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N E Kay

Publications and source records attributed to N E Kay.

At least 19 recordsLinked to original sources
PubMed1992

Frequent clonal abnormalities of chromosome band 13q14 in B-cell chronic lymphocytic leukemia: multiple clones, subclones, and nonclonal alterations in 82 midwestern patients.

We performed cytogenetic analyses of peripheral blood lymphocytes from 82 Midwestern B-cell chronic lymphocytic leukemia (B-CLL) patients. The cells were cultured with mitogens for 3-4 days. At least 15 metaphase cells were analyzed in 79 (96%) cases. Fifty (63%) of the 79 patients had clonal chromosomal alterations. Structural modifications of the long arm of chromosome 13 at or near band 13q14 were the most frequent abnormalities, identified in 23 (46%) of the patients with clonal abnormalities. In several patients, the abnormality involving band 13q14 was the sole chromosomal alteration. There was a high incidence of complex karyotypes. Nine patients had multiple subclones that appeared to result from clonal evolution; seven patients had cytogenetically unrelated clones; three patients had both subclones and cytogenetically unrelated clones. Nonclonal abnormalities were also prominent. Our study confirms the high incidence of clonal abnormalities involving chromosome arm 13q and documents the clustering of abnormalities at band 13q14 in B-CLL. The evidence for clonal evolution and the presence of multiple unrelated clones in these patients suggest that B-CLL may not be a karyotypically stable disease.

Aged↗
PubMed1992

B-chronic lymphocytic leukemia cells contain both endogenous kappa immunoglobulin mRNA and critical immunoglobulin gene activation transcription factors.

B-cell chronic lymphocytic leukemia (B-CLL) is a hematologic malignancy characterized by the proliferation and accumulation of mature-looking B lymphocytes. Patients with B-CLL exhibit a number of immune defects including: auto-antibodies, depressed cell-mediated immunity and hypogammaglobulinemia (HG). We investigated the control of Ig production in the malignant CLL B-cell at a transcriptional and translation level. We isolated fresh leukemic B-cells from CLL patients and analyzed for the presence of nuclear factors OCT-1, OCT-2, and NF-KB. Malignant B-cells were purified to greater than 90% B-cells, and total cellular RNA and nuclear proteins were isolated from these cells. Mobility shift assays were probed with 32P-labeled oligonucleotides specific to the immunoglobulin (Ig) enhancer and promotor regions. We detected endogenous OCT-1, OCT-2, and NF-KB in all patients tested (n = 5). We then evaluated whether activation of CLL B cells could augment kappa-mRNA levels. CLL cells (n = 3) exposed to phorbol ester and A23187 were harvested at 0, 2, 4, 8, and 48 min and examined for kappa-mRNA by Northern blot. All CLL patients (n = 3) had easily detectable levels of endogenous kappa-mRNA. However, only one patient had an obvious increase in kappa-mRNA post-induction with TPA/A23187. There was no concomitant increase in this patient's OCT-1, OCT-2, or NF-KB level. This finding prompted us to survey other B-CLL patients (n = 6) for Ig nuclear transcriptional factors pre- and post-induction. In summary, CLL B cells express Ig transcriptional factor OCT-1, OCT-2, and NF-KB constitutively. The endogenous level of NF-KB may account for the basal kappa-mRNA detected in B-CLL cells. However, the inability to augment NF-KB levels may, in part, explain the low levels of Ig synthesis in CLL B-cells.

Base Sequence↗
PubMed1991

Habituation to repeated painful and non-painful cutaneous stimuli: a quantitative psychophysical study.

Repeated stimuli elicit progressively smaller responses and elevated sensory and/or pain thresholds (habituation). The present experiments were designed to determine the rate of habituation of perceptual responses to supraliminal painful and non-painful cutaneous stimuli. Changes in the perceived intensity of electrical stimuli applied to the digital nerves of the index finger were determined by a matching procedure in which subjects set the current applied to the index finger of one hand to match the perceived intensity of a stimulus train (5 pulses at 20 Hz) applied to the other index finger. Twenty-five volunteers took part in 7 experiments in which both non-painful (2.5 times the sensory threshold Ts) and painful (1.2 times the pain threshold Tp) stimulus trains were presented. Subjects were required to match the stimuli at 30 s intervals over a period of 7.5 min. The percentage change in matching current (Y) was fitted by the function Y = -20.7*[1-exp(-0.56*t)] for both painful and non-painful stimuli repeated at 2 Hz. Responses recovered completely within 2 min of cessation of the stimulation. The degree of habituation increased or decreased with the rate of stimulus presentation. These results did not depend on changes in afferent fibre recruitment or fatigue because the afferent volley on the median nerve remained constant throughout the period of stimulation. Thus perceptual responses to the perceived intensity of supraliminal painful and non-painful stimuli delivered to the index finger habituate to the same extent, and the extent of the habituation is a function of the frequency of presentation of the stimulus.

