Chimerism and cure: hematologic and pathologic correction of murine sickle cell disease

Donor/recipient mixed chimerism does not predict graft failure in children with -thalassemia given an allogeneic cord blood transplant from an HLA-identical sibling

“…37 Indeed, studies in a mouse model, aimed at evaluating the effect of mixed chimerism on sicklecell pathophysiology, also showed that a significant enrichment of erythrocyte over leukocyte chimerism occurred in these mice, because of the very marked survival advantage of donor over sickle red blood cells in the peripheral blood. 38 In agreement with the results of previously reported studies, 35,36,39,40 we observed that mixed chimerism is associated with less GvHD, irrespectively of the type of donor and stem cell source employed. These data suggest that one of the biological mechanisms contributing to the lower incidence and severity of GvHD after CBT, as compared to after BMT, could be a greater frequency of long-lasting donor/recipient hematopoietic chimerism among the cord blood recipients, conceivably favoring the establishment of reciprocal donor/recipient immune tolerance.…”

Extended β-globin locus control region elements promote consistent therapeutic expression of a γ-globin lentiviral vector in murine β-thalassemia

“…In contrast, using the same murine models of ␤-thalassemia and sickle cell disease, bone marrow chimera studies indicate that chimerism levels from 30% to 50% with normal HSCs result in nearly complete hematologic and pathologic correction. 6,7 Although the reasons for the discrepancies between the gene therapy and chimera studies may be several, it is likely that a major factor underlying these contrasting results is the variable globin expression obtained from unique proviral integration sites. 2,3 Previously, using a ␥-globin lentiviral vector, we showed that an average vector copy number of 0.8 in peripheral blood leukocytes (PBLs) resulted in only slight hematologic improvement in murine ␤-thalassemia intermedia but that significant disease correction occurred with a copy number of 2.1 to 2.4.…”

Reduced-Intensity Regimens in Allogeneic Hematopoietic Stem Cell Transplantation for Hemoglobinopathies

“…26 Increasing degrees of erythrocyte chimerism provided progressive correction of hematological and pathologic abnormalities in the mouse model, although sickle bone marrow and splenic hematopoiesis was not corrected until peripheral blood sickle RBCs were fully replaced with donor erythrocytes, indicating that 100% peripheral blood RBC chimerism is the most rigorous benchmark for cure after nonmyeloablative allograft. 26 The presence of residual host cells may also offer the advantage of reducing the incidence and severity of GVHD, as, in animal models, mixed chimerism is associated with reduced susceptibility to GVHD, probably thanks to mechanisms of central tolerance, with negative selection of host-alloreactive donor T cells. 27,28 Having said that the rationale for using reduced-intensity preparative regimens in patients with thalassemia or SCD exists, so far few reports have demonstrated the feasibility of using reduced-intensity preparative regimens for successfully treating patients with hemoglobinopathies, [29][30][31][32][33] and results of well-controlled, clinical trials of less toxic conditioning regimens by centers experienced in HSCT are not available.…”

“…4,11,25 Patients with hemoglobinopathies developing stable chimerism, even with a low percentage of donor marrow progenitors (20-30%), have been reported to experience marked enrichment of donor cells in the mature red blood cell compartment, which makes them clinically asymptomatic and transfusion-independent. 26 Moreover, studies in the mouse model, aimed at evaluating the effect of mixed chimerism on SCD pathophysiology, have shown that a significant enrichment of erythrocyte over leukocyte chimerism occurred in these mice because of the dramatic survival advantage of donor over sickle red blood cells (RBCs) in the peripheral blood. 26 Increasing degrees of erythrocyte chimerism provided progressive correction of hematological and pathologic abnormalities in the mouse model, although sickle bone marrow and splenic hematopoiesis was not corrected until peripheral blood sickle RBCs were fully replaced with donor erythrocytes, indicating that 100% peripheral blood RBC chimerism is the most rigorous benchmark for cure after nonmyeloablative allograft.…”

“…26 Moreover, studies in the mouse model, aimed at evaluating the effect of mixed chimerism on SCD pathophysiology, have shown that a significant enrichment of erythrocyte over leukocyte chimerism occurred in these mice because of the dramatic survival advantage of donor over sickle red blood cells (RBCs) in the peripheral blood. 26 Increasing degrees of erythrocyte chimerism provided progressive correction of hematological and pathologic abnormalities in the mouse model, although sickle bone marrow and splenic hematopoiesis was not corrected until peripheral blood sickle RBCs were fully replaced with donor erythrocytes, indicating that 100% peripheral blood RBC chimerism is the most rigorous benchmark for cure after nonmyeloablative allograft. 26 The presence of residual host cells may also offer the advantage of reducing the incidence and severity of GVHD, as, in animal models, mixed chimerism is associated with reduced susceptibility to GVHD, probably thanks to mechanisms of central tolerance, with negative selection of host-alloreactive donor T cells.…”