation
Abstract BACKGROUND:CTLA4Ig gene transfer directly to graft tissue might have the potential to avoid the need for systemic immunosuppression. In our previous studies of bio-breeding (BB) rats, local adenovirus-mediated CTLA4Ig gene transfer protected the pancreas from autoimmune and alloimmune responses. This study investigated the potency of local CD28/B7 costimulatory blockade for induction of donor-specific tolerance and further examined the existing mechanisms.
METHODS:Brown Norway (BN; RT1)-pancreaticoduodenal grafts transfected with Ad.CTLA4Ig via intraarterial ex vivo perfusion were transplanted into streptozotocin-induced diabetic Lewis (LEW; RT1) rats.
RESULTS:Ad.CTLA4Ig transduced grafts combined with a short course of FK506 resulted in indefinitely prolonged survival (>156 days vs. 19.5 days with FK506 alone). CTLA4Ig was predominantly expressed in grafts on day 4. The expression was gradually diminished and was only slightly detectable at day >100. The proliferative responses against BN antigen were remarkably enhanced among recipients with rejected grafts, but the T-cells from tolerant recipients (>100 days) showed poor cytotoxic responses. On adoptive transfer assay, the splenic T-cells of tolerant recipients were able to suppress the rejection of BN, but not third-party Wistar Furth (WF; RT1) hearts in irradiated (480 cGy) LEW recipients. The percentage of CD4CD25 splenic T-cells was significantly increased in tolerant recipients (13.53 +/- 4.06% vs. 6.06 +/- 0.56% in naive rats).
CONCLUSION:CTLA4Ig gene transfer to the pancreaticoduodenal allograft combined with a short course of FK506 induces donor-specific tolerance. The mechanism of maintaining tolerance could be explained by development of splenic T suppressor cells.
Volume 78(1)
Pages 59-64
Published 2004-7-15
DOI 10.1097/01.tp.0000128330.64007.85
PII 00007890-200407150-00010
PMID 15257039
MeSH Abatacept Adoptive Transfer Animals CD4 Antigens / analysis Duodenum / transplantation Gene Transfer Techniques* Graft Rejection / drug therapy Graft Rejection / immunology Graft Survival / immunology Heart Transplantation / immunology Immunoconjugates / genetics* Immunoconjugates / immunology* Immunosuppressive Agents / pharmacology Male Pancreas Transplantation / immunology* Rats Rats, Inbred BN Rats, Inbred Lew Rats, Inbred WF Receptors, Interleukin-2 / analysis T-Lymphocytes / chemistry T-Lymphocytes / immunology* Tacrolimus / pharmacology Transplantation, Homologous
IF 4.546
Times Cited 12
DNA material AxCALacZ (RDB01745)