Table of contents :

  • sources of HSC
  • bone marrow
  • peripheral blood
  • umbilical cord blood
  • reconstitution
  • expansion of HSC
  • enumeration of HSC
  • HSC delivery
  • compatibility
  • web resources
  • bibliography

  • September 12, 2007, marked the 50th anniversary of E. Donnall (Don) Thomas's initial report of a radical new approach to cancer treatment: radiation and chemotherapy followed by the intravenous infusion of bone marrowref. That publication represented the beginning of a long series of laboratory and clinical investigations; more than a decade would pass before the procedure achieved its first successes. Yet Thomas's persistence in the face of criticism and clinical failure ultimately paid off in a new form of therapy that was used to treat approximately 50,000 people worldwide in 2006. Thomas's interest in the possibility of hematopoietic-cell transplantation was sparked in 1949, during his residency at Peter Bent Brigham Hospital in Boston, when he learned of Leon Jacobson's experiment showing that a mouse exposed to otherwise lethal irradiation would survive if its spleen, or in later studies its marrow, was shieldedref. That its survival was due to a cellular rather than humoral effect was proven several years later, when researchers showed that irradiated mice given an infusion of marrow with a chromosome marker recovered with marrow cells exclusively of donor origin. With that experiment, Thomas became convinced of the clinical potential of human marrow transplantation. In 1955, he moved to the Mary Imogene Bassett Hospital in Cooperstown, New York, and began working with Joseph Ferrebee. Thomas and Ferrebee's 1957 article describes the first experience with allogeneic marrow transplantation in humans: six patients were treated with irradiation and chemotherapy and then intravenous infusion of marrow from a normal donor. Although the infusion was not accompanied by severe adverse effects, only two patients had transiently detectable marrow grafts, and none survived beyond 100 days. Others' attempts at allogeneic marrow transplantation, including some in victims of a nuclear-reactor accident, also failed, and by the early 1960s, many were pessimistic about whether such grafting would ever be possible. With little known about histocompatibility, no one tried to match donors and recipients. Although many researchers abandoned the field, Thomas remained convinced of its potential and began conducting experiments using an outbred canine model. He found that most dogs that were given total-body irradiation and infusion of littermate marrow had the same problems as humans, including graft rejection, graft-versus-host disease (GVHD), and death from opportunistic infection. Occasionally, however, a dog became a healthy long-term survivor with marrow cells of donor origin. Thomas reasoned that appropriate donor selection was the key. In 1963, he moved to Seattle, where he and his colleagues developed rudimentary canine histocompatibility typing. By the mid-1960s, they could show that most dogs given sufficient irradiation followed by grafts from dog leukocyte antigen–matched littermates and a short course of immunosuppression survived long-term. At the same time, the first methods for human leukocyte antigen typing were being developed, and Thomas decided to return to human marrow grafting. He assembled a research team and in 1969 began clinical trials of allogeneic marrow transplantation from matched siblings. His first patients had very advanced leukemia, and Thomas went to extraordinary lengths to support them through the procedure, including asking staff members to donate platelets, using patients with chronic myeloid leukemia as granulocyte donors, and working with Robert Hickman to develop a catheter for intravenous alimentation. When GVHD developed in patients, Thomas inoculated horses with human lymphocytes to create antithymocyte globulin as a treatment (and was kicked more than once in the process). Most patients died of progressive leukemia or complications of transplantation, but some entered complete remission. In 1970, the Seattle group published the results of their efforts in patients with leukemia, and in 1972 they reported the first successful allogeneic transplantations for aplastic anemia. In 1975, Thomas published an article showing a plateau in the survival curve of patients who received transplants for end-stage acute leukemia, suggesting that a cure had been achieved in a minority of patientsref. This cure of even a small percentage of otherwise incurable patients led Thomas to explore transplantation earlier in the course of disease, and in 1979 he and his colleagues reported achieving a cure rate above 50% with transplantation for acute myeloid leukemia that was in remissionref

    Sources of HSCs :

    Expansion of human HSCs : CD34+ cell enumeration : CXCR4 is required for the homing of hematopoietic stem/progenitor cells (HSPC) to the bone marrow immediately after transplantation. Murine HSCs engraft with near absolute efficiency into irradiated mice, but most initially engrafted cells fail to sustain self-renewal, leading to low frequency of permanent reconstitutions. HSC delivery : Compatibility : See also vaccinations for HSCT recipients
    Web resources :
    Bibliography :
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