PubMed · 4887489
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H Brücher. 1969. [The monocytes].. https://pubmed.ncbi.nlm.nih.gov/4887489/
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ANBL-6, a myeloma cell line, proliferates in response to interleukin 6 (IL-6) stimulation, coculture with bone marrow stromal cells, and when harboring a constitutively active mutant N-ras gene. Eighteen samples, including 4 IL-6-treated, 3 mutant N-ras-transfected, 3 normal stroma-stimulated, 2 multiple myeloma (MM) stroma-stimulated, and 6 untreated controls were profiled using microarrays interrogating 12 626 genes. Global hierarchical clustering analysis distinguished at least 6 unique expression signatures. Notably, the different stimuli altered distinct functional gene programs. Class comparison analysis (P =.001) revealed 138 genes (54% involved in cell cycle) that distinguished IL-6-stimulated versus nontreated samples. Eighty-seven genes distinguished stroma-stimulated versus IL-6-treated samples (22% encoded for extracellular matrix [ECM] proteins). A total of 130 genes distinguished N-ras transfectants versus IL-6-treated samples (26% involved in metabolism). A total of 157 genes, 20% of these involved in signaling, distinguished N-ras from stroma-interacting samples. All 3 stimuli shared 347 genes, mostly of metabolic function. Genes that distinguished MM1 from MM4 clinical groups were induced at least by one treatment. Notably, only 3 genes (ETV5, DUSP6, and KIAA0735) are uniquely induced in mutant ras-containing cells. We have demonstrated gene expression patterns in myeloma cells that distinguish an intrinsic genetic transformation event and patterns derived from both soluble factors and cell contacts in the bone marrow microenvironment.
Numerous reports have described the effects of interleukin-4 (IL-4) on bone biology. Previous studies, performed using complex coculture systems, demonstrated the effects of IL-4 on osteoblasts and osteoclasts. To directly test the effect of IL-4 on osteoclasts, we took advantage of a simplified system using recombinant receptor activator of nuclear factor kappaB ligand (RANKL) as the osteoclast differentiation factor. We analyzed the ability of IL-4 to directly regulate osteoclast differentiation and mature osteoclast function. We found that IL-4 inhibited the differentiation of osteoclasts from bone marrow precursors in an irreversible manner and also inhibited the resorptive capacity of mature osteoclasts. In the presence of IL-4, we detected the appearance of tartrate-resistant acid phosphatase (TRAP)-negative multinucleated giant (MNG) cells. Both IL-4 effects were dependent on signal transducer and activator of transcription 6 (STAT6). We found that IL-4 suppresses RANK mRNA expression in the developing precursor cells. When RANK was ectopically expressed under the cytomegalovirus (CMV) promoter in RAW264.7 macrophages, IL-4 treatment did not inhibit osteoclast development. Furthermore, when osteoclastogenesis was induced independently of RANKL by using tumor necrosis factor-alpha (TNF-alpha), IL-4 inhibited osteoclast differentiation through a STAT6-dependent mechanism. These results suggest that IL-4 regulates osteoclast development by regulating gene expression, including RANK. We propose that IL-4 irreversibly regulates the lineage commitment of precursor cells by regulating gene expression, resulting in the suppression of osteoclast development and the generation of MNG cells as an alternative pathway of differentiation.
Donor lymphocyte infusion (DLI) into patients with a relapse of their leukemia or multiple myeloma after allogeneic stem cell transplantation (alloSCT) has been shown to be a successful treatment approach. The hematopoiesis-restricted minor histocompatibility antigens (mHAgs) HA-1 or HA-2 expressed on malignant cells of the recipient may serve as target antigens for alloreactive donor T cells. Recently we treated three mHAg HA-1- and/or HA-2-positive patients with a relapse of their disease after alloSCT with DLI from their mHAg HA-1- and/or HA-2-negative donors. Using HLA-A2HA-1 and HA-2 peptide tetrameric complexes we showed the emergence of HA-1- and HA-2-specific CD8(+) T cells in the blood of the recipients 5-7 weeks after DLI. The appearance of these tetramer-positive cells was followed immediately by a complete remission of the disease and restoration of 100% donor chimerism in each of the patients. Furthermore, cloned tetramer-positive T cells isolated during the clinical response specifically recognized HA-1 and HA-2 expressing malignant progenitor cells of the recipient and inhibited the growth of leukemic precursor cells in vitro. Thus, HA-1- and HA-2-specific cytotoxic T lymphocytes emerging in the blood of patients after DLI demonstrate graft-versus-leukemia or myeloma reactivity resulting in a durable remission. This finding implies that in vitro generated HA-1- and HA-2-specific cytotoxic T lymphocytes could be used as adoptive immunotherapy to treat hematological malignancies relapsing after alloSCT.