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K C Anderson

Publications and source records attributed to K C Anderson.

At least 19 recordsLinked to original sources
PubMed1997

Interleukin-6 inhibits Fas-induced apoptosis and stress-activated protein kinase activation in multiple myeloma cells.

Fas belongs to the family of type-1 membrane proteins that transduce apoptotic signals. In the present studies, we characterized signaling during Fas-induced apoptosis in RPMI-8226 and IM-9 multiple myeloma (MM) derived cell lines as well as patient plasma cell leukemia cells. Treatment with anti-Fas (7C11) monoclonal antibody (MoAb) induced apoptosis, evidenced by internucleosomal DNA fragmentation and propidium iodide staining, and was associated with increased expression of c-jun early response gene. We also show that anti-Fas MoAb treatment is associated with activation of stress-activated protein kinase (SAPK) and p38 mitogen-activated protein kinase (MAPK); however, no detectable increase in extracellular signal-regulated kinases (ERK1 and ERK2) activity was observed. Because interleukin-6 (IL-6) is a growth factor for MM cells and inhibits apoptosis induced by dexamethasone and serum starvation, we examined whether IL-6 affects anti-Fas MoAb-induced apoptosis and activation of SAPK or p38 MAPK in MM cells. Culture of MM cells with IL-6 before treatment with anti-Fas MoAb significantly reduced both DNA fragmentation and activation of SAPK, without altering induction of p38 MAPK activity. These results therefore suggest that anti-Fas MoAb-induced apoptosis in MM cells is associated with activation of SAPK, and that IL-6 may both inhibit apoptosis and modulate SAPK activity.

Antibodies, Monoclonal↗
PubMed1997

Activation signals regulate heat shock transcription factor 1 in human B lymphocytes.

We previously showed that the ability of human B lymphocytes to elicit a cytoprotective heat shock response when confronted by heat or other stresses was dependent upon the state of cell activation. This was unexpected, considering the highly conserved nature of the heat shock response and the widely held belief that all nonmutated mature cells were capable of eliciting a heat shock response when stressed. To elucidate the mechanism by which activation primes B cells to respond to stresses, we examined heat shock transcription factor 1 (hHSF1) in B cells since this factor appears to be solely responsible for stress-induced transcription of heat shock genes in human cells. In the current report, we show that hHSF1-DNA binding complexes are undetectable in extracts of unactivated B cells. In fact, hHSF1 protein is not constitutively expressed in unactivated B cells, nor is its synthesis stress-inducible. However, following activation, hHSF1 can be found in either a transcriptionally active or an inactive state, depending upon whether the cell has been stressed or not. Thus, activation pathways play an important role in enabling B cells to survive and function properly in the context of physiologic stresses by regulating hHSF1.

B-Lymphocytes↗
PubMed1997

Interaction of tumor and host cells with adhesion and extracellular matrix molecules in the development of multiple myeloma.

Adhesion molecules play an important role in the growth regulation and migration of multiple myeloma (MM) cells. They mediate homing of MM cells to the bone marrow and MM cell to bone marrow stromal cell adhesion, with resultant interleukin-6 related autocrine and paracine growth and antiapoptotic affects. Their pattern of expression on tumor cells correlates with the development of plasma cell leukemia or extramedullary disease. Clinically, expression of adhesion molecules on tumor cells or in the serum has already shown prognostic utility. Finally, since adhesion molecules are involved at multiple steps in the pathogenesis of MM, therapeutic studies may target these molecules.

Animals↗
PubMed1997

Transfusion support in acute leukemias.

Patients with acute myeloid leukemia and acute lymphocytic leukemia receive significant numbers of blood products for hematologic support during periods of disease and treatment related cytopenias. These patients may be at increased risk for complications associated with transfusion. This article reviews the indications for platelet and red blood cell transfusion, as well as the incidence and strategies for prevention of the immunohematologic and infectious sequelae arising in the setting of multiple blood component transfusions.

