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J A Merritt

Publications and source records attributed to J A Merritt.

35 records · Page 2Linked to original sources
PubMed1985

Low doses of interferon alpha result in more effective clinical natural killer cell activation.

To define critical parameters concerning interferon (IFN) effects upon natural killer (NK) cells in vivo, we gave cancer patients serial weekly intramuscular injections of purified lymphoblastoid IFN in six doses ranging from 10(5) to 3 X 10(7) U. Dose sequences were determined by randomly allocating patients to one of six levels in a latin square ordering scheme. NK cell stimulation, a threefold peak increase above preinjection levels of cytolysis (P = 0.022), occurred in peripheral mononuclear cells (PMC) sampled 24 h postinjection, of 3 X 10(6) U, but was not detectable at any dose in PMC sampled 7 d postinjection. No blunting occurred in NK cell responsiveness to repeated injection of IFN dosages a second time at or several weeks after study completion. At IFN doses of 3 X 10(6), 10(7), and 3 X 10(7) U, a negative correlation existed between the amount of IFN injected and the average extent of NK cell activation (r = -0.423, P less than 0.05). This contrasted with the progressively increasing response of NK cells to in vitro incubation with increasing concentration of up to 3,000 U/ml of IFN. Overnight culturing of PMC sampled before IFN injections resulted in a mean 1.9-fold increase in cytolytic activity (P = 0.0005) and a mean 53% decrease in variance (P = 0.024) between serial preinjection NK cell activity determinations. Cell separation procedures may, therefore, have resulted in NK cell inactivation, from which overnight culturing permitted recovery. We found that maximal NK cell activation at a low IFN dose, decreasing NK cell responsiveness at higher doses, and the need to culture PMC to efficiently detect NK cell boosting may account for disparities in reported effects of IFN on NK cell function.

Cells, Cultured↗
PubMed1985

2-5A synthetase activity in patients with metastatic carcinoma and its response to interferon treatment.

The interferon-induced enzyme 2-5A synthetase was measured in extracts of ficoll-purified peripheral mononuclear cells from normal healthy volunteers and a large group of patients with metastatic carcinoma. The range of values in both populations was very large and overlapped considerably. On average, individuals with disseminated cancer have a two-fold increase in 2-5A synthetase activity. In addition, several patients have been identified who appear to have fully induced 2-5A synthetase activity with no detectable serum interferon and no history of prior interferon injections. This indicates that the interferon regulated 2-5A system is activated in metastatic carcinoma. Treatment of patients with interferon-alpha caused a dose-dependent increase in enzyme activity. The maximum fold increase varied from individual to individual, as did the dose required for maximum enzyme stimulation. A rigorous attempt must now be made to correlate enzyme induction with the clinical outcome of interferon treatment in order to assess the clinical value of such measurements.

2',5'-Oligoadenylate Synthetase↗
PubMed1984

Transient neurologic dysfunction following moderate-dose methotrexate for undifferentiated lymphoma.

Two patients, aged 24 and 19 years, who had undifferentiated lymphoma, developed the acute onset of focal neurologic deficits 10 days after treatment with moderate-dose methotrexate (2.76 g/m2 by 42-hour intravenous infusion) and 12.5 mg of intrathecal methotrexate. Prior chemotherapy also included intravenous cyclophosphamide, doxorubicin, vincristine, oral prednisone, and intrathecal cytosine arabinoside. Dysarthria with left hemiparesis was noted in one patient and inability to speak and quadriparesis in the other. Cerebrospinal fluid and cranial computerized tomography results were normal; however, EEGs showed focal abnormalities in both patients. Full neurologic recovery occurred within 48 hours. These symptoms developed early in the course of treatment and have not recurred in one patient who continued to receive the same regimen. The mechanism for this neurologic dysfunction is unclear. A similar picture has been reported in patients receiving high-dose methotrexate (8-10 g/m2) for osteogenic sarcoma.

Adult↗
PubMed1984

Comparison of the biologic effects of two recombinant human interferons alpha (rA and rD) in humans.

