Human natural killer (NK) cells comprise 10% to 15% of peripheral blood mononuclear cells and have an important role in immune responses against tumors, viral infections, and graft rejection. NK cells originate in bone marrow (BM), but their progenitors and lineage development have not been completely characterized. We studied the generation of NK cells from purified CD34+HLADR- and CD34+HLADR+ BM progenitors and the influence of various cytokines on their production. We show that CD3-CD56+ cytotoxic NK cells can develop from both progenitors populations when interleukin-2 (IL-2) is present in an in vitro suspension culture system containing IL-1 alpha and stem cell factor. Up to 83.8% and 98.6% CD3-CD56+ cells were detected in CD34+HLADR- and CD34+DR+ cultures, respectively, after 5 weeks of culture; significant numbers of NK cells were first detected after 2 weeks. Cytotoxic activity paralleled NK cell numbers; up to 70% specific lysis at an effector:target ratio of 10:1 was observed at 5 weeks. IL-7 also triggered development of CD3-CD56+ cells from these immature progenitors (up to 24% and 55% appeared in CD34+HLADR- and CD34+HLADR+ cultures, respectively). Our data suggest that BM stromas are not necessary for NK cell development and that IL-2 remains essential for this lineage development and differentiation.
Human natural killer (NK) cells originate from bone marrow, but little is known about NK cell progenitors and ontogeny. We studied the phenotype and functional activity of NK cells derived from highly purified human bone marrow CD34+ cells, which exhibited neither lytic activity nor expression of surface antigens characteristic of NK (CD56) or T (CD3) cells. However, when cultured with hematopoietic growth factors or feeder layers for up to 4 weeks, up to 86% functional CD56+ cells were seen in the absence of mature T cell development. CD56+ cells appeared in all cultures at 2 or 3 weeks, with the largest percentage in those exposed to IL·2. These studies demonstrated that NK cells arise ‘in vitro’ from immature bone marrow progenitors and also suggest a separate origin and differentiation pathway for NK and T cells.
Human natural killer (NK) cells play an important role in first-line defence against primary and metastatic tumours. Their stimulation after autologous bone marrow transplantation (ABMT) may be useful to eradicate residual tumour cells. Human NK cells originate in bone marrow (BM) but little is known about their progenitors and lineage development. We studied NK cell ontogeny from BM progenitors obtained by 'purging' normal BM with 4-hydroperoxycyclophosphamide (4HC); this agent is known to destroy all but the most primitive BM progenitors. NK cells, defined by their phenotypic markers and cytolytic activity, could be generated from 4HC-treated BM cells during in vitro cultures over stromal BM feeder layers and in suspension cultures containing a mixture of soluble cytokines; Interleukine 2 appears to be essential for the full development of this population. A lag period exists before NK cells can be found in significant numbers in culture; this suggests that a delay in initiation of immunotherapy after ABMT ought to be considered, particularly when using purged marrow.
Autologous bone marrow transplantation (ABMT) is widely used to treat hematologic and non-hematologic malignancies. In an attempt to reduce potential neoplastic contamination of the graft, pharmacologic purging with cyclophosphamide derivatives and etoposide (VP16) is often used. Trilineage hemopoietic engraftment is seen following ABMT with VP16-purged bone marrow (BM), but little is known about immune reconstitution in this setting. We studied the in vitro development of natural killer (NK) cells from VP16-purged BM. These cells, defined by phenotypic and functional criteria, undergo rapid regeneration, expansion, and maturation in the presence of interleukin 2 (IL-2). VP16 seems to spare subsets of NK cells, and this cell lineage develops rapidly in VP16-treated BM cultures from patients with acute myelogenous leukemia (AML) and healthy donors. Since relapse rates remain high, immunotherapy following ABMT with purged BM may be useful and should be considered in these patients.
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