Acute Disease↗
PubMed1996

High-dose therapy and autologous bone marrow transplantation in patients with follicular lymphoma during first remission.

We report the results of a study in previously untreated advanced stage patients with follicular lymphoma (FL) who underwent uniform induction chemotherapy with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) followed by myeloablative therapy and anti-B-cell monoclonal antibody purged autologous bone marrow transplantation (ABMT). Eighty-three patients with previously untreated, low-grade FL were enrolled. After CHOP induction, only 36% achieved complete remission (CR) and 77 patients underwent ABMT. Before BM harvest, 70 patients had a known t(14;18), as determined by polymerase chain reaction (PCR), and all remained PCR positive in the BM at harvest. After ABMT, the disease-free survival (DFS) and overall survival are estimated to be 63% and 89% at 3 years, respectively, with a median follow-up of 45 months. Patients whose BM was PCR negative after purging experienced significantly longer freedom from recurrence (FFR) than those whose BM remained PCR positive (P = .0006). Continued PCR negativity in follow-up BM samples was also strongly predictive of continued CR. This study suggests that a subset of patients with advanced FL may experience prolonged clinical and molecular remissions following high-dose ablative therapy, although longer follow-up will be necessary to determine potential impact on overall survival.

Adult↗
PubMed1996

Interleukin-6 promotes multiple myeloma cell growth via phosphorylation of retinoblastoma protein.

Interleukin-6 (IL-6) mediates autocrine and paracrine growth of multiple myeloma (MM) cells and inhibits tumor cell apoptosis. Abnormalities of retinoblastoma protein (pRB) and mutations of RB gene have been reported in up to 70% of MM patients and 80% of MM-derived cell lines. Because dephosphorylated (activated) pRB blocks transition from G1 to S phase of the cell cycle whereas phosphorylated (inactivated) pRB releases this growth arrest, we characterized the role of pRB in IL-6-mediated MM cell growth. Both phosphorylated and dephosphorylated pRB were expressed in all serum-starved MM patient cells and MM-derived cell lines, but pRB was predominantly in its phosphorylated form. In MM cells that proliferated in response to IL-6, exogenous IL-6 downregulated dephosphorylated pRB and decreased dephosphorylated pRB-E2F complexes. Importantly, culture of MM cells with RB antisense, but not RB sense, oligonucleotide (ODN) triggered IL-6 secretion and proliferation in MM cells; however, proliferation was only partially inhibited by neutralizing anti-IL-6 monoclonal antibody (MoAb). In contrast to MM cells, normal splenic B cells express dephosphorylated pRB. Although CD40 ligand (CD40L) triggers a shift from dephosphorylated to phosphorylated pRB and proliferation of B cells, the addition of exogenous IL-6 to CD40L-treated B cells does not alter either pRB or proliferation, as observed in MM cells. These results suggest that phosphorylated pRB is constitutively expressed in MM cells and that IL-6 further shifts pRB from its dephosphorylated to its phosphorylated form, thereby promoting MM cell growth via two mechanisms; by decreasing the amount of E2F bound by dephosphorylated pRB due to reduced dephosphorylated pRB, thereby releasing growth arrest; and by upregulating IL-6 secretion by MM cells and related IL-6-mediated autocrine tumor cell growth.

B-Lymphocytes↗
PubMed1996

Transforming growth factor-beta1: differential effects on multiple myeloma versus normal B cells.