IFN-alpha (rD) was investigated to determine the relationship between antiviral activity in vitro and the modulation of biologic effects in vivo. Eight patients with malignancy were given 15 and 45 micrograms weekly injections of IFN-alpha (rA) and IFN-alpha (rD). The frequency of side effects was much lower with IFN-alpha (rD) injections. This was objectively documented both in incidence of side effects (20 versus 45, p less than 0.01) and mean maximum temperature (1 degree C lower with IFN-alpha (rD), p less than 0.002). A bovine cell line, MDBK, was used to measure interferon concentrations in the serum. Geometric mean peak titers and time-to-peak titers were similar with the two recombinant interferon preparations. Although IFN-alpha (rD) has relatively less antiviral activity on human cells, its effect on the total granulocyte count, natural killer (NK) cell cytotoxicity, and 2'5'-A activity was comparable to IFN-alpha (rA). Mean NK cell percent specific 51Cr release was enhanced by both interferons (after 15 micrograms doses, mean percent NK cell cytotoxicity IFN-alpha (rD) preinjection, 10.5% +/- 2.3%; post-injection, 27.2% +/- 4.5%; IFN-alpha (rA), preinjection, 14.4% +/- 3.2%, postinjection, 25.1% +/- 5%). Species-specific antiviral activity of an interferon does not necessarily predict other biologic properties following in vivo administration.

2',5'-Oligoadenylate Synthetase↗
PubMed1984

Effects of diethyldithiocarbamate, an inhibitor of interferon antiviral activity, upon human natural killer cells.

In support of a postulated role of the Cu++-dependent enzyme, superoxide dismutase (SOD), in antiviral effects of interferon (IFN), a close correspondence was previously shown to exist between inactivation of cellular SOD and concomitant blockade of IFN antiviral activity in fibroblasts by the Cu++-chelating agent, diethyldithiocarbamate (DDC). To further define the extent of "anti-IFN" activity, we initiated studies of DDC effects on IFN stimulation in the NK cell system. Unexpectedly, DDC directly inhibited cytotoxicity mediated by unstimulated NK cells. Pronounced inactivation occurred rapidly (less than 30 min), but was spontaneously reversible in the absence of DDC. Neither cell viability nor lymphocyte binding to target cells was detectably affected. Preincubation of DDC with Cu++ or Zn++ failed to neutralize its inhibitory effects nor could function be restored in DDC-pretreated NK cells by subsequent addition of Cu++, Zn++, Mg++, or Ca++. DDC treatment that inactivated NK cells did not detectably alter lymphocyte SOD activity. Thus, inhibition was probably not attributable to chelating properties of DDC. N-ethyl maleimide (NEM) and para-( hydroxymercuri ) benzoic acid ( PMBA ), enzyme inhibitors that preferentially react with sulfhydryl groups, both inactivated NK cells in a time- and dose-dependent manner similar to that of DDC. Preincubation with the sulfhydryl compound, cysteine, neutralized in parallel fashion the capacity of NEM, PMBA , and DDC to inhibit NK cell activity. Thus, a previously unreported reactivity of DDC with sulfhydryl groups appeared to be the basis of inhibition. NK cells incubated 1 hr with IFN and subsequently cultured 17 to 23 hr without IFN were activated to an extent comparable to cells continuously incubated 18 to 24 hr with IFN. Exposure to IFN for 1 hr was therefore sufficient to commit NK cells to acquisition of a fully activated state. Whether preactivated by a 1-hr or 18- to 24-hr IFN treatment, activated NK cells retained the DDC-sensitive phenotype characteristic of fresh unstimulated NK cells. Thus, prolonged IFN treatment did not render NK cells resistant to DDC or preferentially activate a DDC-sensitive NK cell subset. An 18- to 24-hr incubation of DDC-pretreated cells in the continual presence of IFN resulted in the boosting of NK cell activity. However, the 1-hr IFN pulse treatment protocol was consistently ineffective in boosting when IFN was added just after DDC-pretreatment. These results strongly suggested that DDC temporarily rendered NK cells unresponsive to what, under normal circumstances, approximated an optimally potentiating IFN stimulus.(ABSTRACT TRUNCATED AT 400 WORDS)

2',5'-Oligoadenylate Synthetase↗
PubMed1984

Augmented antiproliferative effects of interferons at elevated temperatures against human bladder carcinoma cell lines.

