Back to Annual Meeting Program
Combined Co-stimulatory Blockade And Donor Bone Marrow Cells Induce Robust Immune Tolerance In A Fully Sla-mismatched Swine Hind Limb Transplantation Model
Zuhaib Ibrahim, MD1, Angelo Leto Barone, MD1, Lehao Wu, MD1, Georg Furtmuller, MD1, Karim Sarhane, MD1, Joani Christensen, BA1, Muhammed Al-Rakan, MD1, Eric G. Wimmers, MD1, Galen Wachtman, MD2, Steve Bonawitz, MD1, Gabriel Santiago, MD3, Jamie T. Shores, MD1, Damon C. Cooney, MD, PhD1, Justin M. Sacks, MD1, WP Andrew Lee, MD1, Gerald Brandacher, MD1.
1Johns Hopkins University School of Medicine, Baltimore, MD, USA, 2University of Pittsburgh Medical Center, Pittsburgh, PA, USA, 3Walter Reed National Military Medical Center, Bethesda, MD, USA.
The creation of hematopoietic chimerism through bone marrow (BM) transplantation remains one of the most reliable methods for inducing transplantation tolerance. Vascular Composite Allografts (VCA), such as hand/arm transplants, contain vascularized long bones that instantly produce BM cells and thus can favor chimerism induction. This study investigates the immunological effects of vascularized BM within VCA under a co-stimulation blockade-based regimen and its impact on allograft survival.
Fully SLA-mismatched MGH miniature swine (n=24) underwent heterotopic hind-limb transplantation and received a short course (30 days) of tacrolimus monotherapy. Group 1 (control): no treatment. Group 2: short-term tacrolimus only; Group 3: irradiation and tacrolimus; Group 4: irradiation, unfractionated BM (60 x 10*6 cells/Kg) and tacrolimus; Group 5: tacrolimus and CTLA4-lg; and Group 6: BM, tacrolimus and CTLA4Ig. Sequential skin and muscle biopsies were performed for histologic analysis (Table 1). Mixed lymphocyte reaction was used to determine donor specific responsiveness while secondary skin grafts were used to demonstrate in vivo robust immune tolerance.
Our co-stimulatory blockade based immunomodulatory protocol resulted in indefinite graft survival in 3 out of 5 animals whereas control and tacrolimus only groups rejected allografts at days 6-8 and 28-30 respectively. Combined costimulation blockade and donor bone marrow infusion resulted in indefinite graft survival in 2 out of 3 animals (Figure 1). Long-term survivors demonstrated stable micro-chimerism in various tissues including skin, lymph node, bone marrow, and spleen. Secondary skin grafting demonstrated advanced rejection of third party graft on day 7 while donor-matched graft was accepted indicating donor-antigen specific immune tolerance (Figure 2 and 3).
Combined costimulatory blockade and donor bone marrow cell infusion can induce robust immune tolerance in a fully mis-matched hind limb transplant model. Such targeted immunomodulatory protocols combining BM cell-based strategies and biologics might facilitate immune tolerance and eliminate the need for multi-drug immunosuppression to maintain graft survival after VCA.
Rejection-free survival of skin comonent of hind limb allograft. (XRT: Irradiation, BM Bone Marrow)
|Groups||Immunosuppressive Protocol||Rejection free survival of Skin component (Days)|
|1||No treatment||5, 6, 8|
|2||Tacrolimus only (30 days)||30, 31,32|
|3||XRT + Tacrolimus(30 days)||35,37|
|4||XRT + BM + Tacrolimus (30 days)||50, 52, 53|
|5||CTLA4Ig + Tacrolimus (30 days)||100, 127, > 150, >150, >150|
|6||CTLA4Ig + BM + Tacrolimus (30 days)||120, >150, >150|
Back to Annual Meeting Program