Regulatory T cells and immune tolerance after allogeneic hematopoietic stem cell transplantation

The story of allogeneic hematopoietic stem cell transplantation (allo-SCT) begins after the atomic bombings of Hiroshima and Nagasaki in 1945. It was observed that fallout radiation caused dose-dependent depression of hematopoiesis 1. Research first focused on how to protect the hematopoietic system from irradiation injury and it was discovered that infusion of spleen or marrow cells from a healthy donor restored hematopoiesis through the establishment of hematopoietic donor chimerism in an irradiated recipient 2. This finding led to the realization that it might also be applied to treat hematological malignancies. In 1957, a new approach to human cancer treatment was reported: radiation and chemotherapy followed by the intravenous infusion of healthy donor bone marrow 3,4. However, all the early clinical transplantation attempts in the late 50’s and early 60’s failed due to, what was later discovered, inappropriate donor selection. Eventually, in 1968, the first successful allogeneic bone marrow transplantations using human leukocyte antigen (HLA)-identical siblings was reported 5,6. More than four decades later, allogeneic hematopoietic stem cell transplantation (allo-SCT) is an established treatment modality for patients with hematological malignancies, aplastic anemia, and inborn errors of hematopoietic progenitor cells 7. The preferred donor for an allogeneic transplant is still an HLA-identical sibling. However, as only 25-30% of patients have an HLA-matched sibling donor available, hematopoietic stem cells (HSC) from HLA-matched-unrelated-donors are increasingly used. Matched-unrelated-donors can be identified from the bone marrow donor worldwide registry, in which more than 10 million HLA-typed volunteer donors are registered 8. Currently, granulocyte-colony stimulating factor-mobilized peripheral blood stem cells are the most common source of stem cells, as transplantation of these cells results in more rapid reconstitution compared to transplantation of bone marrow (BM) cells 9. However, for high-risk patients the time to obtain a transplant from a suitable donor may be too long as the median time span between the start of the search and actual SCT is 4 months 10. In this case, more readily available alternative stem cells sources including haplo-identical donors 11 or cord blood (CB) 12 can be considered.

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