Biomedical subjects

T Grunberger

Publications and source records attributed to T Grunberger.

8 recordsLinked to original sources

PubMed1992

Interleukin 6 induces myeloid differentiation of a human biphenotypic leukemic cell line.

The human leukemic cell line B1, is characterized by a specific 4;11 chromosomal translocation, immature myeloid/pre-B biphenotypic features, expression of multiple cytokine receptors and IL-1-dependent autocrine growth regulation [Cohen et al. (1991) Blood 78, 94]. Exposure of B1 cells to low concentrations of IL-6 abolished the leukemic cells ability to form colonies in semi-solid medium and slowed down their proliferation rate in suspension. Associated with these changes in growth characteristics, the B1 cells differentiated along the myeloid lineage as judged by the induction of the myeloid-specific surface antigens CD33, CD13 and CD11b, as well as histochemical and morphological changes characteristic of myeloid cells. The induction of differentiation was specific to IL-6 since none of the other cytokines which inhibited B1 cell growth (IL-7, gamma IFN and TNF alpha) were able to induce myeloid or lymphoid differentiation in these cells. The IL-6-induced differentiation was completed over a two week period and was essentially irreversible. Together with the phenotypic changes, IL-6 induced the expression of the protein tyrosine phosphatase (CD45) which may be associated with altered growth observed in IL-6-treated cells. Induction of terminal differentiation of leukemic cells by recombinant bioregulators has therapeutic implications and merits further study.

Bone Marrow↗

PubMed1992

Central role of tumour necrosis factor, GM-CSF, and interleukin 1 in the pathogenesis of juvenile chronic myelogenous leukaemia.

In previous studies on patients with juvenile chronic myelogenous leukaemia (JCML), we found excessive proliferation of malignant monocyte-macrophage elements in the absence of exogenous growth factor, and impaired growth of normal haematopoietic progenitors. In the current study, six newly-diagnosed JCML patients were investigated to characterize the disease further. In co-cultures, JCML cell culture supernatant as well as patient plasma obtained at diagnosis produced a striking reduction in numbers of control marrow BFU-E, CFU-GM, CFU-Meg and CFU-GEMM colonies. Monoclonal anti-tumour necrosis factor alpha neutralizing antibodies (anti-TNF-alpha Ab) abolished these inhibitory properties. In sharp contrast, JCML supernatants exerted a marked growth-promoting effect on autologous JCML cells cultured in clonogenic assays. Anti-TNF-alpha Ab and anti-granulocyte-macrophage colony-stimulating factor neutralizing antibodies (anti-GM-CSF Ab) both reversed the stimulating effect. Recombinant GM-CSF and recombinant TNF alpha produced a profound increase in JCML colonies when tested individually and anti-GM-CSF Ab reversed the TNF-alpha effect. Expression studies of TNF-alpha and TNF-alpha receptor genes of cultured JCML cells demonstrated mRNAs for both. Further, TNF-alpha activity was assayed in a wide variety of cell culture supernatants and in normal and patients' plasma, and only the JCML specimens showed increased TNF-alpha values. Recombinant interleukin-1 alpha (IL-1 alpha) also stimulated JCML colony growth, but polyclonal anti-IL-1 neutralizing antibodies did not suppress JCML colony numbers nor did it reverse the effects of TNF-alpha or GM-CSF. The evidence indicated that the JCML monokine which inhibits normal haematopoiesis is TNF-alpha and that the endogenously-produced TNF-alpha and GM-CSF from JCML cells play an important role in the pathogenesis of the disease by acting as autocrine growth factors. IL-1 alpha also stimulates JCML cell proliferation as an accessory factor and augments the effect of GM-CSF, TNF-alpha or both.

Base Sequence↗

PubMed1992

Differential kinetics of engraftment and induction of CD10 on human pre-B leukemia cell lines in immune deficient scid mice.

The sensitivity of the scid mouse model was assessed by comparing the growth of two pre-B acute lymphoblastic leukemia (ALL) cell lines, A1 and G2, established from patients at relapse. When cell numbers varying from 10(4) to 10(7) were injected intravenously into scid mice, advanced growth and dissemination of leukemia was observed at 10-12 weeks with the G2 cells. Bone marrow, spleen and thymus contained high levels of human leukemic cells and infiltration into lung, kidney, liver, and brain was observed. Two of three mice grafted with only 100 cells showed high levels of infiltration at 15 weeks, suggesting that 100 G2 cells was near the limiting cell number that could produce disseminated leukemia. With the A1 line, a minimum of 10(5) cells was needed to obtain dissemination to liver, lung, brain, and kidney; a low level of spleen infiltration occurred and thymus invasion was not observed. In vitro, both lines showed a density dependent growth in clonogenic assays but the cloning efficiency of the A1 line was 10-fold higher than for G2 cells. These results indicate that G2 and A1 lines have a dissimilar aggressiveness in vivo which does not correlate with clonogenic assay in vitro. Neither G2 nor A1 lines, growing in vitro, expressed CD10/CALLA on their surface, despite low levels of antigen on the freshly obtained relapse samples. Although A1 cells remained CD10-negative in the scid mice, G2 cells showed detectable levels of CD10, particularly on those cells found in the thymus. Several subclones of the G2 line were derived from isolated colonies in vitro; they were found to be CD10- in vitro, but to become CD10+ when proliferating into scid mouse thymus, suggesting the induction of CD10 by the murine microenvironment.

