Prolongation of islet allograft survival by coexpression of CTLA4Ig and CD40LIg in mice.
BACKGROUND
B7/CD28 and CD40/CD40L have been well established as important costimulatory pathways. Cytotoxic T lymphocyte-associated antigen-4 (CTLA4) delivers negative signals to antigen-presenting cells to down-regulate proinflammatory responses and competitively inhibits the binding of B7 and CD28. Signals from the CD40/CD40L costimulatory pathway also play an important role in acute rejection of organ grafts.


METHODS
Recombinant adenoviruses Ad-sCD40LIg-IRES2-CTLA4Ig, Ad-CTLA4Ig, and Ad-sCD40LIg were constructed to express sCD40LIg and CTLA4Ig simultaneously or separately as described previously. Streptozocin-induced diabetic BALB/c mice were injected with recombinant adenovirus, receiving approximately 500 donor islets isolated from C57BL/6 mice under the left kidney capsule. Five groups were assigned according to the treatment: nontreated group, Ad-Shuttle-CMV-treated group, Ad-CTLA4Ig-treated group, Ad-sCD40LIg-treated group, and Ad-sCD40LIg-IRES2-CTLA4Ig-treated group. The islet graft mean survival time (MST) was evaluated in the present study.


RESULTS
Compared to the islet graft MST of the nontreated group (7.3+/-0.82 days) or Ad-Shuttle-CMV-treated group (7.2+/-1.47 days), the Ad-CTLA4Ig-treated and Ad-CD40LIg-treated islet graft survivals in recipients were 56.3+/-13.71 days (P<.01) and 47.3+/-15.64 days (P<.05), respectively. The islet graft MST was dramatically prolonged to 116.3+/-20.32 days in the Ad-sCD40LIg-IRES2-CTLA4Ig-treated group (P<.01).


CONCLUSIONS
Simultaneous blockade of the CD40/CD40L and B7/CD28 costimulatory pathways via coexpression of sCD40LIg and CTLA4Ig mediated by replication-defective adenovirus may be an acceptable method to induce immune tolerance.
Li
Z-L
ZL
Department of Renal Transplantation, First Affiliated Hospital, Xi'an Jiaotong University Medical College, Xi'an, Shannxi, PR China.
Xue
W-J
WJ
Tian
P-X
PX
Ding
X-M
XM
Tian
X-H
XH
Feng
X-S
XS
Hou
J
J
D000069594:Abatacept; D000818:Animals; D019013:CD40 Antigens / Q000235:genetics*; D003921:Diabetes Mellitus, Experimental / Q000601:surgery*; D006085:Graft Survival / Q000276:immunology*; D018796:Immunoconjugates / Q000235:genetics*; D007165:Immunosuppression Therapy; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D011993:Recombinant Fusion Proteins / Q000235:genetics*
D019013:CD40 Antigens; C526581:CD40LIg fusion protein; D018796:Immunoconjugates; D011993:Recombinant Fusion Proteins; D000069594:Abatacept