Cytokines with possible clinical utility.
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Biological Products↗
Biomedical subjects
R Mertelsmann
Publications and source records attributed to R Mertelsmann.
Leukemic colony-forming cells in acute myeloblastic leukemia: maturation hierarchy and growth conditions.
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Bone Marrow↗
T-cell activation defect in common variable immunodeficiency: restoration by phorbol myristate acetate (PMA) or allogeneic macrophages.
Common variable immunodeficiency (CVI) represents a group of familial and sporadic diseases characterized by a range of B-cell, T-cell, and macrophage defects. A defect in T-cell activation, involving reduced proliferation and IL-2 production after stimulation with OKT3 antibody, has been described previously. In the present study we found that these defects could be corrected in vitro by adding phorbol myristate acetate (PMA) to OKT3-stimulated peripheral blood mononuclear cells (PBMC) of 14 patients with CVI. PBMC of 6 out of 7 patients with CVI studied also exhibited a profound defect in IL-2 receptor expression when incubated with OKT3 antibody. IL-2 receptor expression after stimulation with PMA alone was normal, indicating that the OKT3- but not the PMA-induced pathway of IL-2 receptor expression was defective. On the RNA level, the genes for IL-2 and IL-2 receptor were expressed after stimulation with OKT3 antibody. IL-2 and IL-2 receptor gene expression were normal, indicating a possible post-transcriptional defect. To investigate whether the defect in T-cell activation was at the macrophage or the T-cell level, we prepared adherent cells and monocyte-depleted T cells (E+) from 3 patients with CVI and from normal blood donors. Incubating CVI E+ cells with normal adherent cells resulted in normal proliferation and IL-2 production in the presence of OKT3, whereas incubation of normal E+ cells with adherent cells from patients with CVI under the same conditions showed reduced IL-2 production and proliferation, suggesting the macrophage as the origin of the failure in T-cell activation in the patients with CVI studied. Inhibition by macrophage-secreted prostaglandins was excluded by failure to correct the IL-2 production and proliferation defects in the presence of indomethacin.
Adult↗
Interleukin-2 production and response to interleukin-2 by peripheral blood mononuclear cells from patients after bone marrow transplantation: II. Patients receiving soybean lectin-separated and T cell-depleted bone marrow.
The ability of peripheral blood mononuclear cells (PBMC) to produce and respond to interleukin-2 (IL-2) was evaluated in 50 recipients of HLA-identical bone marrow (BM) depleted of mature T cells by soybean agglutination and E rosetting (SBA-E-BM). In contrast to our previous findings in recipients of unfractionated marrow, during weeks 3 to 7 post-SBA-E-BM transplantation (BMT), PBMC from the majority of patients spontaneously released IL-2 into the culture medium. This IL-2 was not produced by Leu-11+ natural killer cells, which were found to be predominant in the circulation at this time, but by T11+, T3+, Ia antigen-bearing T cells. The IL-2 production could be enhanced by coculture with host PBMC frozen before transplant but not by stimulation with mitogenic amounts of OKT3 antibody, thus suggesting an in vivo activation of donor T cells or their precursors by host tissue. Spontaneous IL-2 production was inversely proportional to the number of circulating peripheral blood lymphocytes and ceased after 7 to 8 weeks post-SBA-E-BMT in most of the patients. In patients whose cells had ceased to produce IL-2 spontaneously or never produced this cytokine, neither coculture with host cells nor stimulation with OKT3 antibody thereafter induced IL-2 release through the first year posttransplant. Proliferative responses to exogenous IL-2 after stimulation with OKT3 antibody remained abnormal for up to 6 months post-SBA-E-BMT, unlike the responses of PBMC from recipients of conventional BM, which responded normally by 1 month post-BMT. However, the upregulation of IL-2 receptor expression by exogenous IL-2 was found to be comparable to normal controls when tested as early as 3 weeks post-SBA-E-BMT. Therefore, the immunologic recovery of proliferative responses to IL-2 and the appearance of cells regulating in vivo activation of T cells appear to be more delayed in patients receiving T cell-depleted BMT. Similar to patients receiving conventional BMT, however, the ability to produce IL-2 after mitogenic stimulation remains depressed for up to 1 year after transplantation.
