Abstract 13165: Heart Allograft Tolerance Induced and Maintained by Vascularized Bone Marrow Transplant in a Rat Model
Introduction Donor-specific transplant tolerance has been viewed as the ultimate solution to chronic rejection and life-long use of immunosuppressants. Accumulating evidence indicates that engraftment of donor hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) may promote organ transplant tolerance and stem cell niches in the bone marrow play a key role in stem cell self-renewal and differentiation. We hypothesize that vascularized bone marrow transplant (VBMT) which contains intact donor stem cells and their niches may induce donor specific tolerance to both VBMT itself and organs from the same donor.
Materials and Methods Orthotopic hind-limb transplantation from Brown-Norway to Lewis rats was used as VBMT so that rejection could be easily monitored. Four groups were employed: Group 1: anti-lymphocye (ALS) (day - 4 and day +1, 0.5 ml i.p.); Group 2: CsA (day 0 - day 20, 3mg/kg, ip); Group 3, ALS+CsA (21 days) and Group 4, ALS+CsA (d0-d44 days). Donor specific tolerance was tested by secondary BN skin allografts or third party strain at >150 days post primary transplant. Heart transplantation was performed at >200 days post hind-limb transplant. Flow cytometry was used to monitor multilineage mixed chimerism. Microchimerism was detected by PCR.
Results Mean survival in group 1, 2, and 3 was 9.25+1.5, 44.8+5.5 and 52.5+5.7, respectively. In contrast, all of the recipients in group 4 had long-term allograft survival > 150 days. Moreover, all recipients in group 4 accepted secondary BN skin allografts without immunosuppression >150 days post skin transplant and acutely rejected third party ACI skin allografts. All recipients in group 4 accepted BN heart allograft without immunosuppression >100 days. All group 4 recipients lost chimerism (both mixed and micro) at day>150 post primary transplant.
Conclusions ALS combined with 45-day CsA treatment induce donor-specific tolerance in this VBMT model while ALS combined with 21-day CsA treatment do not. Length of immunosuppressive therapy may play a critical role in vascularized bone marrow transplant tolerance induction. Peripheral blood cell chimerism may not be necessary for the maintenance of transplant tolerance. VBMT may be a new means for heart transplant tolerance induction and maintenance.
- © 2011 by American Heart Association, Inc.