Evaluation of natural killer and lymphokine-activated killer (LAK) cell activity in vivo in patients treated with high-dose interleukin-2 and adoptive transfer of autologous LAK cells

1989 ◽  
Vol 115 (2) ◽  
pp. 170-174 ◽  
Author(s):  
J. Walewski ◽  
E. Paietta ◽  
J. Dutcher ◽  
P. H. Wiernik
Keyword(s):  
Natural Killer ◽  
Adoptive Transfer ◽  
Interleukin 2 ◽  
Cell Activity ◽  
Lak Cells ◽  
High Dose ◽  
Lak Cell ◽  
Lak Cell Activity

Preclinical Evaluation of a Bone-Marrow Autograft Culture Procedure for Generating Lymphokine-Activated Killer Cells in Vitro

1992 ◽  
Vol 3 (suppl b) ◽  
pp. 123-127 ◽  
Author(s):  
Hans-Georg Klingemann ◽  
Heather Deal ◽  
Dianne Reid ◽  
Connie J Eaves
Keyword(s):  
Bone Marrow ◽  
Calf Serum ◽  
Cell Activity ◽  
Hematopoietic Cells ◽  
Lak Cells ◽  
High Dose ◽  
Lymphokine Activated Killer Cells ◽  
Lak Cell

Despite the use of high dose chemoradiotherapy for the treatment of acute leukemia. relapse continues to be a major cause of death in patients given an autologous bone marrow transplant. Further augmentation of pretransplant chemotherapy causes life threatening toxicity to nonhematopoietic tissues and the effectiveness of currently available ex vivo purging methods in reducing the relapse rate is unclear. Recently, data from experimental models have suggested that bone marrow-derived lymphokine (IL-2)-activated killer (BM-LAK) cells might be used to eliminate residual leukemic cells both in vivo and in vitro. To evaluate this possibility clinically, a procedure was developed for culturing whole marrow harvests with IL-2 prior to use as autografts, and a number of variables examined that might affect either the generation of BM-LAK cells or the recovery of the primitive hematopoietic cells. The use of Dexter long term culture (LTC) conditions, which expose the cells to horse serum and hydrocortisone. supported LAK cell generation as effectively as fetal calf serum (FCS) -containing medium in seven-day cultures. Maintenance of BM-LAK cell activity after a further seven days of culture in the presence of IL-2 was also tested. As in the clinical setting. patients would receive IL-2 in vivo for an additional week immediately following infusion of the cultured marrow autograft. Generation ofBM-LAK activity was dependent on the presence of IL-2 and could be sustained by further incubation in medium containing IL-2. Primitive hematopoietic cells were quantitated by measuring the number of in vitro colony-forming progenitors produced after five weeks in secondary Dexter-type LTC. Maintenance of these 'LTC-initiating cells' was unaffected by lL-2 in the culture medium. These results suggest that LAK cells can be generated efficien tly in seven-day marrow autograft cultures containing IL-2 under conditions that allow the most primitive human hematopoietic cells currently detectable to be maintained.

scholarly journals Defective natural immunity: an early manifestation of human immunodeficiency virus infection.

1995 ◽  
Vol 182 (3) ◽  
pp. 789-799 ◽  
Author(s):  
H Ullum ◽  
P C Gøtzsche ◽  
J Victor ◽  
E Dickmeiss ◽  
P Skinhøj ◽  
...  
Keyword(s):  
Nk Cell ◽  
Interleukin 2 ◽  
Cell Activity ◽  
Lak Cells ◽  
Natural Immunity ◽  
Cd4 Cells ◽  
Nk Cell Activity ◽  
Ifn Alpha ◽  
Lak Cell ◽  
Lak Cell Activity