Adult↗
High-dose cytosine arabinoside and mitoxantrone: a highly effective regimen in refractory acute myeloid leukemia.
In a clinical phase I/II study, high-dose cytosine arabinoside and mitoxantrone (HAM) were given in combination to 40 patients with refractory acute myeloid leukemia. All patients had received a 9-day combination of thioguanine, Ara-C, and daunorubicin (TAD-9) as standardized first-line treatment. Refractoriness was defined as (a) nonresponse against two TAD-9 induction cycles, (b) early relapse within the first 6 months on monthly maintenance or after TAD-9 consolidation, (c) relapse after 6 months with nonresponse against one additional TAD-9 cycle, and (d) second and subsequent relapses after successful TAD-9 therapy at the preceding relapse. Therapy consisted of HD-Ara-C 3 g/m2 every 12 hours on days 1 through 4; mitoxantrone was started at 12 mg/m2/day on days 3, 4, and 5 and was escalated to 4 and 5 doses of 10 mg/m2/day on days 2 through 5 and 2 through 6. Of the 40 patients, 21 achieved a complete remission (53%), 1 patient had a partial remission, and 5 patients were nonresponders. Thirteen patients died in aplasia due to infections (n = 11), pericardiac effusion, or acute cardiomyopathy. Nonhematologic side effects consisted predominantly of nausea and vomiting, mucositis, and diarrhea. Central nervous system (CNS) symptoms were observed during six treatment courses. Recovery of blood counts occurred at a median of 27 days from the onset of treatment; the median time to complete remission was 36 days. Two of the 21 responders underwent successful bone marrow transplantations. The median remission duration for the remaining 19 patients is 4.5 months, and the median survival time is 9 months. These data emphasize that HAM has high antileukemic activity in refractory AML and strongly suggest starting the combination at earlier stages in AML therapy.
Adolescent↗
High-dose cytosine arabinoside in combination with mitoxantrone for the treatment of refractory acute myeloid and lymphoblastic leukemia.
In the present study 55 patients with refractory acute myeloid leukemia (AML) (n = 44) and acute lymphoblastic leukemia (ALL) (n = 11) were treated with high-dose cytosine arabinoside (HD-ara-C) and mitoxantrone (HAM) to assess the toxicity and antileukemic activity of the two-drug combination. All patients had received a standardized first-line therapy according to the corresponding multicenter trials of the German AML and ALL cooperative groups and were considered refractory to conventional treatment. Therapy consisted of HD-ara-C 3 g/m2 every 12 hours on days 1 to 4; mitoxantrone was started at 12 mg/m2/d on days 3, 4, and 5 and was escalated to four and five doses of 10 mg/m2/d on days 2 to 5 and 2 to 6. From the 44 patients with AML, 24 (54%) achieved a complete remission, two a partial remission, and five were nonresponders. Thirteen patients died of infections (n = 11), pericardiac effusion, or acute cardiomyopathy. In refractory ALL, seven of 11 patients (64%) went into a complete remission, one patient was resistant, and three patients were early deaths. Nonhematologic side effects consisted predominantly of nausea and vomiting, mucositis, and diarrhea. More severe CNS symptoms were encountered during five treatment courses. The median time to complete remission was 36 days. Excluding five patients who underwent bone marrow transplantations, the median remission duration was 4.5 months in AML and 2.3 months in ALL. The median survival time was three months for all patients and nine months for responders only. These data emphasize a high antileukemic activity of HAM in refractory AML and ALL and support the incorporation of the HAM regimen into first-line treatment.
Adolescent↗
Tumor necrosis factor (TNF)-alpha but not TNF-beta induces secretion of colony stimulating factor for macrophages (CSF-1) by human monocytes.
Tumor necrosis factor (TNF)-alpha has been identified as a major inducer of colony stimulating factor (CSF)-secretion by human vascular endothelial cells and fibroblasts. In the present study we assessed the capacity of TNFs to induce release of CSF-1 from highly purified peripheral blood monocyte preparations. Whereas monocytes do not accumulate CSF-1 messenger (m)RNA constitutively and consequently do not produce CSF-1 protein, CSF-1 mRNA and protein secretion became detectable, when monocytes were cultured in the presence of TNF-alpha, that was synergistically enhanced by interferon-gamma (IFN-gamma). However, under identical experimental conditions TNF-beta failed to induce monocyte CSF-1 synthesis. Cultures of monocytes in the presence of TNF-beta before addition of TNF-alpha abolished the CSF-1 inducing capacity of TNF-alpha, suggesting that TNF-beta may act as antagonist to TNF-alpha for CSF-1 production. These data point out a previously unrecognized function of TNF-alpha to modulate CSF-1 release by monocytes and demonstrate disparate biological properties of different TNF species in hematopoiesis.