Adult↗
PubMed1990

Expansion of a lymphocyte population co-expressing T4 (CD4) and T8 (CD8) antigens in the peripheral blood of a normal adult male.

Approximately 2% to 3% of circulating human T cells co-express CD4 and CD8 (CD4+, CD8+) T-cell antigens. These CD4+, CD8+ cells may be immature precursors that function to replenish functional T-cell subsets. We detected a very high level of CD4+, CD8+ cells in the peripheral blood lymphocytes of a healthy white male, ranging from 21% to 36%. The morphology of his peripheral blood lymphocytes was normal, and he has maintained an elevated level of CD4+, CD8+ cells without clinical disease over a 19-month observation period. The CD4+, CD8+ cells did not possess thymocyte membrane antigen (CD6), nor did they have increased Tac (CD25) antigen. His intact, purified blood T cells had a normal proliferative response to phytohemagglutinin and interleukin-2 (IL-2), provided help for B-cell proliferation at control levels and exposure to IL-2 resulted in generation of cytotoxic cells. However, the purified blood CD4+, CD8+ cells were deficient in these latter functions except for help in B-cell function. Despite defective function, the isolated CD4+, CD8+ cells co-expressed CD2 and CD3. Prolonged in vitro culture of CD4+, CD8+ cells was possible in the presence of recombinant IL-2. The cultured CD4+, CD8+ cells retained the double antigens (CD4 and CD8) throughout a 4-week period. It is likely these cells are less mature than CD4+, CD8- or CD4-, CD8+ T cells as the CD4+, CD8+ have less in vitro function than the former cells, but it is not yet clear if they mature into either CD4+, CD8-, or CD4-, CD8+ cells. Finally, the presence of an expanded, hypofunctioning CD4+, CD8+ cell population in a normal adult male is apparently compatible with excellent clinical health.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1990

Immunoregulatory cell dysfunction in chronic B-cell leukemias.

Chronic B-cell malignancies are routinely characterized as B-cell clonal diseases that have signs and symptoms primarily related to the continuing expansion of these cells. This review discusses chronic lymphocytic leukemia, multiple myeloma and hairy cell leukemia from the perspective of secondary abnormalities in non-malignant cells. Thus, our main purpose is to elaborate on the alterations/abnormalities of the immunoregulatory (IR) cells in these diseases and focus on the qualitative and quantitative aspects of T-cells, natural killer (NK) cells and monocytes. The relevance of the IR-cell changes to the basic disease process and their complications are emphasized.

Humans↗
PubMed1990

Interaction between endogenous opioids and IL-2 on PHA-stimulated human lymphocytes.

Endogenous opioids exert a variety of extra central nervous system (CNS) functions, including modulation of some human lymphocyte functions. The latter opioid activity may result in elevation of human natural killer (NK) function (i.e. by beta-endorphin), which is reversed by an opioid antagonist, Naloxone. Since recent evidence has suggested both structural and functional similarities between lymphokines known to elevate human NK function (interferon and interleukin-2) and endogenous opioids, we investigated if Naloxone could modulate lymphokine-enhanced human NK activity. Naloxone blunted, in a dose-dependent fashion, the NK-enhancing activity of peripheral blood lymphocytes or large granular lymphocytes by recombinant interferon-alpha (IFN-alpha) or interleukin-2 (IL-2). Naloxone decreased the uptake of radiolabelled IL-2 receptors. beta-endorphin also decreased the binding of radiolabelled IL-2 or IL-2 receptor-positive human lymphocytes. Finally, labelled Naloxone was inhibited from binding to phytohaemagglutinin (PHA)-stimulated lymphocytes by either beta-endorphin or IL-2. These findings strongly suggest that human lymphocyte receptors for opioid, IFN or IL-2 molecules, once occupied, have distinct influences on the alternate receptor. In addition, these data further strengthen the potential role of CNS-mediated influences on the human immune system.

Binding, Competitive↗
PubMed1989

Malignant chronic lymphocytic leukemia B cells elaborate soluble factors that down-regulate T cell and NK function.

To determine if the frequently observed T cell and natural killer dysfunction in B-chronic lymphocytic leukemia might be related to the presence of large numbers of malignant B cells, we studied the effects of secretory or shed products of CLL B cells on normal (control) T cell and NK function. The cell-free supernatants from CLL B cells cultured from 24 to 48 hr inhibited a variety of T cell functions including: PHA-induced proliferation, PHA-stimulated entry of T cells into the cell cycle, and PHA-induced production of interleukin-2. In addition, B-CLL supernatants diminished control NK activity. Purified control B cells and other malignant cell lines produced little or no inhibitory activity toward these T cell or NK functions. The sera from these same B-CLL patients diminished PHA-induced interleukin-2 production by control T cells. Initial molecular characterization of the inhibitory factor(s) revealed it to be of low molecular weight (less than 5000 daltons) with loss of functional activity after treatment with neuraminidase. This suggested that this substance might be either a ganglioside or glycoprotein whose inhibitory activity depends on the presence of a sialic acid moiety. If CLL B cells are capable of secreting or shedding immunosuppressive factor(s), then alteration of this property may result in a more normal immune system for these patients.

