Development of Stable Mixed T Cell Chimerism and Transplantation Tolerance Without Immune Modulation in Recipients of Vascularized Bone Marrow Allografts

Bilateral hand transplantation: Bone healing under immunosuppression with tacrolimus, mycophenolate mofetil, and prednisolone

“…29 Bone marrow seems to be not so important in allograft rejection, but it plays an important role in allograft survival, which seems to depend on the persistence of donor marrow progenitor cells in the bone marrow compartment. 30,31 Cell-mediated immunity plays a minor role in the rejection of composite tissue allografts and of bone alone as compared with antibody-mediated response.…”

Immunologic Approaches to Composite Tissue Allograft

“…[82][83][84] This observation could be explained by the fact that a very small amount of active BM is expected to be transferred with this type of CTA. 79,80,85 Furthermore, since the first successful transplantation of BM in humans in 1968, 86 much progress has been made in clinical use as well as in experimental models to treat non-life-threatening conditions through hematopoietic reconstitution. The extension of lower-risk protocols, such as the "non-total body irradiation" approach, to establish the state of mixed chimerism across MHC barriers seems to be an important point to reduce the toxicity occurring from the conditioning of the host.…”

“…After additional investigation, it was shown that the recipients became mixed chimeras after hind limb transplantation and that most of the animals expressing a T-cell chimerism with a level of 11% demonstrated tolerance, whereas others with T-cell chimerism levels of 52% showed evidence of GVHD. 80 Hence, this group has shown that the level of mixed lymphocyte chimerism plays an important role in the induction of GVHD. Indeed, a low-level of mixed lymphocyte chimerism is associated with the induction of tolerance after limb transplantation, but unstable highlevel lymphocyte chimerism is associated with the development of GVHD, indicating that a very fine balance exists between tolerance and GVHD.…”

Past, present, and future research in the field of composite tissue allotransplantation

“…Numerous studies by our laboratory have used this VBMT model to demonstrate that the development of low-level, stable mixed lymphocyte chimerism after limb allografting is associated with alloimmune tolerance induction, while unstable, high-level lymphocyte chimerism is associated with the development of graft-versus-host disease (GVHD). 32,[74][75][76][77][78][79] The work of Lee and associates 80 in Boston concerning tolerance induction has also been instrumental in the field of CTA. They have been successful in inducing long-term tolerance to vascularized musculoskeletal allografts in major histocompatibility complex-matched, minor antigenmismatched pigs after only a 12-day postoperative course of cyclosporine A. Lee has also used intrathymic injection of donor-derived bone marrow cells along with the short-term use of an anti-lymphocyte serum to prolong survival of skin allografts in rats.…”