Colony-Forming Units Assay↗
Recombinant human granulocyte colony-stimulating factor: effects on normal and leukemic myeloid cells.
Experiments were conducted to isolate and characterize the gene and gene product of a human hematopoietic colony-stimulating factor with pluripotent biological activities. This factor has the ability to induce differentiation of a murine myelomonocytic leukemia cell line WEHI-3B(D+) and cells from patients with newly diagnosed acute nonlymphocytic leukemia (ANLL). A complementary DNA copy of the gene encoding a pluripotent human granulocyte colony-stimulating factor (hG-CSF) was cloned and expressed in Escherichia coli. The recombinant form of hG-CSF is capable of supporting neutrophil proliferation in a CFU-GM assay. In addition, recombinant hG-CSF can support early erythroid colonies and mixed colony formation. Competitive binding studies done with 125I-labeled hG-CSF and cell samples from two patients with newly diagnosed human leukemias as well as WEHI-3B(D+) cells showed that one of the human leukemias (ANLL, classified as M4) and the WEHI-3B(D+) cells have receptors for hG-CSF. Furthermore, the murine WEHI-3B(D+) cells and human leukemic cells classified as M2, M3, and M4 were induced by recombinant hG-CSF to undergo terminal differentiation to macrophages and granulocytes. The secreted form of the protein produced by the bladder carcinoma cell line 5637 was found to be O-glycosylated and to have a molecular weight of 19,600.
Animals↗
Cytofluorometric detection of chronic myelocytic leukemia supervening in a patient with chronic lymphocytic leukemia.
An 82-year-old woman with stage I chronic lymphocytic leukemia presented with systemic symptoms, minimal adenopathy, hepatosplenomegaly, and anemia five years after the initial diagnosis was made and while receiving no therapy. Her white blood cell count was 231,000/mm3 with an absolute neutrophil count of 164,360/mm3 and lymphocyte count of 43,890/mm3. Peripheral blood smear inspection revealed both increased mature lymphocytes and myeloid cells at all stages of maturation. Flow cytometric analysis of forward- and right-angle light scatters demonstrated the presence of two populations of cells, one lymphoid, bearing predominantly lambda light chain surface immunoglobulin and showing phenotypic characteristics of B cell chronic lymphocytic leukemia (HLA-DR-positive, BL-1-positive, BL-2-positive, BL-7-positive, Leu-1-positive, Leu-10-positive, BL-5-negative, BL-6-negative, and OKM1-negative), and another granulocytic population expressing phenotypic features compatible with myeloid lineage (HLA-DR-negative, Leu-1-negative, BL-1-negative, BL-2-negative, BL-7-negative, Leu-10-negative, BL-5-positive, BL-6-negative, OKM1-positive, and surface immunoglobulin-negative). All of the peripheral blood cell metaphases were Philadelphia chromosome-positive after 24 hours of culture, confirming the diagnosis of chronic myelocytic leukemia, whereas all of the Epstein-Barr virus-treated B lymphocyte metaphases showed a normal karyotype after two weeks of culture. In this patient, analysis of surface antigens and immunoglobulin fractions by flow cytometry proved to be useful in recognizing concomitantly expressed leukemic lineages. This approach allows the increasing recognition of the heterogeneity of leukemic populations.
Aged↗
Treatment of stages I and II Hodgkin's disease with three different therapeutic modalities.
Since 1969, 184 previously untreated and evaluable adult patients with Hodgkin's disease, staged as I (43) or II (141), have been treated. Eighty patients were part of the National Hodgkin's Disease Study, randomly assigned to receive radiotherapy to either an involved (39) or extended field (41). In a subsequent single-arm study, 104 patients were treated with involved-field radiotherapy preceded and followed by three cycles of MOPP chemotherapy. Median durations of follow-up have been 172, 172, and 92 months, for the involved-field radiotherapy, extended-field radiotherapy, and MOPP plus involved-field radiotherapy treatment groups, respectively. Although significant differences among the three treatment groups were observed with respect to disease-free survival (p less than 0.001), only the group of patients treated with involved-field radiotherapy had a statistically significant decline in overall survival as compared with the two other treatment groups (p less than 0.001). Moreover, patients who underwent clinical staging and were treated with MOPP plus involved-field radiotherapy had significantly prolonged disease-free survival compared with those who underwent surgical staging and were treated with extended-field radiotherapy (p less than 0.001). One of the patients who received MOPP plus involved-field radiotherapy had subsequent development of acute monocytic leukemia, and another had refractory anemia with excess blasts. One instance of diffuse poorly differentiated lymphocytic lymphoma was also observed. Acute monocytic leukemia developed in another patient treated with involved-field radiotherapy. The rates of amenorrhea in the group treated with MOPP plus involved-field radio-therapy were 9.6 percent and 78.5 percent for female patients younger and older than 30 years of age, respectively. Despite the universal azoospermia ensuing after MOPP plus involved-field radiotherapy, in three patients whose sperm counts were checked sequentially for 26 to 53 months after treatment, evidence of spermatogenesis was observed. Three patients with remission of Hodgkin's disease after involved-field (two) and extended-field (one) radiotherapy died from cardiovascular disease that could only be attributed to the prior radiotherapy. Although further follow-up evaluation will be required to determine the impact of the three different treatment modalities on survival and long-term toxicity, MOPP plus involved-field radiotherapy appears to be superior to involved-field or extended-field radiotherapy alone in achieving prolonged disease-free survival without significant leukemogenic potential.
Adult↗
Human pluripotent hemopoietic colony stimulating factor: activities on human and murine cells.
Human pluripotent colony stimulating factor (Pluripoietin) was shown to act synergistically with human pluripotent alpha-like colony-stimulating activity (Pluripoietin-alpha) supporting the proliferation and differentiation of human CFU-GM progenitor cells in vitro, increasing colony size and numbers. In addition, Pluripoietin enhanced cytotoxic activity of mature human neutrophil granulocytes in an antibody-dependent cellular cytotoxicity assay. Biological activities of Pluripoietin known so far suggest great potentials for clinical use. Preclinical in vivo studies of Pluripoietin in different disease situations may be feasible in mice, because Pluripoietin is active on granulocyte precursors and on a variety of other murine cells.
Animals↗
Human interleukin 2: molecular biology, physiology and clinical possibilities.
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Animals↗
Current status of treatment of acute leukemia in adults: an overview of the Memorial experience and review of literature.
The results of treatment of 629 previously untreated adults with acute leukemia at Memorial Hospital are reviewed. During the past 14 years, 135 adults (greater than 15 years) with acute lymphoblastic leukemia (ALL) have been treated with one of three successive multidrug-intensive treatment protocols (L2, L10/10M, and L17/17M), each calling for 2.5 to 3 years of systemic chemotherapy and prophylactic intrathecal methotrexate without cranial irradiation. The complete remission (CR) rates were L2 (n = 22) = 77%; L10/10M (n = 69) = 86%; L17/17M (n = 44) = 77%. The median durations of survival and remission were, respectively, L2 = 33 and 30 months; L10/10M = 62 months and not reached; and L17/17M = not reached. Almost all relapses occurred within the first 3 years while still continuing treatment, and there were only rate late relapses after stopping treatment. It appears that approximately half of the patients may have been cured with the latest two protocols. During the last 17 years, 494 adults aged 15 to greater than 70 with acute nonlymphoblastic leukemia (ANLL) were treated with one of five successive multiple drug treatment protocols of varying intensity (arabinosylcytosine + 6-thioguanine [n = 36]; L6 [n = 101]; L12 [n = 104]; L14/14M [n = 121]; and L16/16M [n = 132]). Patients with myelodysplastic syndromes generally were not treated until they developed acute leukemia, but were then entered and included in the results. Secondary leukemias following treatment of other neoplastic diseases were not included. The complete remission rates were fairly constant between 47 and 64% and the median durations of remissions were between 9 and 21 months. The intensive treatment L14 and L16 protocols were associated with more early deaths and did not result in a significantly improved remission incidence or duration or survival. With all protocols, the majority of relapses occurred within the first 2 years, but relapses continued to occur at a decreasing rate for 4 years and occasionally even later. Whereas a small fraction (approximately 10 to 15%) of adults with ANLL are now apparently being cured with combination chemotherapy, despite intensive efforts there has been little improvement during the last decade and more selective and effective forms of treatment are urgently needed.
