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D L Longo

Publications and source records attributed to D L Longo.

At least 217 records · Page 12Linked to original sources
PubMed1993

Treatment of cancer patients with ex vivo anti-CD3-activated killer cells and interleukin-2.

PURPOSE: This study describes the physiologic and biologic effects resulting from the adoptive transfer of ex vivo anti-CD3-stimulated T-killer cells (T-AK) to patients with advanced cancer in combination with interleukin-2 (IL-2). METHODS: Autologous peripheral-blood mononuclear cells were obtained by leukapheresis and stimulated ex vivo with anti-CD3. The stimulated cells were reinfused at one of three dose levels on the next day (5 x 10(9), 7.5 x 10(9), and 1 x 10(10)). Cell administration was followed by IL-2 given by bolus and continuous infusion (1.5 x 10(6) U/m2 and 3.0 x 10(6) U/m2, respectively) for 7 days, or continuous infusion alone (3.0 x 10(6) U/m2) for 14 days. RESULTS: Pronounced leukocytosis and atypical lymphocytosis were observed with individual values as high as 80,000 and 50,000 cells/microL, respectively. The other major clinical sequelae included a marked lactic acidosis with bicarbonate levels as low as 4.0 mmol/L in some patients, and prolongation of the prothrombin time (PT) and partial thromboplastin time (PTT) due to decreases in clotting factors VII, IX, and X. Antithrombin III levels were also reduced. Hypotension associated with increased serum nitrate and neopterin levels was observed. These toxicities were accompanied by increases in hepatocellular enzymes and creatinine previously described with IL-2. These events occurred at a time when the number of circulating T-AK cells reached their peak. The amount of bolus IL-2 correlated with increases in WBC count (P = .0311), atypical lymphocytes (P = .0241), PT (P = .0006), and PTT (P = .0122). CONCLUSION: Substantial in vivo expansion of activated T lymphocytes was induced by a protocol combining ex vivo activation of peripheral-blood cells with anti-CD3 antibody followed by adoptive transfer and IL-2 administration. The synchronous expansion of these T cells superimposed on diminished liver and kidney function from IL-2 can cause profound but reversible metabolic changes.

Acidosis↗
PubMed1993

Inducible accessory function of a macrophage cell line.

Costimulatory molecules in addition to occupancy of the T-cell antigen receptor, are required to induce T-cell proliferation. Previous work suggested that membrane molecules responsible for costimulatory activity were not constitutively expressed on the antigen presenting cell (APC) surface. In the present study, we have identified a cloned macrophage cell line (FLJ2) with inducible APC function. The unactivated FLJ2 line could not induce T-cell proliferation. FLJ2 could present alloantigen, and stimulate proliferation of either a T-cell clone or normal resting T cells following activation with IFN gamma or unexpectedly with lipopolysaccharide (LPS)-Activated FLJ2 cells could be fixed and APC function was preserved. The relevant inducible molecules required for APC function appeared distinct from Ia and IL1. The expression of ICAM-1 and LFA-1 was increased during activation and anti-LFA-1 antibody blocked APC function. This suggests that one important feature of the activation process may be improvement of cellular adhesion.

Animals↗
PubMed1993

Follicular center cell lymphoma with the t(14;18) translocation in which the rearranged BCL-2 gene is silent.

Using reverse transcription and the polymerase chain reaction (RT-PCR), we determined the level of expression of BCL-2/IgH in 18 follicular center cell lymphomas containing a t(14;18) translocation involving the major breakpoint region and five non-neoplastic lymph nodes. BCL-2/IgH transcripts were demonstrated in 16 follicular center cell lymphoma cases (five high, 11 low) and were not present in any of the five non-neoplastic lymph nodes. In the two follicular lymphoma cases in which BCL-2/IgH transcripts could not be detected by RT-PCR, PCR amplification of genomic DNA indicated this was not due to primer selection. In addition, non-expression was confirmed at the protein level by immunoperoxidase studies. We therefore conclude that these represent true negative cases. This is the first time primary follicular lymphoma cases have been quantitatively studied at the RNA level for expression of BCL-2. We conclude that RT-PCR is a sensitive method for determining levels of expression of this oncogene and may be useful in studying the involvement of BCL-2 in follicular lymphoma.

Adult↗
PubMed1993

Hodgkin's disease in adults. Part II.