B-Lymphocytes↗
PubMed1989

Large granular lymphocytes from B-chronic lymphocytic leukemia patients inhibit normal B cell proliferation.

Large granular lymphocytes (LGL) may exert regulatory influences on B cell immunoglobulin synthesis. We, therefore, investigated the influence of LGL from controls and B cell chronic lymphocytic leukemia patients (B-CLL) on control B cell proliferation to costimulation with the F(ab')2 fragment of goat antihuman mu and B cell growth factor (BCGF). Purified LGL (greater than 90% by morphology) from control and B-CLL peripheral blood were added in various concentrations to purified control B cells and incubated with anti-mu and BCGF for 3 days. [3H]-thymidine uptake of B cells was then measured. There was no proliferation of control or CLL LGL alone to the costimulatory signals of the F(ab')2 fragments of goat antihuman mu chain and BCGF. Addition of control LGL to equal numbers of control B cells did not blunt control B cell responsiveness to BCGF (with control LGL 8,649 +/- 298 cpm vs. control B cells alone 8,336 +/- 556 cpm, mean +/- SEM). When control LGL were increased to 10:1 LGL:B cell ratio, the maximal inhibition by control LGL of control B cell proliferative response to BCGF was 23%. In contrast, addition of CLL LGL at a 1:1 LGL:B cell ratio resulted in marked impairment of the control B cell proliferative response to BCGF (with CLL LGL 3,586 +/- 954 cpm vs. control B cells alone 8,649 +/- 298 cpm). Inhibition by CLL LGL occurred in a cell-concentration-dependent manner. No difference in CLL LGL's inhibitory effect on either resting or activated control B cell responsiveness to BCGF was noted. Inhibition of de novo protein synthesis (by cycloheximide inhibition) of CLL LGL did impair CLL LGL's inhibitory capacity for BCGF-induced B cell proliferation. A possible explanation for these findings includes the possibility that a subgroup of LGL with B cell suppressive activity may have expanded as a host response to the B cell leukemia or as part of the disordered cell regulation in B-CLL.

Agammaglobulinemia↗
PubMed1989

Evidence that large granular lymphocytes from B-CLL patients with hypogammaglobulinemia down-regulate B-cell immunoglobulin synthesis.

B-chronic lymphocytic leukemia (CLL) patients frequently suffer from moderate to severe hypogammaglobulinemia. This complication is a serious cause of morbidity and mortality in this disorder. There is recent evidence that natural killer (NK) cells modulate B-cell immunoglobin (Ig) synthesis/secretion. The authors therefore evaluated the circulating NK cells from B-CLL patients on their ability to regulate mitogen-induced B-cell Ig synthesis. Blood, NK cells (CD16+, CD3-) from three B-CLL patients with hypogammaglobulinemia were able to clearly down-regulate the pokeweed mitogen (PWM)-induced-B-cell Ig secretion. In contrast, CD16+, CD3- cells from age-sex-matched controls or B-CLL patients with normal Ig were either nonregulatory or enhanced mitogen-induced B-cell Ig secretion. An alternative explanation for hypogammaglobulinemia in B-CLL patients is the immunomodulation of B-cell Ig production/secretion by CD16+, CD3- blood cells.

Agammaglobulinemia↗
PubMed1986

Inhibition of B cell growth factor (BCGF) by monoclonal antibodies directed against the C3d receptor (CR2).

Normal human B cell proliferation is controlled by various immunoregulatory signals including the T cell-derived lymphokine B cell growth factor (BCGF). Human BCGF provides the final proliferative signal to normal, activated B cells. We herein show that anti-CR2 monoclonal antibodies inhibit human B cell responsiveness to purified BCGF. Addition of anti-CR2 antibody, AB5, was capable of completely inhibiting BCGF-mediated enhancement of either anti-mu or staphylococcal protein A-activated human B cells (191 +/- 21 cpm vs. 3942 +/- 622 cpm, mean +/- SEM). Inhibition of B cell response to BCGF by AB5 occurred in a dose-dependent manner. Monoclonal antibody anti-B2, which recognizes the same 140-kDa glycoprotein as AB5, in comparable concentrations also inhibited B cell responsiveness to BCGF. Monoclonal antibodies of the same subclass (IgG1) showed no inhibitory effect on BCGF enhancement of B cell proliferation. The F(ab')2 fragment of AB5 generated by pepsin digestion was similarly inhibitory as was the intact Ig. AB5-mediated inhibition was independent of the target B cell state of activation. Both resting and activated B cells (anti-mu or staphylococcal protein A activated) incubated with similar concentrations of AB5 were unresponsive to BCGF. The ability of anti-CR2 antibodies to block BCGF-dependent B cell proliferation suggests that occupancy of C3d membrane receptors may result in modulation of B cell proliferation in physiologic or clinical disease states.