The in vitro antiproliferative effects of interferons (IFN) against the human bladder carcinoma cell lines T24, RT4, HT1197, and 647V were evaluated at temperatures ranging from 37-41 degrees. At 37 degrees, the antiproliferative activities of IFN, either naturally produced or produced by recombinant DNA technology, were different against different cell lines. An increase in temperature markedly enhanced the antimitotic effect of IFN for all cells. For example, T24 cells grown at 37 degrees and treated with 200 units naturally produced IFN-alpha or IFN-beta per ml for 7 days were inhibited 50 to 60%. No change in cell proliferation occurred in untreated T24 cells grown at 39.5 degrees. Treatment with 200 units IFN-alpha or IFN-beta per ml at 39.5 degrees inhibited these cells 80 to 90%. Similar results were obtained with IFN produced by recombinant DNA technology and purified to homogeneity. Colony formation by the RT4 cell line, at 37 degrees, was decreased less than 10% with 200 units IFN-alpha per ml and 63% by 200 units IFN-beta per ml. At 39.5 degrees, colony formation by untreated RT4 cells was inhibited 48%. Treatment with IFN-beta at 39.5 degrees did not result in an enhancement of the antiproliferative effect; however, treatment with IFN-alpha enhanced the inhibition from less than 10% to 98%. These results suggest that a supraadditive relationship exists between antiproliferative effects of IFN and temperature elevation. The differences seen between IFN-alpha and IFN-beta may be due to the different stabilities of these two molecules. In order to probe the mechanism of the enhanced antiproliferative effect, activity of an IFN-induced enzyme, 2'-5'-oligoadenylate synthetase, was measured. IFN-alpha treatment resulted in significantly greater 2'-5'-oligoadenylate synthetase induction at 39.5 degrees than at 37 degrees. Thus, two cellular effects resulting from IFN were augmented by increased temperature.

2',5'-Oligoadenylate Synthetase↗
PubMed1978

Decreased monocyte function in patients with Hodgkin's disease.

Monocyte function in nine untreated and nine treated patients with Hodgkin's disease in different stages was studied simultaneously with normal controls. Monocyte chemotactic responses were decreased in 6 of the 14 patients with advanced disease regardless of previous therapy. None of our patients with stage II disease had abnormal results. Decreased monocyte chemotactic responses correlated with the presence of cutaneous anergy. In addition, decreased chemotaxis was associated with diminished monocyte bactericidal activity. This suggests that decreased bactericidal activity may be related to abnormal migration and possible diminished ingestion. The data support the hypothesis that depressed monocyte function may contribute to the increased susceptibility to infections of patients with Hodgkin's disease and it may be an additional factor favoring tumor dissemination in the advanced stages of the disease.

Adolescent↗
PubMed1977

Monoclonal macroglobulinemia with osteolytic lesions: a case report and review of the literature.

A patient with monoclonal macroglobulinemia and osteolytic lesions was studied and 24 previously reported closely related cases were reviewed. Cases studied by ultracentrifugation without an immunoelectrophoresis were not considered. Patients presenting with a primary increase in monoclonal IgM molecules may be divided into three groups: typical Waldenstrom's macroglobulinemia, macroglobulinemia with osteolytic lesions resembling multiple myeloma, and a group displaying features of both diseases. At present, cell morphology is not helpful in separating these groups, and a bone survey is recommended. The authors underscore the clinical importance of the early recognition of these entities since procedures such as plasmapheresis for the management of hyperviscosity syndrome, mobilization and local radiotherapy to symptomatic lytic lesions may be necessary for optimal management.

Adult↗