The development of a secondary cancer is an often fatal and therefore devastating complication of the successful therapy of Hodgkin's disease. The risk of developing a secondary cancer is not the same for all patients, nor is it the same for all treatments. In 1993, treatment decisions are complicated because there are often a number of management approaches that can effectively eradicate Hodgkin's disease. Certain subgroups can be treated safely with more limited therapy. Patients with peripheral IA disease experience excellent survival following involved field radiotherapy alone without staging laparotomy. Early-stage patients with good prognostic factors can be treated with radiotherapy or chemotherapy alone after a discussion of the short and long-term risks of both approaches. If unfavorable prognostic factors are present or if the patient has IIIA disease, we favor chemotherapy alone while others may employ combined modality therapy, a treatment strategy we reserve for patients with massive mediastinal disease. For advanced-stage disease, full-dose combination chemotherapy with a regimen that is familiar to the oncologist should be given. The addition of radiotherapy in this setting has not been shown to be of benefit. Each treatment strategy has to consider the individual patient and their likelihood of developing one of the complications, fatal or otherwise, of treatment. Although secondary complications must be considered in the initial strategy, unfounded fears about toxicity should not detract from delivery of therapy that has the greatest chance of cure while at the same time minimizing the risk to the patient.

Hodgkin Disease↗
PubMed1993

Lymphomas.

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Child↗
PubMed1993

Hodgkin's disease following non-Hodgkin's lymphoma. A clinicopathologic and immunophenotypic study of nine cases.

We describe nine patients who initially developed non-Hodgkin's lymphoma and subsequently developed Hodgkin's disease. The median interval from the diagnosis of non-Hodgkin's lymphoma (NHL) to the diagnosis of Hodgkin's disease (HD) was 5 years (range, 2-12 years). The median age of the patients at time of diagnosis of NHL was 54 years (range, 27-81 years). Seven of nine cases (78%) of NHL were primarily nodal. According to the Working Formulation, seven NHL were follicular (two small cleaved cell, three mixed small and large cell, two large cell), one was diffuse large cell, and one was large cell immunoblastic. All NHL had histologic or immunophenotypic findings indicative of B-cell lineage. Seven of the nine patients were treated in a nonuniform manner: four with chemotherapy and three with chemotherapy and radiation therapy. At the time of HD, the median age of the patients was 59 years (range, 35-85 years). Lymph nodes were involved in all patients. Six HD biopsies were subclassified as nodular sclerosis, one as mixed cellularity, and two cases were not further subclassified. Immunophenotypic studies revealed that the Reed-Sternberg and Hodgkin cells were LeuM1 or BerH2 positive and LCA negative in eight of nine biopsies, supporting the histologic diagnosis. These results further demonstrate that patients with NHL may subsequently develop HD. The NHLs are usually of B-cell lineage. The results also emphasize the need for rebiopsy in patients with NHL who experience an apparent clinical relapse.

Adult↗
PubMed1993

Increased granulopoiesis after sequential administration of transforming growth factor-beta 1 and granulocyte-macrophage colony-stimulating factor.

Transforming growth factor-beta 1 (TGF-beta 1) is an inhibitor of the growth and differentiation of immature hematopoietic progenitors in vitro; however, we have demonstrated that TGF-beta 1 can promote granulopoiesis in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) in vitro. We therefore examined the effect of the combined administration of TGF-beta 1 and GM-CSF in vivo. First, TGF-beta 1 enhanced the specific binding of GM-CSF (2.0-fold) on bone marrow cells, reaching a maximum 40 hours after injection, while the specific binding of interleukin-3 (IL-3) was unaffected. Using GM-CSF-specific binding to determine the optimal regimen for cytokine administration in vivo, we found that the administration of TGF-beta 1 and GM-CSF in sequence increased myelopoiesis. Total numbers of colony-forming units-granulocyte/macrophage (CFU-GM) and myeloblasts per femur were increased above the level obtained with the simultaneous injection of TGF-beta 1 plus GM-CSF, GM-CSF alone or TGF-beta 1 alone. Further, the sequential administration of TGF-beta 1 and GM-CSF resulted in enhanced numbers of mature granulocytes in both the bone marrow and peripheral blood. In contrast, the sequential combination of TGF-beta 1 and GM-CSF did not enhance the numbers or increase the recovery of erythroid cells in the bone marrow. These results show that TGF-beta 1 in vivo as in vitro has a multifunctional effect on bone marrow progenitors, and by using an optimal combination of TGF-beta 1 and GM-CSF in vivo, one can selectively increase both the central and peripheral granulopoietic compartments.

