CTLA4-Ig-based conditioning regimen to induce tolerance to cardiac allografts.
BACKGROUND
Transplant rejection and toxicity associated with chronic immunosuppressive therapy remain a major problem. Mixed hematopoietic chimerism has been shown to produce tolerance to solid organ transplants. However, currently available protocols to induce mixed hematopoietic chimerism invariably require toxic pre-conditioning. In this study, we investigated a non-toxic CTLA4-Ig-based protocol to induce donor-specific tolerance to cardiac allografts in rats.


METHODS
Fully mismatched, 4 to 6 week old ACI (RT1.A(a)) and Wistar Furth (RT1.A(u)) rats were used as cell/organ donors and recipients, respectively. Recipients were treated with CTLA4-Ig 2 mg/kg/day (on days 0, 2, 4, 6, 8), tacrolimus 1 mg/kg/day (daily, from days 0 to 9), and a single dose of anti-lymphocyte serum (10 mg) on day 10, soon after total body irradiation (300 cGy) and donor bone marrow (100 x 10(6) T-cell depleted cells) transplantation (BMT). Six weeks after BMT, chimeric animals received heterotopic heart transplants.


RESULTS
Hematopoietic chimerism was 18.8 +/- 10.6% at day 30, and was stable (24 +/- 10%) at 1 year post-BMT; there was no graft versus host disease. Chimeric recipients (RT1.A(u)) permanently accepted (>360 days) donor-specific (RT1.A(a); n = 6) hearts, yet rapidly rejected (<9 days) third-party hearts (RT1.A(l); n = 5). Graft (heart) tolerant (>100 days) recipients accepted donor-specific secondary skin grafts (>200 days) while rejected the third-party skin grafts (<9 days). Lymphocytes of graft tolerant animals demonstrated hyporesponsiveness in mixed lymphocyte cultures in a donor-specific manner. Tolerant graft histology showed no obliterative arteriopathy or chronic rejection.


CONCLUSIONS
The CTLA4-Ig based conditioning regimen with donor BMT produced mixed chimerism and induced donor- specific tolerance to cardiac allografts.
Li
Sen
S
Division of Cardiothoracic Surgery, University of Miami School of Medicine, Miami, Florida 33156, USA.
Salgar
Shashikumar K
SK
Thanikachalam
Mohan
M
Murdock
Alan D
AD
Gammie
James S
JS
Demetris
Anthony J
AJ
Zeevi
Adriana
A
Pham
Si M
SM
D000069594:Abatacept; D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology; D002908:Chronic Disease; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology*; D007108:Immune Tolerance / Q000187:drug effects; D018796:Immunoconjugates / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008214:Lymphocytes / Q000276:immunology; D051381:Rats; D011912:Rats, Inbred ACI; D011920:Rats, Inbred WF; D016038:Skin Transplantation / Q000276:immunology; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000379:methods*; D014181:Transplantation Immunology / Q000187:drug effects; D014184:Transplantation, Homologous
D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept