Establishment of Stable Multilineage Hematopoietic Chimerism and Donor-Specific Tolerance Without Irradiation1

Abstract

These studies demonstrate for the first time that cytoreduction/ablation with ALS combined with sirolimus and reconstitution with donor bone marrow induces tolerance and chimerism in a completely mismatched murine combination. The use of ALS and sirolimus, currently employed therapies in clinical transplantation, and the lack of requirement for radiation make this tolerance protocol attractive for clinical application.

Rapamycin and T cell costimulatory blockade as post-transplant treatment promote fully MHC-mismatched allogeneic bone marrow engraftment under irradiation-free conditioning therapy

“…Hematopoietic macrochimerism could be induced across fully MHC-mismatched barriers under our nonirradiative and nonmyeloablative conditioning therapy with different posttransplant treatments. Hale et al 7 reported that 8-10% of donor chimerism and donor-specific tolerance could be induced after transplantation of megadoses of bone marrow combined with high doses of ALS and rapamycin. In our protocol, a relatively low dose of ALS was given because we found that the 0.5 ml ALS used by Hale et al was very toxic and associated with high mortality (data not shown).…”

“…Our dose of rapamycin is low compared with Hale et al's study. 7 In their study, rapamycin at a dose of 24 mg/kg was used to facilitate the establishment of mixed hematopoietic chimerism. Rapamycin blocks signal transduction and inhibits cell cycle progression.…”

“…3,4 Recent studies have indicated that hematopoietic macrochimerism can be induced by either costimulatory blockade and high-dose bone marrow infusion 5 or by repeated bone marrow infusion. 6 Hale et al 7 also reported that stable hematopoietic macrochimerism can be established by a high dose of bone marrow and anti-lymphocyte serum (ALS) plus rapamycin treatment. However, these protocols may be difficult to apply clinically, because of the total number of bone marrow cells required for transplantation.…”

Infusion of nonmyeloablative bone marrow alleviates acute rejection reaction in liver allotransplantation

“…Meanwhile the effect of non-radiation preconditioning DSBM on immunotolerance induction in heart and skin transplantation is not satisfactory yet. Some successful studies are also the results of infusion of DSBM combined with blocking of the co-stimulation molecular pathway (CTLA4Ig) or selective deletion of recipient T cell subgroups by anti-CD3, anti-CD4, anti-CD8 and anti-CD25 antibodies (Li et al, 2001;Shirasugi et al, 2002;Hale et al, 2000). It is well known that the difficulty of tolerance induction depends on different organs transplantation.…”

“…Consequently, we speculated that short-term administration of CsA would create "space" for bone marrow engraftment, and facilitate chimerism induction. A study by Hale et al(2000) showed that sirolimus with antilymphocyte serum, combined with infusion of DSBM, induced tolerance and chimerism (Kita et al, 1999) and play important roles in the rejection reaction of allograft, and their expression increased during rejection. The results of ELISA and Western blot indicated that the expression of IL-2 and IFN-γ in Group IV were significantly lower than that in Group II, though expression of IFN-γ increased slightly with prolongation of survival time.…”