Animals↗
PubMed1993

Detection of c-mos proto-oncogene expression in human cells.

Although the human c-mos proto-oncogene has been characterized for more than a decade, very little is known about its protein product and its expression in somatic cells. We generated three human c-mos-specific antisera and report here the detection of c-mos protein in a human neuroblastoma cell line, SK-N-BE2 (BE2). Both Western (immuno-) blot and immunoprecipitation analyses detected a p37 as the major form and p40 and p35 as minor forms of the c-mos protein. Using Northern blot analysis, 3.5- and 1.7-kb c-mos messages were detected. Using a highly sensitive method that combines reverse transcription and the polymerase chain reaction (RT-PCR), c-mos RNA was detected in all the human samples examined. With Western blot analysis, we further showed that c-mos proteins are expressed in cervical carcinoma-derived cell lines. This ubiquitous expression of low levels of c-mos suggests a fundamental role for the c-mos proto-oncogene.

Animals↗
PubMed1992

Role of neuroendocrine hormones in murine T cell development. Growth hormone exerts thymopoietic effects in vivo.

Growth hormone (GH) and other neuroendocrine mediators have been implicated previously in T cell development. We therefore examined thymic development in DW/J dwarf mice. DW/J mice lack acidophilic anterior pituitary cells and consequently are totally deficient in the production of GH, as well as other neuroendocrine hormones. DW/J dwarf mice had greatly hypoplastic thymi that continued to decrease in size as the mice aged. Characterization of the different T cell subpopulations within the thymi of dwarf mice indicated a deficiency in CD4+/CD8+ double-positive thymocytes. This deficiency of progenitor cells became more complete as the mice aged culminating in the total disappearance of this subpopulation in some dwarf mice > 3 mo of age. Analysis of the lymph nodes indicated that a population of double-positive (CD4/CD8) T cells appeared in some mice concurrent with the disappearance of double-positive cells in the thymus suggesting that these thymocytes may have migrated to the periphery. However, peripheral T cells from dwarf mice did exhibit Ag-specific responses indicating that these mice have functional T cells. Treatment of the mice with recombinant human GH, which binds both murine growth hormone receptors and murine prolactin receptors, or ovine GH, which binds murine growth hormone receptors but not murine prolactin receptors, resulted in an increase in thymic size and the reappearance of the CD4+/CD8+ double-positive cells within the thymus. Additionally, after GH treatment, the double-positive cells disappeared from the lymph nodes. The thymi of mice treated with GH failed to attain normal size but did develop a normal distribution of T cell progenitors. Thus, GH exerts significant thymopoietic effects in vivo. Neuroendocrine hormones may be important for normal T cell differentiation to occur within the murine thymus.

Animals↗
PubMed1992

Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice.

Impaired immune responses occur frequently in cancer patients or in tumor-bearing mice, but the mechanisms of the tumor-induced immune defects remain poorly understood. In an in vivo murine colon carcinoma model (MCA-38), animals bearing a tumor longer than 26 days develop CD8+ T cells with impaired cytotoxic function, decreased expression of the tumor necrosis factor-alpha and granzyme B genes, and decreased ability to mediate an antitumor response in vivo. T lymphocytes from tumor-bearing mice expressed T cell antigen receptors that contained low amounts of CD3 gamma and completely lacked CD3 zeta, which was replaced by the Fc epsilon gamma-chain. Expression of the tyrosine kinases p56lck and p59fyn was also reduced. These changes could be the basis of immune defects in tumor-bearing hosts.

Animals↗
PubMed1992

Enhanced lymphokine production and lymphokine receptor expression in multiple antibody-stimulated human CD4+ peripheral blood lymphocytes.