Cytotoxicity mediated by natural killer (NK) and lymphokine-activated killer (LAK) cells may be of significance in host defense against viral infections. This study included 347 patients infected with human immunodeficiency syndrome virus (HIV) type 1 and 110 controls. The NK cell activity, either unstimulated or stimulated with interferon-alpha (IFN-alpha) or interleukin-2 (IL-2), and the LAK cell activity were suppressed in patients, but the NK/LAK cell activity did not differ between patients with AIDS and patients without AIDS. However, the IFN-alpha-stimulated NK cell activity and LAK cell activity were reduced in patients with symptoms of HIV disease (CDCIV) when compared with asymptomatic patients (CDCII+III). When the data were analyzed by multiple linear regression, the percentage of CD4+ cells had a positive effect on these two parameters in patients without AIDS, whereas the percentage of CD4+ cells had no significant effect on unstimulated and IL-2-stimulated NK cell activity in these patients. In controls and AIDS patients, the percentage of CD4+ cells had no effect on NK/LAK cell activity in multiple linear models. The total number of CD16+ cells was low in patients compared to controls, whereas the percentages of CD16+, CD56+, and CD16+CD56+ were either normal or elevated. Therefore, the decrease in NK cell subpopulations did not contribute to the observed depression in NK/LAK cell activity in vitro. It is concluded that natural immunity is suppressed in HIV-seropositive patients primarily because of a qualitative defect of the NK/LAK cells. This qualitative defect includes a reduced responsiveness to IFN-alpha, which is progressive until the onset of symptoms, and possibly related to the loss of CD4+ cells.

Experimental study on interleukin 6 activity against tumor; Regulation of interleukin-2 induced lak cell activity

1993 ◽  
Vol 5 (4) ◽  
pp. 263-267
Author(s):  
Lisheng Lu ◽  
Zhengyan Cui ◽  
Ling Zhang ◽  
Denghua Li ◽  
Zhigang Tian
Keyword(s):  
Experimental Study ◽  
Interleukin 6 ◽  
Interleukin 2 ◽  
Cell Activity ◽  
Lak Cell ◽  
Lak Cell Activity

Influence of in vivo hypobaric hypoxia on function of lymphocytes, neutrocytes, natural killer cells, and cytokines

1993 ◽  
Vol 74 (3) ◽  
pp. 1100-1106 ◽  
Author(s):  
M. Klokker ◽  
A. Kharazmi ◽  
H. Galbo ◽  
I. Bygbjerg ◽  
B. K. Pedersen
Keyword(s):  
Immune System ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Interleukin 2 ◽  
Cell Activity ◽  
Nk Cell Activity ◽  
Cd8 Cells ◽  
The Absolute

We have investigated the effects of short-term hypoxia in vivo on the human cellular immune system. Seven young healthy volunteers were placed in a decompression chamber (380 Torr) for 20 min with or without supplemental O2. The leukocyte concentration increased during hypobaric conditions because of an increased concentration of lymphocytes. The absolute and relative concentration of CD16+ natural killer (NK) cells increased markedly during hypoxia and returned to pretest values after 2 h of recovery. The NK cell activity of blood mononuclear cells (BMNC, %lysis/fixed no. of BMNC) boosted with interferon-alpha, interleukin-2 (IL-2), and indomethacin rose in parallel with unboosted NK cell activity during hypoxia. The percentage of CD4+ and CD8+ cells declined during hypoxia, whereas the absolute concentration of both CD8+ cells and CD14+ monocytes increased. Although the BMNC composition varied, the proliferative responses of BMNC after stimulation with phytohemagglutinin, purified derivative of tuberculin, and IL-2 did not change significantly. The in vitro production of interleukin-1 beta and IL-2 in supernatants obtained after stimulation of BMNC with phytohemagglutinin or lipopolysaccharide was not affected. The chemiluminescence response of neutrocytes increased 2 h after hypoxia. It was concluded that acute hypoxia induced marked alterations in the immune system and that the NK cells are especially sensitive to the hypoxic stimulus.

A phase I trial of recombinant interleukin-2 combined with recombinant interferon-gamma in patients with cancer.

1990 ◽  
Vol 8 (7) ◽  
pp. 1269-1276 ◽  
Author(s):  
B G Redman ◽  
L Flaherty ◽  
T H Chou ◽  
A al-Katib ◽  
M Kraut ◽  
...  
Keyword(s):  
Phase I ◽  
Interferon Gamma ◽  
Phase I Trial ◽  
Interleukin 2 ◽  
Cell Activity ◽  
Ifn Gamma ◽  
Recombinant Interferon ◽  
Lak Cell ◽  
Recombinant Interleukin 2 ◽  
Lak Cell Activity

