[Adenovirus-mediated CTLA4 immunoglobulin based conditioning for non-myeloablative allogeneic hematopoietic cell transplantation to induce tolerance to hind limb allografts in rats].
OBJECTIVE
To investigate a non-toxic AdCTLA4-Ig-based protocol for non-myeloablative allogeneic hematopoietic cell transplantation to induce donor-specific tolerance to hind limb allografts in rats.


METHODS
Fully mismatched, 4 to 8 week old Brown Norway (RT1(n)) and Lewis (RT1(1)) rats were used as cell/organ donors and recipients, respectively. Recipients were treated with AdCTLA4-Ig (5 x 10(9) PFU, day -30, 0, 30), standard immunosuppressive therapy (MP: 10 mg x kg(-1) x d(-1), MMF: 20 mg x kg(-1) x d(-1), RAPA: 0.2 mg x kg(-1) x d(-1);day -33 - 100), soon after total body irradiation (3 Gy, day -30) and donor bone marrow (100 x 10(6), day -30) transplantation (BMT). Thirty days after BMT, chimeric animals received hind limb transplantations. And 100 days after hind limb transplantations, immunosuppressive therapy was changed for low-dosed CsA (8 mg x kg(-1) x d(-1), day 100-), until the allografts were rejected.


RESULTS
In Group C, hematopoietic chimerism was (38.8 +/- 10.6)% at day 0, and was stable (29.3 +/- 11.9)% at 330 days post-BMT. There was no graft versus host disease in both Group C and Group D. When the standard immunosuppressive therapy was stopped and changed for low-dosed CsA, chimeric recipients (Lewis, RT1(1)) permanently accepted (> 200 days) donor specific (Brown Norway, RT1(n)) hind limb allografts in Group C, yet rapidly rejected in Group A (8 +/- 2) d, Group B (18 +/- 3) d and in Group C (20 +/- 2) d. Lymphocytes of graft tolerant animals' demonstrated hyporesponsiveness in mixed lymphocyte cultures in a donor-specific manner in Group C. Tolerant graft histology showed no obliterative arteriopathy or chronic rejection.


CONCLUSIONS
The AdCTLA4-Ig based conditioning regimen with donor BMT produce stable mixed chimerism and induce donor-specific tolerance to hind limb allografts.
Pan
Hua
H
Institute of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Wang
Lu
L
Zhang
Xu-Dong
XD
Mai
Hai-Xing
HX
Liu
Dan
D
Liu
Yin
Y
Guo
Shu-Zhong
SZ
D000069594:Abatacept; D000256:Adenoviridae; D000818:Animals; D006085:Graft Survival; D006614:Hindlimb / Q000637:transplantation*; D007108:Immune Tolerance; D018796:Immunoconjugates / Q000494:pharmacology*; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D011897:Random Allocation; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D018183:Transplantation Chimera / Q000276:immunology; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous
D018796:Immunoconjugates; D000069594:Abatacept