Treatment of T lymphocytes with antibodies directed against the T cell receptor CD3 complex results in cellular activation that can be augmented by costimulation through other cell surface receptors. The activities of anti-CD3-stimulated human CD4+ PBL were compared to anti-CD3 plus anti-CD2-, anti-CD4-, or anti-CD11a (LFA-1)-stimulated cells. [3H]thymidine incorporation, lymphokine receptor expression, expansion of cell numbers, and lymphokine mRNA and protein were measured. Forty-eight hours after activation, costimulated CD4+ cells demonstrated increased numbers of cells positive for surface IL-2R alpha-chain, IL-2R beta-chain, IFN-gamma receptors, and TNF-alpha receptors. By day 6, costimulated cells exhibited a sevenfold greater expansion in cell numbers compared to cells stimulated with anti-CD3 alone. Anti-CD3 plus anti-CD11a stimulation consistently induced the highest secretion of IL-2 and IFN-gamma, whereas variation in secretion of TNF-alpha and IL-4 between different donors was noted. Analysis of lymphokine receptor mRNA demonstrated increased levels of mRNA for IL-2R alpha-chain and IFN-gamma receptor that preceded the phenotypic changes on the cell surface. In contrast, levels of IL-2R beta-chain and the TNF-alpha receptor mRNA decreased after stimulation. Amounts of IL-2, IL-4, and TNF-alpha, but not IFN-gamma, secreted also correlated with the levels of mRNA measured in the cells. Although costimulation through CD2, CD4, or LFA-1 appeared equally effective for the induction of the lymphokine receptors, these additional stimuli had a different impact on lymphokine secretion. These results indicate that specific control of lymphokine secretion and receptor induction can be another function of the CD2, CD4, and CD11a cell surface receptors. This control is evident at both transcriptional and post-transcriptional levels.

Antibodies↗
PubMed1992

In vivo effect of interleukin-1 alpha on hematopoiesis: role of colony-stimulating factor receptor modulation.

To determine the mechanism(s) by which interleukin-1 (IL-1) promotes granulopoiesis in vivo, we examined the effect of in vivo administration of IL-1 alpha on colony-stimulating factor (CSF) receptor expression on bone marrow cells (BMCs) and whether this directly correlated with progenitor cell responsiveness. Administration of IL-1 alpha to mice induced the upregulation of both granulocyte-macrophage-CSF (GM-CSF) and IL-3 receptors, which reached a maximum 24 hours after IL-1 alpha injection on unfractionated BMCs. This upregulation was more pronounced on the progenitor-enriched cell population (lineage-negative [Lin(-)]). The enhanced GM-CSF and IL-3 receptor expression directly correlated with enhanced IL-3- or GM-CSF-induced growth of colony-forming unit-culture (CFU-c) or CFU-mixture (CFU-Mix; colonies containing macrophages, granulocytes, and erythroid cells). In addition, the absolute number of high proliferative potential-colony-forming cells (HPP-CFC) was increased fivefold. In contrast, granulocyte-CSF (G-CSF)-specific binding on unfractionated BMCs was rapidly (4 hours) reduced after IL-1 alpha administration and returned to control levels by 24 hours. This reduction correlated with IL-1 alpha-induced margination of mature granulocytes (RBC-8C5hi cells), which express high levels of G-CSF receptors. IL-1 alpha treatment did not affect G-CSF receptor expression on Lin- cells. Pretreatment of mice with anti-type I IL-1 receptor antibody blocked the IL-1 alpha-induced upregulation of GM-CSF and IL-3 receptor expression on BMCs. Taken together, as one possible mechanism, IL-1 alpha in vivo may stimulate the expression of functional GM-CSF and IL-3 receptors on BMCs indirectly, and, in concert with the induction of circulating CSF levels, may account for the ability of IL-1 alpha to stimulate hematopoiesis in vivo.

Animals↗
PubMed1992

Regulation of IL-2 receptor subunit genes in human monocytes. Differential effects of IL-2 and IFN-gamma.

We investigated the effects of IFN-gamma and IL-2 on IL-2R alpha and beta mRNA expression in human monocytes. Low basal expression of IL-2R beta mRNA was detected in fresh monocytes. Stimulation of monocytes with IL-2 induced a significant increase of IL-2R beta mRNA, but did not induce IL-2R alpha mRNA. In contrast, stimulation of monocytes with IFN-gamma-induced IL-2R alpha mRNA, but did not modify IL-2R beta mRNA. Five U/ml of IFN-gamma induced IL-2R alpha mRNA and 2.2 nM of IL-2 induced IL-2R beta mRNA, both within 3 h. Nuclear run-on experiments demonstrated that the induction of IL-2R alpha mRNA by IFN-gamma is controlled, at least in part, at the transcriptional level. In contrast, the enhancement of IL-2R beta mRNA by IL-2 is controlled at a posttranscriptional level and is associated with an increase in the half-life of IL-2R beta mRNA. The results of studies on the cytotoxic activity and on the expression of c-fms mRNA of monocytes activated by the combination of IFN-gamma and IL-2 show that pretreatment with IFN-gamma renders monocytes more sensitive to activation by IL-2. These results demonstrate that the IL-2R alpha and IL-2R beta subunits are induced by different lymphokines through distinct mechanisms and that both receptor subunits can influence the response of monocytes to IL-2.

