Development of donor-specific immunoregulatory T-cells after local CTLA4Ig gene transfer to pancreatic allograft.
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).


CONCLUSIONS
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.
Miao
Gang
G
Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Ito
Toshinori
T
Uchikoshi
Fumihiro
F
Akamaru
Yusuke
Y
Kiyomoto
Tetsuma
T
Komodo
Hiroshi
H
Song
Jinghai
J
Nozawa
Masumi
M
Matsuda
Hikaru
H
D000069594:Abatacept; D019264:Adoptive Transfer; D000818:Animals; D015704:CD4 Antigens / Q000032:analysis; D004386:Duodenum / Q000637:transplantation; D018014:Gene Transfer Techniques; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D018796:Immunoconjugates / Q000235:genetics* / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D016035:Pancreas Transplantation / Q000276:immunology*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D015375:Receptors, Interleukin-2 / Q000032:analysis; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D016559:Tacrolimus / Q000494:pharmacology; D014184:Transplantation, Homologous
D015704:CD4 Antigens; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D015375:Receptors, Interleukin-2; D000069594:Abatacept; D016559:Tacrolimus