Interleukin-6 (IL-6), a product of bone marrow stromal cells (BMSCs), is a growth factor for multiple myeloma (MM) cells. Transforming growth factor-beta1 (TGF-beta1) is also produced by BMSCs and can regulate IL-6 secretion by several tissues, including BMSCs. The present study was designed to characterize in vitro tumor growth regulation by TGF-beta1 in MM. Sorted CD38+CD45RA- MM cells secreted significantly more TGF-beta1 (8.2 +/- 2.0 ng/mL) than peripheral blood mononuclear cells (P < .001), splenic B cells (P < .001), and CD40 ligand (CD40L) pretreated B cells (P < .05). TGF-beta1 secretion by MM-BMMCs (3.8 +/- 0.9 ng/mL) was significantly greater than by N-BMMCs (1.2 +/- 0.1 ng/mL, P < .001). MM-BMSCs also secreted significantly more TGF-beta1 (6.6 +/- 2.5 ng/mL, n = 11) than N-BMSCs (4.4 +/- 0.6 ng/mL, P < .02, n = 10) and N-BMSC lines (3.9 +/- 0.2 ng/mL, P < .02, n = 6). TGF-beta1 secretion was correlated with IL-6 secretion in MM-BMSCs. Anti-TGF-beta1 monoclonal antibody both blocked IL-6 secretion by BMSCs and inhibited the increments in IL-6 secretion by BMSCs induced by MM cell adhesion. Moreover, exogenous TGF-beta1 upregulated IL-6 secretion by MM-BMSCs, normal BMSCs, and CD38+ CD45RA- MM cells, as well as tumor cell proliferation. This is in contrast to the inhibitory effect of TGF-beta1 on proliferation and Ig secretion of normal splenic B cells. Finally, retinoblastoma proteins (pRB) are constitutively phosphorylated in MM cells; TGF-beta1 either did not alter or increased pRB phosphorylation. pRB are dephosphorylated in splenic B cells and phosphorylated in CD40L triggered B cells in contrast to its effects on MM cells, TGF-beta1 decreased phosphorylation of pRB in CD40L treated B cells. These results suggest that TGF-beta1 is produced in MM by both tumor cells and BMSCs, with related tumore cell growth. Moreover, MM cell growth may be enhanced by resistance of tumor cells to the inhibitory effects of TGF-beta1 on normal B-cell proliferation and Ig secretion.

B-Lymphocytes↗
PubMed1996

Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B.

Adhesion of multiple myeloma (MM) cells to bone marrow stromal cells (BMSCs) not only localizes MM cells in the marrow microenvironment, but also triggers interleukin-6 (IL-6) secretion by BMSCs and related MM cell proliferation. In the present study, we characterized the regulation of IL-6 gene expression in BMSCs during MM cell adhesion. Adhesion of ARH-77, HS-Sultan, IM-9, and U266 MM cell lines to BMSCs and BMSC lines (LP 101 and AA 101) triggered 5-through 15-fold and 2-through 4-fold increases in IL-6 secretion, respectively. IL-6 mRNA transcripts were undetectable by Northern blotting in IM-9 MM cells or LP 101 BMSCs cultured alone; however, adherence of IM-9 cells to LP 101 cells induced a transient increase in IL-6 transcripts at 6 hours, followed by peak IL-6 secretion at 24 hours. To confirm increased IL-6 transcription and characterize its regulation, LP101 BMSCs were transiently transfected with full length and deletion fragments of the IL-6 promoter linked to the chloramphenicol acetyltransferase (CAT) reporter gene. Transient transfection of LP101 BMSCs with plasmid containing an intact NF-kappa B site showed a 6.8 +/- 0.4-fold increase in CAT activity triggered by IM-9 MM cell adhesion (n = 3, P < .05). Transfection of LP 101 cells with plasmid containing a single base pair deletion from the NF-kapp B binding motif abolished the MM adhesion-induced increase in CAT activity, whereas transfection with plasmid containing three copies of synthetic NF-kappa B sequence resulted in an 8.1 +/- 0.7-fold increase in CAT activity related to MM adhesion (n = 3, P < .05). These data suggest that the NF-kappa B site is one of the essential regulatory elements for MM cell adhesion-induced IL-6 transcription in BMSCs. Electrophoretic mobility shift assays confirmed the involvement of NF-kappa B activation in regulating MM adhesion-induced IL-6 transcription in BMSCs. Further characterization of the upstream events in the signalling cascade regulating IL-6 may not only delineate mechanisms of IL-6 regulation during paracrine MM cell growth, but also provide new therapeutic strategies based on interruption of IL-6 mediated tumor cell growth.

