Cytotoxicity In Patients Research Articles

Cefodizime stimulates subpopulations of cells mediating spontaneous or antibody-dependent cytotoxicity in patients with bacterial infections.

The influence of cefodizime (CDZ) on spontaneous cell-mediated cytotoxicity (SCMC) and antibody-dependent cell-mediated cytotoxicity (ADCC) was investigated in nine patients with conditions predisposing to infection (T-cell deficiency, humoral immune deficiency, myeloproliferative syndrome, kidney or liver damage, or chronic pulmonary disease). SCMC, using the K562 and LIK cell lines as targets, and ADCC, using the LIK cell line, were measured at baseline and after ten days of therapy with CDZ for lower respiratory tract infections. Six patients were cured; clinical outcome was not evaluable in the other three. SCMC lysis of K562 cells did not change significantly. SCMC and ADCC lysis of LIK (lymphoblastoid) cells both increased significantly. CDZ selectively stimulated a subpopulation of NK cells in this population of immunocompromised patients with lower respiratory tract infections.

Deficient antiendometrium lymphocyte-mediated cytotoxicity in patients with endometriosis

To study the possible role of the immune system in the pathogenesis of endometriosis. A cytotoxicity assay by 51Cr release was performed to determine the lymphocyte cytotoxic response toward endometrial targets and an erytroleukemic cell line (K562). The assays were performed in an academic research environment. Twenty-five control women and 25 patients with endometriosis were selected on the basis of laparoscopic examination. The lymphocyte cytotoxic activity was evaluated separately on endometrial stromal and epithelial cells after 4 hours' incubation. The study was designed to determine, in controls and endometriosis patients, the lymphocyte-mediated cytotoxicity toward stromal and epithelial cells of endometrium. The lymphocyte response in the presence of stromal cell antigens was significantly lower (P less than 0.02) in disease-affected women when compared with that obtained in controls (2.89 +/- 0.87 and 7.64 +/- 1.66, respectively). In contrast, when the same assay was performed on K562 cells, no difference was observed between endometriosis patients and controls. These data suggest that an altered immune recognition might be one of the pathogenic mechanisms of endometriosis. Moreover, they indicate that this is not a general phenomenon but is specific for the endometrial target.

Induction and clinical utilization of lymphokine‐activated killer cells in patients with gastrointestinal tract cancers

In 18 patients with cancers of the gastrointestinal tract, lymphokine-activated killer (LAK) cell activity was studied and compared with that of healthy subjects. After cultivation with 10(3) iu/mL of recombinant interleukin-2, the cytotoxicity of patients' lymphoid cells was increased from 13.6 +/- 6.8% to 76.2 +/- 19.5% against Daudi cells and from 12.8 +/- 8.1% to 76.2 +/- 19.5% against K-562 cells. Based on these results, autologous LAK cells were given to patients. LAK cells injected into subdermal metastatic tumours demonstrated a significant inhibitory effect on tumour growth in comparison with that of control tumour nodules. Of four patients with metastatic tumours in the liver, to whom LAK cells were administered via the hepatic artery, tumour size was reduced by about 25% (minor response) in one patient, with a decrease of computerized tomography attenuation in the tumours occurring in the other three patients.

Decreased natural killer cell activity in late-onset hypogammaglobulinaemia

1. Natural killer cell activity and monocyte cytotoxicity was evaluated in three subgroups of patients with primary hypogammaglobulinaemia (ten patients with late-onset, eight with X-linked and five with early-onset disease) and in two patients with secondary late-onset hypogammaglobulinaemia against the K-562 erythroleukaemia, the CaCo-2 colon carcinoma and the HGT-1 gastric carcinoma cell lines and compared with the results found in healthy control subjects. 2. The natural killer cell activity, both spontaneous and after stimulation with recombinant gamma-interferon, was found to be decreased in patients with late-onset hypogammaglobulinaemia. The natural killer cell activity in this subgroup was found to be impaired in 60% of the patients (P less than 0.05). Within the other forms of primary hypogammaglobulinaemia a decreased natural killer cell activity was found to be less frequent (33%). 3. The lectin-mediated cytotoxicity by phytohaemagglutinin resulted in a similar maximal cytotoxicity in patients and control subjects. 4. The cytotoxicity of monocytes, spontaneous and after recombinant gamma-interferon stimulation, was found to be normal in all patients with hypogammaglobulinaemia. 5. The impaired natural killer cell activity which was found in patients with late-onset hypogammaglobulinaemia may contribute to the increased susceptibility to infections and to the increased incidence of malignancies in this subgroup of patients with primary hypogammaglobulinaemia.

Clinical implications of natural killer (NK) cytotoxicity in patients with squamous cell carcinoma of the uterine cervix

Natural killer (NK) activity in peripheral blood mononuclear cells (PBMC) from women with squamous cell carcinoma of the uterine cervix (SCCUC) was studied. PBMC were obtained from 26 previously untreated patients with SCCUC at different stages of disease according to the FIGO classification (5 at stage I, 4 at stage II, 5 at stage III, 6 at stage IVa, and 6 belonging to stage IVb), as well as from 23 healthy age-matched women. These cells were used as effectors against 51Cr-labeled K-562 target cells in standard 4-hr cytotoxic assays. The NK activity displayed by PBMC from patients with local stages of the neoplasm (I, II, III, and IVa) was found to be similar to that exerted by PBMC from healthy controls ( P > 0.05). Furthermore, there were no significant differences among mean values of NK activity in PBMC from women at these different stages of the disease ( P > 0.05). However, the NK activity detected in the PBMC of patients with distant metastatic spread of the disease (stage IVb) was significantly depressed with respect to both controls and patients at any other earlier stage ( P < 0.05). We conclude that a decrease in the NK activity present in PBMC from women with SCCUC coincides with distant tumoral dissemination of the disease.

