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Blood, 1 June 2002, Vol. 99, No. 11, pp. 4174-4181
TRANSPLANTATION
Tolerance induction by megadose hematopoietic progenitor cells:
expansion of veto cells by short-term culture of purified human
CD34+ cells
Hilit Gur,
Rita Krauthgamer,
Alain Berrebi,
Tirza Klein,
Arnon Nagler,
Antonio Tabilio,
Massimo F. Martelli, and
Yair Reisner
From the Department of Immunology, Weizmann Institute
of Science, Rehovot, Israel; Department of Hematology,
Kaplan Medical Center, Rehovot, Israel; Rabin Medical
Center, Petah Tikva, Israel; Bone Marrow Transplant, Hadassah
University Hospital, Jerusalem, Israel; and Universita
Degli Studi di Perugia, Ematologia E Immunologia Clinica, Perugia,
Italy.
Stem cell-dose escalation is one way to overcome immune rejection
of incompatible stem cells. However, the number of hematopoietic precursors required for overcoming the immune barrier in recipients pretreated with sublethal regimens cannot be attained with the state-of-the-art technology for stem cell mobilization. This issue was
addressed by the observation that cells within the human
CD34+ population are endowed with veto activity. In the
current study, we demonstrated that it is possible to harvest about 28- to 80-fold more veto cells on culturing of purified CD34+
cells for 7 to 12 days with an early-acting cytokine mixture including
Flt3-ligand, stem cell factor, and thrombopoietin. Analysis of the
expanded cells with fluorescence-activated cell-sorter scanning
revealed that the predominant phenotype of
CD34+CD33 cells used at the initiation of the
culture was replaced at the end of the culture by cells expressing
early myeloid phenotypes such as CD34+CD33+ and
CD34CD33+. These maturation events were
associated with a significant gain in veto activity as exemplified by
the minimal ratio of veto to effector cells at which significant veto
activity was detected. Thus, whereas purified unexpanded
CD34+ cells exhibited veto activity at a veto-to-effector
cell ratio of 0.5, the expanded cells attained an equivalent activity
at a ratio of 0.125. The availability of novel sources of veto cells such as those in this study might contribute to the realization of
immunologic tolerance in "minitransplants," without any risk of
graft-versus-host disease.
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