Base Sequence↗
PubMed1996

CD40 ligand triggers interleukin-6 mediated B cell differentiation.

Interleukin-6 (IL-6) is the major cytokine to date mediating antigen (Ag)- or mitogen-driven B cell differentiation. Recently, CD40 ligand (CD40L), with the co-stimulatory cytokines IL-4 and IL-10, has been shown to trigger immunoglobulin (Ig) secretion and class switching. In the present report, we have examined the role of IL-6 in mediating B cell differentiation and Ig secretion triggered with CD40L and/or these cytokines. Culture of splenic B cells with CD40L triggered (1) significant (5.4-fold) increases in IL-6 secretion; (2) differentiation, evidenced by sequential loss of B cell (CD20, CD21) and acquisition of plasma cell (CD38, PCA-1) surface antigens (Ags); and (3) Ig secretion. Interleukin-4 increased both IL-6 and IgG secretion stimulated by CD40L. Interleukin-10+ CD40L triggered 100-fold increments in IgG, IgA and IgM secretion, but IL-10 suppressed IL-6 secretion triggered with CD40L +/- IL-4. Exogenous IL-6 can further increase IgG secretion induced by CD40L + IL-10; moreover, the anti-IL-6 monoclonal antibody partially blocked IgG secretion triggered by CD40L +/- IL-4 or IL-10. Finally, IL-10 suppressed differentiation of B cells induced by CD40L. These studies suggest that CD40L augments Ig secretion in at least two mechanisms: by triggering IL-6 secretion and related differentiation, and by priming B cells for responsiveness to IL-10.

B-Lymphocytes↗
PubMed1996

Adhesion of multiple myeloma cells to the bone marrow microenvironment: implications for future therapeutic strategies.

Multiple myeloma is characterized by excess plasma cells within the bone marrow in association with monoclonal antibody protein in the serum and/or urine. Tumor cells localize within the marrow via an interaction of cell-surface adhesion molecules with their respective ligands on marrow stromal cells and extracellular matrix proteins. Stimulation of myeloma cells via these cell-surface molecules, either directly or via tumor cell adhesion to stromal cells, can induce autocrine or paracrine tumor cell growth mediated by interleukin 6. It might therefore be possible to develop innovative treatment strategies either to inhibit interleukin 6 production or to interrupt interleukin 6 signal transduction in multiple myeloma.

Antibodies, Monoclonal↗
PubMed1996

Interleukin-6 is required for pristane-induced plasma cell hyperplasia in mice.

Intraperitoneal injection of pristane induces production of interleukin-6 (IL-6) and either plasmacytosis or plasmacytoma in mice, depending upon the genetic background. Pristane does not induce plasmacytoma in IL-6 knockout (IL-6-/-) mice, suggesting that IL-6 is required for this process. In the present study we determined whether IL-6 is also required for pristane-induced hyperplasia of normal plasma cells. Pristane was injected intraperitoneally into IL-6-/- and IL-6 wild-type (IL-6+/+) mice. Overall there were more deaths in IL-6+/+ mice (85%) than in IL-6-/- mice (40%), P = 0.024. Hyperplastic lymph node and spleen weight did not differ (P = 0.82 and P = 0.15, respectively) in IL-6-/- versus IL-6+/+ mice. Lymphocytosis with similar patterns of expression of B-cell (B220) and T-cell (Thy-1) antigens was noted in both IL-6-/- and IL-6+/+ mice. However, morphological studies, dual fluorescent staining for Syn-1 and B220 antigens (syn-1+ B220+ cells), and intracytoplasmic Ig staining revealed plasma cell hyperplasia in lymph node and spleen from IL-6+/+, but not IL-6-/-, mice. These plasma cells from IL-6+/+ mice were polyclonal and unable to induce tumour formation in severe combined immunodeficient mice. These data demonstrate that IL-6 is required for pristane-induced hyperplasia of polyclonal plasma cells in mice.