Acute Disease↗
Pluripoietin alpha: a second human hematopoietic colony-stimulating factor produced by the human bladder carcinoma cell line 5637.
We have identified a factor constitutively produced by the human bladder carcinoma cell line 5637, which has the following capacities: to induce the differentiation of the human promyelocytic leukemic cell line HL-60; to induce the expression of chemotactic peptide receptors in leukemic cells as well as in normal peripheral blood granulocytes; to function as a chemoattractant for neutrophils as well as, under certain conditions, inhibiting their migration; to support the growth of eosinophil and granulocyte/macrophage progenitors, which is maximal when scored at day 14; and to support the growth of human mixed pluripotent progenitors and erythroid bursts from normal human bone marrow. This factor has a molecular size of 32 kDa by gel filtration and 16.5 kDa by NaDodSO4/PAGE. We have termed this factor pluripoietin alpha.
Bone Marrow Cells↗
Lymphoblastic lymphoma in adults.
Fifty-one patients with lymphoblastic lymphoma (LBL) treated with one of five successive intensive chemotherapy protocols for acute lymphoblastic leukemia (ALL) since 1971 were reviewed. The patients were divided into leukemic and nonleukemic groups, and their clinical and laboratory parameters compared. The projected 5-year survival rate for all patients treated with the L10/17 protocols was 45% for both leukemic and nonleukemic LBL. The response to treatment was compared with that of 111 patients with ALL and was nearly identical. Poor prognostic factors were age beyond 30, WBC greater than 50,000/microL, failure to achieve a complete response (CR), and a late CR during induction. Leukemia at presentation, T cell surface markers, and the presence of a mediastinal mass did not adversely affect survival. The use of intensive chemotherapy protocols has proven to be a significant advance in the treatment of LBL.
Adolescent↗
Prognostic significance of terminal deoxynucleotidyl transferase activity in acute nonlymphoblastic leukemia.
Bone marrow and/or peripheral blood samples from 133 (75%) of a total of 177 consecutive previously untreated protocol patients with acute nonlymphoblastic leukemia (ANLL) were analyzed for terminal deoxynucleotidyl transferase (TdT) activity at the time of presentation. Twenty-nine (22%) were found to exhibit TdT activity (greater than or equal to 0.10 U/10(8) cells, TdT+) as measured in a biochemical microassay. There were no differences between TdT+ as compared with TdT-negative (TdT-) patients with respect to age, sex, French-American-British (FAB) classification, or the presence of Auer's rods. Remission induction rates were higher for the TdT- patients, with 68% v 48% for the TdT+ patients (P = .05). TdT- patients also experienced longer remissions (P = .003) than TdT+ patients, especially in the Auer's rod-positive subgroup (P = .002). None of five patients with TdT+ ANLL treated with vincristine and prednisone as initial therapy achieved complete remission; all required induction regimens containing daunorubicin or amsacrine in combination with cytosine arabinoside and 6-thioguanine. It is concluded that TdT activity in ANLL indicates biphenotypia or lineage infidelity and is associated with a poor prognosis on chemotherapy protocols currently used for the treatment of ANLL.
Bone Marrow↗
Biological activities of a human pluripotent hemopoietic colony stimulating factor on normal and leukemic cells.
We studied the biological effects of pluripoietin, a human pluripotent hemopoietic colony-stimulating factor (CSF) purified from the 5637 bladder carcinoma cell line. We found that this human CSF appears to be a unique hemopoietic growth factor, differing from interleukin 3 (IL-3) by virtue of its leukemia differentiating activity in mouse and man, and from mouse granulocyte CSF, which does have differentiation-inducing activity, but lacks pluripoietic activity. In addition, differences from IL-3 were observed in cross-species activity on normal and leukemic cells.
Animals↗
Purification to apparent homogeneity and biochemical characterization of human pluripotent hematopoietic colony-stimulating factor.
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Cell Line↗