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Canada↗
Biomedical subjects
A LeFever
Publications and source records attributed to A LeFever.
Comparison of four cytokine regimens for mobilization of peripheral blood stem cells: IL-3 alone and combined with GM-CSF or G-CSF.
Improved methods for mobilization may reduce the number of aphereses required to collect adequate numbers of peripheral blood stem cells (PBSC) and hasten engraftment following high-dose therapy. Mobilization with cytokines alone enables engraftment after myeloablative therapy. The optimal cytokine regimen for mobilization has not been established. The study evaluated the effects of four interleukin-3-containing cytokine regimens administered during steady state hematopoiesis on PBSC mobilization in 30 patients with breast cancer or lymphoid malignancies. These regimens included IL-3 alone (Arm 1), sequential IL-3 --> G-GSF (Arm 2), sequential IL-3 --> GM-CSF (Arm 3) and combined IL-3 + G-CSF (Arm 4). Consecutive days of apheresis were performed until a target of 4-6 x 10(8) mononuclear cells/kg were collected. All patients received intravenous GM-CSF after PBSC infusion. Median days to an ANC > or = 500/ microliters in Arm 3(22 days) was significantly slower than for patients in Arm 2 (13 days) but not significantly different from patients in Arm 1 or Arm 4. There was no significant difference in platelet engraftment or days of hospitalization between the study arms. Addition of GM-CSF to IL-3-containing mobilization regimens results in collection of PBSC that lead to delayed engraftment. Further development of Arms 1, 2, and 4 appear warranted.
Adult↗
Association of increased prostaglandin E2 content in bronchoalveolar lavage fluid and intrathoracic malignancy.
Prostaglandin E2 (PGE2), a metabolite of arachidonic acid, plays an important role in immunoregulation. We have previously reported an increased PGE2 content in bronchoalveolar lavage fluid (BALF) in 18 patients who had primary lung cancer as compared with 6 patients who had benign lung diseases and 10 normal smokers. In this article, we report our further observation, including additional 73 patients with primary lung cancer, 11 patients who had carcinoma other than lung cancer with and without lung metastases, and 24 patients with various benign lung diseases. Prostaglandin E2 content of BALF in patients with primary lung cancer and patients with extrathoracic cancer with lung metastases was markedly increased to 283.7 +/- 423.8 and 278.3 +/- 303.4 pg/ml, respectively. In contrast, patients who had extrathoracic cancer without lung metastases and patients with benign lung diseases had PGE2 content in BALF of 22.6 +/- 6.6 and 27.2 +/- 12.4 pg/ml, respectively. Values between the subgroups of patients with lung cancer (primary and metastatic) and patients with benign diseases or extrathoracic cancer without lung metastasis were significantly different (p < .001). Follow up of eight patients who successfully underwent surgical resection of cancer showed decreased levels of PGE2 in all but two patients. Although the exact cause and mechanism of the observed increase of PGE2 in BALF of patients with lung cancer are not clear at this point, current study together with our previous observations clearly indicates that the presence of lung cancer, both primary and metastatic, is associated with an elevated PGE2 content of BALF. The clinical significance of this observation is not known. However, an increased amount of PGE2 in BALF might adversely affect the course of lung cancer, because PGE2 is a down regulator of immune response against infection and neoplasm. Further investigations into the mechanism(s) and the role of PGE2 in BALF are warranted.
Aged↗
Lymphokine-activated killer cell activity in lung cancer.
This study evaluates local pulmonary immune effector cell lytic activity. Purified lymphocyte populations were isolated from BALF obtained from 18 patients with bronchogenic carcinoma, six patients with lung disorders other than cancer, and ten normal control volunteers matched for age and smoking history. These cells were evaluated for NK and LAK cell lytic activity against NK-resistant LAK-sensitive tumor targets (A549 pulmonary tumor and Daudi tumor cells) and an NK-sensitive tumor (K562); LAK activity was detected in BALF from 6 of the 18 patients with cancer. The remaining patients with cancer, the subjects with pulmonary disease other than cancer, and the normal volunteers had no detectable lytic activity. Peripheral blood lymphocytes from all subjects had only NK lytic activity and did not kill the pulmonary tumor target; AMs were not tumoricidal. Interleukin-2, which is required for LAK cell activation, was detected only in BALF recovered from the six patients with pulmonary LAK lytic activity. These results demonstrate that activated LAK cells, capable of killing pulmonary tumor cells, are present in BALF of some patients with bronchogenic carcinoma. This lytic LAK cell population represents a local pulmonary response against the lung cancer in the absence of systemic tumoricidal activity. The functional status of pulmonary immune effector cells, as well as the type and quantities of cytokines in the lung determine local responsiveness to bronchogenic carcinoma and may well control the course of this disease.
Aged↗
Elevated prostaglandin E2 levels in bronchoalveolar lavage fluid of patients with bronchogenic carcinoma.
Understanding local pulmonary immunoregulatory mechanism(s) in patients with carcinoma of the lung is an important step towards the development of innovative methods of treatment. Prostaglandin E2 plays an integral role in immunoregulation. Therefore, we evaluated PGE2 concentrations in BALF from 18 patients with bronchogenic carcinoma, compared to that from six patients with pulmonary diseases other than carcinoma and ten normal smokers of similar age. The level of PGE2 in patients with lung carcinoma (158.1 +/- 88.7 pg/ml) was significantly (p less than 0.001) higher than the other two groups (16.2 +/- 6.9 and 4.4 +/- 3.4 pg/ml). Levels of PGE2 also varied among patients with carcinoma of different cell types. Patients with SQCA had significantly (p less than 0.001) higher levels of PGE2 (242.7 +/- 29.4 pg/ml) than patients with ADCA or SCCA (82.3 +/- 27.9 and 66.3 +/- 15.2 pg/ml, respectively). Furthermore, there was a marked difference in PGE2 concentration between carcinomatous lung and clinically noninvolved lung in patients with SQCA and ADCA. Further study is warranted to determine the interactions between PGE2 and other cytokines (interleukin-1, IL-2, and tumor necrosis factor), as well as the activity of cytolytic lymphocytes (LAK cells) in the lungs of patients with bronchogenic carcinoma.