Animals↗
PubMed1996

Hypotensive reactions: a previously uncharacterized complication of platelet transfusion?

BACKGROUND: In 1993, the American Association of Blood Banks (AABB) received reports of severe hypotensive reactions associated with platelet transfusions. The question arose as to whether these reports were indicative of a previously uncharacterized platelet transfusion reaction. STUDY DESIGN AND METHODS: To further characterize these reactions, the AABB Transfusion Practices Committee developed a series of three questionnaires. The initial questionnaire was sent to all AABB institutional members; the two subsequent questionnaires were sent to those institutions reporting severe and/or unusual platelet transfusion reactions. This report focuses on the 24 responses to the third and most detailed questionnaire, which specifically addressed reactions that were characterized by hypotension and/or unexplained respiratory failure. RESULTS: Of the 24 detailed responses received, 4 were not considered to represent unusual reactions to platelet transfusion, 3 described reactions consistent with a (presumably unrecognized) diagnosis of transfusion-related acute lung injury, and 17 described reactions that were primarily characterized by hypotension. The majority of the hypotensive reactions occurred within 1 hour of the beginning of the transfusion (88%), were associated with respiratory distress (82%), and resolved rapidly after cessation of the transfusion (82%). Eighty-eight percent of implicated components had been white cell reduced by filtration. CONCLUSION: The hypotensive platelet transfusion reactions that were described appear to represent a previously uncharacterized complication of platelet transfusion. However, the nature of the questionnaires used in this investigation does not allow the drawing of firm conclusions as to the frequency or the cause of these reactions.

Adolescent↗
PubMed1996

Characterization of reactions after transfusion of cellular blood components that are white cell reduced before storage.

BACKGROUND: During the storage of cellular components before transfusion, cytokines that may mediate transfusion reactions are released from white cells (WBCs). Adverse effects of transfused cellular blood components therefore depend not only on the number of residual WBCs in blood components, but also on the timing of WBC reduction. STUDY DESIGN AND METHODS: Febrile nonhemolytic transfusion reactions (FNHTRs), allergic reactions, and other reactions were characterized in recipients of 4728 units of red cells (RBCs) and 3405 bags of single-donor apheresis platelets (SDAPs), all of which underwent prestorage WBC reduction. To delineate the impact of prestorage versus poststorage WBC reduction of RBCs on transfusion reactions, these results were compared with reactions occurring after the transfusion to similar recipients of 6447 bags of RBCs that underwent poststorage WBC reduction by bedside filtration and 5197 units of SDAPs that underwent prestorage WBC reduction. The levels of interleukin (IL) 1 beta, IL-6, IL-8, and tumor necrosis factor-alpha (TNF-alpha) were measured in a subset of 20 implicated cellular blood components at the time of transfusion reactions and correlated with the duration of storage before transfusion. RESULTS: The incidence of reactions was greater after transfusions of SDAPs (5.49%) than of RBCs (1.63%). The incidence of FNHTRs after transfusion of RBCs that were WBC reduced before storage (1.1%) was significantly lower (p = 0.0045) than that after transfusion of RBCs that were WBC reduced after storage (2.15%). Although allergic reactions to RBCs that were WBC reduced before storage were also less common (0.41%) than those to RBCs that were WBC reduced after storage (0.51%), the difference was not significant (p = 0.067). At the time of reactions to RBCs and SDAPs that were reduced before storage, the level of IL-6 was negatively correlated (r = -0.54, p = 0.014) with the duration of storage before transfusion, and there was no correlation between the level of either IL-1 beta or IL-8 and the interval before transfusion. TNF-alpha was not detectable in any implicated component. CONCLUSION: FNHTRs, but not allergic reactions, were less common after transfusion of RBCs that were WBC reduced before storage than after the transfusion of those WBC reduced after storage at the bedside by filtration. The level of IL-6 in implicated cellular blood components that were WBC reduced before storage was inversely correlated with the length of storage before transfusion. Further studies are needed to determine whether the transfusion of cellular blood components that were WBC reduced before storage can both diminish the incidence of adverse reactions and improve outcome.

