Hilit Gur

Hematopoietic stem cell transplantation across major genetic barriers: tolerance induction by megadose CD34 cells and other veto cells.

Abstract: Studies in mice and humans demonstrate that transplantation of hematopoietic progenitors in numbers larger than commonly used overcomes major genetic barriers. In vitro studies suggest that veto cells, within the population of hematopoietic progenitors, facilitate this favorable outcome. Tolerance induction can be further enhanced by other veto cells. Perhaps the most potent veto cell is the CD8+ CTL. However, this cell is also associated with marked GVHD, which can be separated from the veto activity by generating anti‐third party CTLs under IL‐2 deprivation.

Hematopoietic Stem Cell Transplantation across Major Genetic Barriers

Abstract: Studies in mice and humans demonstrate that transplantation of hematopoietic progenitors in numbers larger than commonly used (“megadose” transplants) overcomes major genetic barriers. In vitro studies suggest that veto cells, within the population of hematopoietic progenitors, facilitate this favorable outcome. Thus, when purified CD34+ cells were added to bulk mixed‐lymphocyte reactions (MLRs) they suppressed CTLs against the donors stimulators, but not against stimulators from a third party. This tolerizing activity depends on cell contact and can be blocked by the caspase inhibitor BD‐FMK, suggesting that the effector host T cells are deleted by apoptosis upon interaction with the CD34+ cells. Early myeloid CD33+ cells generated by short‐term ex vivo expansion of CD34+ cells also exhibit veto activity, and these cells can be grown in large numbers. Tolerance induction can be further enhanced by other veto cells. Perhaps the most potent veto cell is the CD8+ CTL. However, this cell is also associated with marked GVHD (graft‐versus‐host disease. GVHD can be separated from the veto activity by generating anti‐third party CTLs under IL2 deprivation. Under such selective pressure only the stimulated clones which make IL2 can survive, while anti‐host clones die. In vivo studies show that such anti‐third party veto CTLs can be used safely for tolerance induction without GVHD.

Megadose of hematopoietic stem cells for haploidentical transplants

Studies in mice and humans demonstrate that transplantation of hematopoietic progenitors in numbers larger than commonly used (“megadose” transplants) overcomes major genetic barriers without induction of graft-versus-host disease. Therefore, transplantation from a human leukocyte antigen mismatched family member is a viable option for patients with acute leukemia at high risk of relapse who urgently need a transplant and who do not have a well matched unrelated donor. In vitro studies suggest that veto cells, contained in the population of hematopoietic progenitors, facilitate this favorable outcome. Future developments may extend the full-haplotype mismatched transplant to the elderly who cannot withstand highly intensive conditioning, patients with counter indications for intensive radiotherapy or chemotherapy and patients with nonmalignant hematological disorders in whom the current transplant related mortality rates are unacceptable.