Antibodies, Monoclonal↗
PubMed1986

Natural killer cells.

It is proposed that this article will encompass a review of primarily the human natural killer cell. The following parameters of the human natural killer (NK) cell will be reviewed: its ontogeny; surface membrane characteristics including monoclonal antibody reactivity, cell lineage, the natural killer sensitive targets, and the proposed mechanism of action of natural killer cells cytotoxicity against these NK sensitive targets; the status of natural killer cell in relationship to clinical disease; the alteration of natural killer cells both in vitro and in vivo; and finally postulate relevance of the natural killer cell in context of the evolution or pathophysiology of human disease. There will be an attempt through this review to encompass the more recent publications that pertain to the various sections.

Biological Products↗
PubMed1985

Monoclonal antibodies to the 140,000 mol wt glycoprotein of B lymphocyte membranes (CR2 receptor) initiates proliferation of B cells in vitro.

Several mouse monoclonal IgG antibodies (AB1, AB2, AB3, and AB5) were developed that reacted with a 140,000 mol wt glycoprotein on the surface of cultured RAJI B lymphoid cells. The antibodies reacted with purified normal human peripheral blood B cells and CLL Ig+ B cells and showed specific germinal center and mantle zone staining in tissue sections of secondary lymphoid organs. Immunodepletion studies using 125I surface-labeled Raji cell membrane antigens demonstrated that the antigen identified by AB5 is the same 140,000 mol wt glycoprotein detected by anti-B2 that has recently been shown to react with the C3d fragment or CR2 receptor. (Iida et al: J Exp Med 158:1021, 1983). Addition of the AB series and anti-B2 monoclonal antibodies to cultures of purified human peripheral blood B cells resulted in the uptake of 3H-thymidine at two to six times background control levels provided that irradiated autologous T cells were added to the culture. Stimulation was not evoked by other monoclonal antibodies to B cell surface molecules (ie, B1, BA-1, BA-2, and HLA-DR). Pepsin-generated F(ab')2 fragments of anti-CR2 antibodies were essentially as effective as the intact IgG molecule in stimulating B cells. Induction of B cell proliferation by antibody binding to CR2 suggests that the C3d receptor may have an integral role in regulation of humoral immune response.

Animals↗
PubMed1979

Abnormal erythrocyte metabolism in hepatic disease: effect of NADP repletion.

Erythrocytes from ten patients with severe liver disease displayed low methylene blue-stimulated hexose monophosphate (HMP) shunt activity and glucose recycling despite elevated total glucose consumption when compared to controls. Heinz body formation was increased and reduced glutathione concentration significantly decreased. After hemolysis, no differences in methylene-blue estimulated HMP shunt activity or glucose recycling could be demonstrated between patients and controls. The addition of 2- and 4-mM NADP to the hemolysates produced significantly greater HMP shunt activity and glucose recycling in the patients' hemolysates. The addition of NADPH to the incubation mixture produced no significant stimulation of either HMP shunt activity or glucose recycling, unless methylene blue was also added. Omission of NAD or phosphate from the incubation mixture produced no change in shunt metabolism. The absence of supplemental ATP resulted in extremely low shunt metabolism and refractoriness to NADP stimulation in both patients and controls. In the absence of additional magnesium, a reduction of shunt metabolism was noted. These data suggest that the defect in stimulated shunt metabolism in the intact erythrocytes of patients with hepatic disease does not result from an absolute enzyme deficiency, but rather from an unavailability of NADP or other cofactor.

Adult↗
PubMed1979

Chronic lymphocytic leukemia in association with a second lymphoproliferative disorder: response to chemotherapy in two cases.

The development of either histiocytic lymphoma or Hodgkin disease in association with pre-existing chronic lymphocytic leukemia has been described in the literature as a terminal event. We describe two patients in whom the diagnosis of a second malignant lymphoma was made during life and who achieved objective clinical response after a change in therapy to a more aggressive combination of drugs. We conclude that patients with chronic lymphocytic leukemia who have had a sudden change in their clinical course should have thorough reevaluation, looking specifically for the development of a second lymphoproliferative disorder. If this is discovered, more aggressive therapy should be initiated.

Aged↗