Antigens, CD↗
PubMed1992

Growth hormone exerts hematopoietic growth-promoting effects in vivo and partially counteracts the myelosuppressive effects of azidothymidine.

Recombinant human growth hormone (rhGH) was administered to mice to determine its effect on hematopoiesis. BALB/c mice and mice with severe combined immune deficiency (SCID), which lack T cells and B cells, were administered intraperitoneal injections of rhGH for 7 days. Upon analysis, both strains of mice exhibited an increase in splenic and bone marrow hematopoietic progenitor cell content and cellularity, indicating that rhGH can act as a hematopoietic growth factor. C57BL/6 mice were then placed on azidothymidine (AZT). AZT is a reverse transcriptase inhibitor currently used as a treatment for acquired immune deficiency syndrome (AIDS), but which also produces significant myelotoxic effects. Treatment of mice with rhGH partially counteracted the myelosuppressive properties of AZT. Bone marrow cellularity, hematocrit values, white blood cell counts, and splenic hematopoietic progenitor cell content were all significantly increased if rhGH (20 micrograms injected intraperitoneally every other day) was concurrently administered with AZT. Administration of ovine GH (ovGH), which, unlike rhGH, has no effect on murine prolactin receptors, also prevented the erythroid-suppressive effects of AZT in mice, but had no significant effect on granulocyte counts. Thus, the effects of GH are mediated at least in part through GH receptors in vivo. Additionally, when mice were initially myelosuppressed by several weeks of AZT treatment, the subsequent administration of ovGH resulted in an increase in splenic hematopoietic progenitor cells. No significant pathologic effects were observed in mice receiving either repeated rhGH or ovGH injections. Thus, GH exerts significant direct hematopoietic growth-promoting effects in vivo and may be of potential clinical use to promote hematopoiesis in the face of myelotoxic therapy.

Animals↗
PubMed1992

Hematopoietic growth-promoting effects of natural killer cells in mice in response to in vivo administration of human interleukin-2.

BACKGROUND: Interleukin-2 (IL-2) is currently being evaluated as an anti-neoplastic agent because of its stimulatory effects on the immune system. However, little is known about the effects of systemic IL-2 administration on hematopoietic parameters. PURPOSE: Recombinant human IL-2 (rHuIL-2) was administered to mice to evaluate its in vivo hematopoietic effects. The mechanism underlying the effects of rHuIL-2 administration was also determined. METHODS: Mice were given 5 x 10(4) IU of rHuIL-2 for 5 days, and their hematopoietic progenitor cell status was determined as measured by growth in soft agar. Antiserum to natural killer (NK) cell-specific markers was used to ascertain if NK cells were responsible for the hematopoietic effects of rHuIL-2. NK cells were purified and cultured in vitro with rHuIL-2 and then adoptively transferred into syngeneic mice to determine the effects on hematopoiesis. RESULTS: Treatment of mice with rHuIL-2 resulted in a significant increase in bone marrow and splenic hematopoietic progenitor cell content. Mice with severe combined immune deficiency (SCID), which lack T cells and B cells yet have NK cells, also responded to the myelostimulatory effects of rHuIL-2. However, removal of NK cells from the SCID mice with antiserum to NK cell-specific markers abrogated the myelostimulatory properties of rHuIL-2. Adoptive transfer of NK cells that were propagated in vitro with rHuIL-2 into mice also resulted in an increase in splenic hematopoietic progenitor cells. CONCLUSIONS: rHuIL-2 exerts significant myelostimulatory effects after in vivo administration, and NK cells are responsible for at least some of these effects. IMPLICATIONS: These results suggest that NK cells and rHuIL-2 may be of use clinically to promote hematopoiesis after bone marrow transplantation or in the face of other myelotoxic therapy in the treatment of cancer.

Animals↗