Blood Component Removal↗
PubMed1996

Posttransfusion graft-versus-host disease in Japanese newborns.

BACKGROUND: Posttransfusion graft-versus-host disease (PT-GVHD) is underdiagnosed and underreported. Risk factors predisposing to PT-GVHD in newborn recipients, the clinical manifestations of the disease in newborns, and its mechanism are not well characterized. STUDY DESIGN AND METHODS: A literature review identified 27 cases of PT-GVHD in newborns in Japan. Detailed information on volume of blood transfused, donor(s), and clinical course was analyzed. Infants with known immunodeficiency were excluded. RESULTS: Of 27 newborns, 20 were premature and 7 were full-term. Thirteen premature neonates were transfused frequently because of anemia; in 10 cases, exchange transfusion was performed. Fresh blood (<or=72 hours after donation) and blood from family member(s) were transfused to 25 and 22 neonates, respectively. The clinical manifestations of PT-GVHD developed later after transfusion than is reported in adults; the median intervals were: fever, 28 days; erythematous rash, 30 days; leukopenia, 43 days; and death, 51 days. Thymic damage was a striking feature among newborns. Two thirds of the cases of PT-GVHD were associated with overwhelming infections, and all patients died in spite of various treatments. CONCLUSION: These data suggest that cellular blood components, especially those from family members, should be irradiated before transfusion to premature and full-term neonates. Extrathymic and/or thymic semitolerance for allogeneic-donor cytotoxic T-lymphocytes may explain the longer period of latency before the onset of clinical manifestations and the longer course of disease before death in newborns than are noted in adults, as well as the fewer than expected reported cases of PT-GVHD in neonates.

Female↗
PubMed1996

Kinetics of peripheral blood mononuclear cell mobilization with chemotherapy and/or granulocyte-colony-stimulating factor: implications for yield of hematopoietic progenitor cell collections.

BACKGROUND: Peripheral blood progenitor cells (PBPCs) are commonly collected and used to reconstitute hematopoiesis after high-dose chemotherapy. However, strategies for optimal collection and assessment of leukapheresis components are not standardized. STUDY DESIGN AND METHODS: Hematopoietic progenitor cell assays were performed on 369 leukapheresis components collected from 95 patients who had received doxorubicin-based chemotherapy and/or granulocyte-colony-stimulating factor (G-CSF). Precollection patient hematologic values, leukapheresis collection values, component hematopoietic progenitor cell assays, and patient outcome measures were summarized. The kinetics of mononuclear cell (MNC) and PBPC mobilization were assessed among four patient groups. RESULTS: Patient group was a significant predictor of the peripheral blood MNC count on the day of collection (p<0.0001), and that value was a significant predictor of granulocyte-macrophage--colony-forming unit (CFU-GM) yield (p<0.0001). This relationship between the peripheral blood MNC count on the day of collection and CFU-GM yield differed according to patient group (p<0.0001). CFU-GM made up a larger fraction of peripheral blood MNCs collected from patients who received chemotherapy plus G-CSF than collected from those who received G-CSF alone. Moreover, the peripheral blood MNC count and the corresponding CFU-GM yield increased significantly on consecutive days of collection in patient groups receiving chemotherapy and G-CSF but were unchanged or decreased in patients receiving G-CSF alone. CONCLUSION: The relationship between peripheral blood MNC count and leukapheresis component CFU-GM yield differed significantly between patients who received chemotherapy and G-CSF and those who received G-CSF alone for the mobilization of PBPCs. Patient peripheral blood MNC count and component CFU-GM yield are useful for both assessing and suggesting revisions to PBPC mobilization and collection strategies.

Antineoplastic Agents↗