Quantitatively different red cell/nucleated cell chimerism in patients with long-term, persistent hematopoietic mixed chimerism after bone marrow transplantation for thalassemia major or sickle cell disease

Abstract

BackgroundPersistent mixed chimerism represents a state in which recipient and donor cells stably co-exist after hematopoietic stem cell transplantation. However, since in most of the studies reported in literature the engraftment state was observed in the nucleated cells, in this study we determined the donor origin of the mature erythrocytes of patients with persistent mixed chimerism after transplantation for hemoglobinopathies. Results were compared with the engraftment state observed in singly picked out burst-forming unit -erythroid colonies and in the nucleated cells collected from the peripheral blood and from the bone marrow. Design and MethodsThe donor origin of the erythrocytes was determined analyzing differences on the surface antigens of the erythrocyte suspension after incubation with anti-ABO and/or anti-C, -c, -D, -E and -e monoclonal antibodies by a flow cytometer. Analysis of short tandem repeats was used to determine the donor origin of nucleated cells and burst-forming unit -erythroid colonies singly picked out after 14 days of incubation. ResultsThe proportions of donor-derived nucleated cells in four transplanted patients affected by hemoglobinopathies were 71%, 46%, 15% and 25% at day 1364, 1385, 1314 and 932, respectively. Similar results were obtained for the erythroid precursors, analyzing the donor/recipient origin of the burst-forming unit -erythroid colonies. In contrast, on the same days of observation, the proportions of donor-derived erythrocytes in the four patients with persistent mixed chimerism were 100%, 100%, 73% and 90%. ConclusionsOur results showed that most of the erythrocytes present in four long-term transplanted patients affected by hemoglobinopathies and characterized by the presence of few donor engrafted nucleated cells were of donor origin. The indication that small proportions of donor engrafted cells might be sufficient for clinical control of the disease in patients affected by hemoglobinopathies is relevant, although the biological mechanisms underlying these observations need further investigation.Key words: hemoglobinopathies, persistent mixed chimerism, hematopoietic stem cell transplantation.Citation: Andreani M, Testi M, Gaziev J, Condello R, Bontadini A, Tazzari PL, Ricci F, De Felice L, Agostini F, Fraboni D, Ferrari G, Battarra M, Troiano M, Sodani P and Lucarelli G. Quantitatively different red cell/nucleated cell chimerism in patients with long-term, persistent hematopoietic mixed chimerism after bone marrow transplantation for thalassemia major or sickle cell disease. Haematologica 2011;96(1):128-133. doi:10.3324/haematol.2010 This is an open-access paper.Quantitatively different red cell/nucleated cell chimerism in patients with long-term, persistent hematopoietic mixed chimerism after bone marrow transplantation for thalassemia major or sickle cell disease

Split chimerism between nucleated and red blood cells after bone marrow transplantation for haemoglobinopathies

“…11 Up to now, it is not clear if the mechanisms inducing an immunological tolerance in patients with PMC might also influence a different maturation of the donor erythroid precursors after HSCT for hemoglobinopathies. However, the presence of a split chimerism between mature erythrocytes and their progenitors has been recently described in persistent mixed chimera patients 13,14 with a predominant erythroid engraftment in the peripheral blood, while the proportion of erythroid precursors (BFU-E-burst forming unit erythroid) colonies and nucleated cells of donor origin in the bone marrow were equivalent (Fig. 1).…”

Hematopoietic Stem Cell Transplantation in Thalassemia and Sickle Cell Anemia

“…Moreover, by analyzing singularly picked-up burst-forming unit erythroid colonies, we showed that the proportion of donorderived erythroid precursors was equivalent to that observed in the mature nucleated cells, rather than that of the red blood cells. These results suggest that in patients characterized by the presence of PMC after HSCT, a selective advantage of the maturation of donor erythroid precursors might successfully contrast the problems associated with the recipient ineffective erythropoiesis (Andreani et al 2011b). …”

The role of donor-derived veto cells in nonmyeloablative haploidentical HSCT

“…Mixed chimerism after nonmyeloablative HSCT has been found beneficial for both thalassemia and SCA patients, [76][77][78][79] where a limited percentage of engrafted donor cells may be sufficient to overcome disease phenotype. Thus, the rationale for lowerintensity conditioning is relevant, because of its ability to promote mixed tolerance and the decreased risk for transplant-related toxicity and mortality, which will open HSCT-curative treatment to more patients.…”