Adenocarcinoma↗
Kinetic analysis of K+ ion channel function in lymphokine-activated killer (LAK) cells.
K+ ion channels of lymphocytes have been implicated in cellular differentiation, activation and cytolytic functions. We previously demonstrated that K+ channel blockers modulate lytic activity of CTLs and LAK cells. In the present study, we define and quantitate the inhibitory effects of ion channel blockers on the lytic process using kinetic analysis of lysis. The K+ channel blocker, 4-aminopyridine, the neuroendocrine monoamine, serotonin, its agonist, quipazine, and the Ca++ dependent K+ channel blocker, quinidine were found to non-competitively inhibit the lytic process in a dose-dependent manner. These compounds inhibit lytic activity by causing a decrease in the maximum velocity (Vmax) by which LAK cells lyse tumor targets. These ion channel blockers did not alter effector or target cell viability or the binding of LAK cells to tumor cells. The inhibitory effects occurred at the effector cell level, since preincubation of LAK effector cells resulted in a dose-dependent decrease in Vmax which was related to a slower rate of target cell lytic programming (k2) by the LAK effector cells. Modulation of LAK cell lytic function occurs at a post-binding step, perhaps in the generation or release of the lytic signal.
4-Aminopyridine↗
Kinetic analysis of lymphokine-activated killer (LAK) cells: lytic parameters and determination of LAK cell frequency.
Kinetic analysis was used to define lytic events in murine lymphokine-activated killer (LAK) cell-mediated tumour cell lysis. The maximum rate of target cell lysis (Vmax) and Km (target cell number resulting in 1/2 Vmax) were determined. Single cell lytic assays demonstrated that only LAK effector cells bound to target cells (i.e. non-lytic, bystander lymphocytes did not influence the determination of kinetic parameters) in contrast to natural killer (NK) cell lysis. This finding allowed for LAK cell frequency determinations where Km approximates the concentration of lytic LAK effector cells within a given number of lymphocytes. Frequencies determined in this manner were not significantly different from those obtained using the more cumbersome single cell lytic assay. Furthermore, frequencies determined for the same lymphocyte population against four different NK-resistant tumour targets, that varied in their sensitivity to LAK cell lysis, were not significantly different. In addition, LAK cell lytic programming of target cells was found to be the rate limiting lytic event. This study provides a means of determining reliable estimates of LAK cell frequencies within a lymphocyte population, which will be useful in studies evaluating LAK cytolytic mechanisms and the effects of drugs, biological response modifiers, or disease states on LAK cell lytic activity.
Animals↗
Serotonin modulated Ca++ dependent K+ channels in alloimmune effector cell lytic function.
Potassium channel activity has been implicated in the lytic function of cloned murine effector T lymphocytes (5) and human NK cells (12) as well as in the initiation of the injury process in tumor cells (23). In the present studies, the effects of various K+ channel blockers on the cytolytic function of in vivo derived alloimmune lymphocytes towards P815 tumor cells were evaluated. The classical K+ channel blocker 4-aminopyridine (4-AP), the naturally occurring monoamine serotonin (5-hydroxytryptamine, 5-HT) and its agonist, quipazine, as well as the Ca++ dependent K+ channel blocker quinidine were chosen for investigation based on their known ion channel gating properties. These agents, when present in the assay medium, inhibited in a dose dependent manner the lysis of P815 tumor cells as measured by specific 51Cr release. Preincubation of effector lymphocytes with the various K+ channel blockers resulted in greater inhibition of lysis than did the preincubation of target cells. The 5-HT agonist quipazine was of particular interest in that it inhibited the lytic process with equal effectiveness when continuously present in the assay medium or when the effector cells alone were preincubated. Quinidine was used to investigate whether Ca++ dependent K+ channels were the predominant ion channel involved in the lytic process. When present during the lytic assay, quinidine was similar to quipazine in terms of their dose range at which they inhibited the lytic process. These results indicate that 5-HT sensitive Ca++ dependent K+ channels are likely to be involved in the delivery of lytic signal(s) by immune effector lymphocytes and suggests that neuroendocrine products may modulate the functional activity of in vivo derived lymphocytes.
4-Aminopyridine↗
Role of K+ ion channels in lymphokine-activated killer (LAK) cell lytic function.
Cells of the immune system possess K+ ion channels which have been implicated in various cellular functions including activation, differentiation and cytolytic function. To define the role of K+ ion channels in the lytic function of lymphokine-activated killer (LAK) cells, we investigated the effects of K+ channel blockers on their cytolytic activity. Results show that when LAK cell mediated cytolysis of AKIL-20 tumor cells was carried out in the presence of: a) the K+ channel blocker, 4-aminopyridine (4-AP); b) the monoamine, serotonin (5-hydroxytryptamine; 5-HT); c) the serotonin agonist, quipazine; d) or the Ca++ dependent K+ channel blocker, quinidine, the cytolytic activity of the LAK cells was inhibited in a dose-dependent manner. Preincubation of LAK effector cells also inhibited lysis in a dose-dependent manner, whereas preincubation of the AKIL-20 tumor target cells produced no inhibitory effects. This study demonstrates that K+ ion channels are involved in the LAK cell cytolytic process and that compounds, including neuroendocrine products, which modulate K+ ion channel function are capable of modulating the lytic activity of these effector cells.
4-Aminopyridine↗