Twenty-six patients with metastatic cancer were entered into a phase I trial of concurrent recombinant interleukin-2 (IL-2) and recombinant interferon-gamma (IFN-gamma). IL-2 was administered as a continuous intravenous infusion for 5 days. IFN-gamma was administered by a daily intramuscular (IM) injection during the 5 days of IL-2 administration. Treatment was repeated twice after 9-day rest periods. After a 2-week rest, patients without evidence of tumor progression were retreated. Natural killer (NK)- and lymphokine-activated killer (LAK)-cell activity were assayed in each patient before treatment, on day 1, and on day 5 of each cycle. Constitutional symptoms occurred in most patients but were not dose-limiting. Other toxicities included hypotension responsive to fluids, transient elevations in liver function tests, erythema/pruritus, eosinophilia, and transient leukopenia/thrombocytopenia. The maximum-tolerated dose (MTD) of the combination was 1 x 10(6) U/m2/d of IL-2 combined with 0.50 mg/m2/d of IFN-gamma. The dose-limiting toxicity was pulmonary manifesting as rales and shortness of breath. The dose of the combination that resulted in the optimal generation of in vivo LAK-cell activity was a dose of at least 0.25 mg/m2/d of IFN-gamma combined with 1 x 10(6) U/m2/d of IL-2. Objective clinical responses were seen in five of 26 patients. These included a partial response of 2 months duration in a patient with non-Hodgkin's lymphoma (NHL), mixed responses in a patient with NHL and two patients with renal cell carcinoma (RCC), and an ongoing assessable response in a patient with bone metastases from RCC. The recommended dose for phase II trials of this combination is 0.50 mg/m2 of IFN-gamma and 1 x 10(6) U of IL-2.

Role of Spontaneous and Interleukin-2–Induced Natural Killer Cell Activity in the Cytotoxicity and Rejection of Fas+and Fas− Tumor Cells

Blood ◽  
1998 ◽  
Vol 92 (11) ◽  
pp. 4248-4255 ◽  
Author(s):  
Mike Bradley ◽  
Ahmet Zeytun ◽  
Asimah Rafi-Janajreh ◽  
Prakash S. Nagarkatti ◽  
Mitzi Nagarkatti
Keyword(s):  
Natural Killer ◽  
Tumor Cells ◽  
Fas Ligand ◽  
Natural Killer Cell Activity ◽  
Killer Cell ◽  
Interleukin 2 ◽  
Cell Activity ◽  
Lak Cells ◽  
Poly I:C ◽  
Lak Activity

Abstract In the current study, we investigated whether the naive, poly I:C or interleukin-2 (IL-2)–induced natural killer (NK)/lymphokine-activated killer (LAK) cells use perforin and/or Fas ligand (FasL) to mediated cytotoxicity. We correlated these findings with the ability of mice to reject syngeneic Fas+ and Fas− tumor cells either spontaneously or after IL-2 treatment. The spontaneous NK-cell–mediated cytotoxicity was primarily perforin based, whereas the poly I:C and IL-2–induced NK/LAK activity was both FasL and perforin dependent. L1210 Fas+ tumor targets were more sensitive than L1210 Fas− targets to poly I:C and IL-2–induced cytotoxicity in wild-type, gld/gld, and perforin knockout mice. When L1210 Fas+ and Fas– tumor cells were injected subcutaneously (sc) or intraperitoneally into syngeneic mice, Fas− tumor cells caused mortality earlier than Fas+ tumor cells. Also, approximately 20% of the mice injected sc with L1210 Fas+ tumor cells survived the challenge(>60 days), whereas all mice injected similarly with L1210 Fas− tumor cells died. When immunotherapy using IL-2 (10,000 U, three times/d for a week, followed by once/d for an additional week) was attempted in mice injected sc with tumor cells, IL-2 treatment was very effective against mice bearing L1210 Fas+ (40% survival) but not L1210 Fas− (0% survival) tumors. These data correlated with the finding that the LAK cells from IL-2–injected mice caused increased cytotoxicity against L1210 Fas+ when compared with L1210 Fas− targets. Also, L1210 Fas+tumor-bearing mice showed increased tumor-specific cytotoxic T lymphocyte (CTL) activity when compared with those bearing L1210 Fas− tumor cells. Together our studies show for the first time that expression of Fas on tumor targets makes them more immunogenic as well as susceptible to CTL- and IL-2–induced LAK activity. The Fas+ tumor cells are also more responsive to immunotherapy with IL-2.

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