Animals↗

PubMed1991

Bone marrow from children in relapse with pre-B acute lymphoblastic leukemia proliferates and disseminates rapidly in scid mice.

Bone marrow samples from patients with pre-B acute lymphoblastic leukemia (pre-B ALL), either at diagnosis or at relapse, were transplanted into scid mice to determine whether these freshly obtained leukemic cells could proliferate in vivo and whether there were any differences in their in vivo growth characteristics. Cells from three patients who relapsed within 13 months of diagnosis proliferated rapidly in the murine bone marrow, spleen, and thymus, invaded peripheral organs, and resulted in morbidity and mortality of the animals within 4 to 16 weeks. Cells from two patients who relapsed 3.5 years after diagnosis grew much slower than the early relapse samples, taking up to 30 weeks to infiltrate the bone marrow of recipient mice. In contrast, leukemic cells were absent or were detected at low numbers in scid mice transplanted with cells obtained at diagnosis from three patients who have not yet relapsed. These results show an increased ability of leukemic cells from patients with aggressive lymphoblastic leukemia of poor prognosis to proliferate in scid mice.

Adolescent↗

PubMed1991

Diamond-Blackfan anemia: heterogenous response of hematopoietic progenitor cells in vitro to the protein product of the steel locus.

Diamond-Blackfan anemia is a congenital disorder of erythropoiesis in humans, characterized by a macrocytic anemia often associated with physical anomalies. Mutations at either the W or Steel loci in the mouse also leads to a severe macrocytic anemia, as well as other developmental abnormalities. The W locus encodes the proto-oncogene c-kit, a member of the receptor tyrosine kinase family, while the Steel locus encodes a potent hematopoietic growth factor that is the ligand for c-kit. Growth of clonogenic marrow erythroid progenitor cells in vitro in the presence of the recombinant hematopoietic growth factors interleukin-3 (IL-3) and Steel was used to characterize this disease at the cellular level. Three patterns of in vitro marrow response to both recombinant IL-3 or Steel were observed among 10 Diamond-Blackfan patients: those that responded quantitatively and qualitatively almost as well as cells from normal marrow, those that responded at an intermediate level, and those that did not respond at all. These results provide evidence for cellular heterogeneity underlying the pathogenesis of this disorder and therefore raise the possibility that there may be more than one underlying molecular basis for the disease. No gross abnormalities in the structure of either the c-kit or Steel loci were observed in these patients. The normal response in culture of the progenitor cells from at least some patients to Steel with or without IL-3 raises the possibility of using this novel growth factor as a therapeutic agent in Diamond-Blackfan anemia.

Adolescent↗

PubMed1991

Constitutive expression and role in growth regulation of interleukin-1 and multiple cytokine receptors in a biphenotypic leukemic cell line.

A cell line (B1) was established from the bone marrow of a patient with a relapse of acute leukemia characterized by a 4;11 chromosomal translocation and biphenotypic features of early B and myeloid lineages. Analysis of the growth requirements of this cell line showed density-dependent growth and secretion of an autostimulatory growth factor, suggesting an autocrine mechanism. Several lines of evidence implicate the participation of interleukin-1 (IL-1) in the autocrine growth regulation of B1 cells. These cells constitutively express the messenger RNA (mRNA) for IL-1 and IL-1 receptor and secrete IL-1; recombinant IL-1 stimulated the growth of colonies when cells were seeded at low density, and anti-IL-1 antibodies inhibited the growth of colonies with cells seeded at higher density. B1 cells do not express detectable levels of mRNA for any of the other cytokines tested, and other cytokines failed to support the growth of B1 cells at low density. In addition, B1 cells express multiple cytokine receptor genes, including the receptors for IL-6, IL-7, tumor necrosis factor and gamma-interferon. Addition of the respective cytokines to the B1 cells resulted in inhibition of the growth of leukemic cells in vitro. The multiplicity of growth-inhibitory cytokine receptors on this leukemic cell line might be due to its biphenotypic lineage and may suggest new therapeutic possibilities in controlling leukemic cell proliferation.

Acute Disease↗

PubMed1975

Influence of albumin on rubella virus hemagglutination and the hemagglutination-inhibition test.

The HEPES-saline-albumin-gelatin (HSAG) diluent found optimal for agglutination of fowl erythrocytes by rubella virus antigen is also optimal for agglutination of trypsin-treated human group O cells. Albumins from different commercial sources, however, can have varying inhibitory effects on rubella hemagglutination titers. This can have a significant effect on the hemagglutination-inhibition test since antibody titers measured by this procedure are related to the amount of antigen used.

Animals↗

PubMed1975

A microplaque reduction assay for human and mouse interferon.

A microplaque reduction assay for human and mouse interferons is described, using plastic disposable multicompartmental plates with flat-bottomed wells of 6 mm in diameter. The procedure is rapid and reproducible and lends itself to a considerable degree of automation. Its potential application in other areas of virology, such as rapid screening of samples for virus content or assay of neutralizing antibodies, is also discussed.

Cell Line↗