Down-regulation of LAK cell-mediated cytotoxicity: cancer and ageing

A comparative study was made of the generation of lymphokine-activated killer (LAK) cells in patients with melanoma and healthy donors of different age groups. Significant reduction of effector il cytotoxicity in patients following 72_h culture with 1 000 U/ml or recombinant IL-2 (rIL-2) as well as a decreased ability to generate LAK cells in elderly individuals were shown to be correlated with suppressor cell activation in rIL-2 stimulated cell population. Suppressor effect depends on monocytes and T-lymphocytes: partial abolition of suppression in LAK cells was observed following removal of adherent cells or treatment with OKT8 monoclonal antibodies and complement.

Phenotypic Analysis of Lymphocytes Involved in Major Histocompatibility Complex Unrestricted Cellular Cytotoxicity in Patients with Alcoholic Cirrhosis

Lymphocyte subpopulations known to exert major histocompatibility complex (MHC) unrestricted cytotoxicity were enumerated in 33 patients with alcoholic cirrhosis and in 10 patients with alcohol-induced fatty changes of the liver. Absolute numbers and percentages of lymphocytes bearing the CD57 (median 12 vs. 20%; p = 0.007) and CD16 (median 12 vs. 19%; p = 0.0027) antigens were significantly reduced in cirrhotic patients as compared to healthy control individuals, whereas no significant change in CD56+ cells (median 13 vs. 13%; n.s.), comprising a subpopulation with a high natural killer activity in normal individuals, was observed. A subset of these cells, cytotoxic T cells coexpressing CD56 and CD3 antigens and capable of MHC-unrestricted cellular cytotoxicity, was significantly increased in patients with alcoholic cirrhosis as compared to healthy control individuals (median 2 vs. 1%; p = 0.024). Patients with alcohol-induced fatty changes of the liver did not show any deviation of lymphocyte subpopulation from normal. The finding that lymphocyte subsets capable to exert most of the MHC-unrestricted cytotoxic capacity in peripheral blood (CD56+ non-T-cells and CD3+ CD56+ T cells) were unchanged or even increased in number suggests that the reduced natural killer cell activity known to occur in patients with alcoholic liver cirrhosis might be due to a functional defect of these cells. Furthermore, our results indicate that changes in frequency of MHC-unrestricted cytotoxic cells are not found in a similar manner in all subsets of these cells, but are dependent on the particular cell surface marker investigated.

Transfusion History, T Cell Subsets and Natural Killer Cytotoxicity in Patients with Colorectal Cancer1

Blood transfusions are associated with clinical phenomena which are attributable to immune suppression. Since suppression of immune function is associated with a high risk of spontaneous malignancies, we studied T cell subsets and natural killer (NK) cytotoxicity in colorectal cancer patients and correlated the results with patients' transfusion histories. Twelve percent (14) of the 115 patients had been transfused an average of 19 years previously. Recipients of blood transfusions had low levels of peripheral lymphocytes (p = 0.191), T cells (p = 0.015), helper cells (p = 0.016) and suppressor cells (p = 0.2651) compared to previously untransfused patients. NK cytotoxicity was also significantly reduced in transfusion recipients although NK cell numbers were comparable in both groups. These results support previous studies indicating that blood transfusions cause lifelong immune modulation in the recipient. Since blood transfusions have numerous beneficial effects and immune modulation is often beneficial, longitudinal studies are necessary to define the lifetime risks and benefits.

Transfusion History, T Cell Subsets and Natural Killer Cytotoxicity in Patients with Colorectal Cancer

Blood transfusions are associated with clinical phenomena which are attributable to immune suppression. Since suppression of immune function is associated with a high risk of spontaneous malignancies, we studied T cell subsets and natural killer (NK) cytotoxicity in colorectal cancer patients and correlated the results with patients’ transfusion histories. Twelve percent (14) of the 115 patients had been transfused an average of 19 years previously. Recipients of blood transfusions had low levels of peripheral lymphocytes (p=0.191 ), T cells (p=0.015), helper cells (p=0.016) and suppressor cells (p=0.2651) compared to previously untransfused patients. NK cytotoxicity was also significantly reduced in transfusion recipients although NK cell numbers were comparable in both groups. These results support previous studies indicating that blood transfusions cause lifelong immune modulation in the recipient. Since blood transfusions have numerous beneficial effects and immune modulation is often beneficial, longitudinal studies are necessary to define the lifetime risks and benefits.

Natural killer and lymphokine-activated killer cell-mediated cytotoxicity in patients with oral cancer.

Peripheral blood lymphocytes (PBL) from untreated and treated oral cancer patients, lymph node lymphocytes (LNL) from metastatic (met) and nonmetastatic (non-met) lymph nodes, and tumor infiltrating lymphocytes (TIL) were tested for natural killer (NK) and lymphokine activated killer (LAK) cell cytotoxicity using appropriate targets in a short-term chromium release assay. The results showed that while both NK and LAK functions of PBL from oral cancer patients were comparable to those of normal healthy donors, the NK activity of metastatic and nonmetastatic LNL and TIL was highly compromised. On the other hand, potent LAK activity could be generated from all three lymphoid populations. Individual patients showing low NK activity displayed good LAK cytotoxicity, indicating that endogenous cells with low NK potential have adequate ability to respond to interleukin 2 (IL-2). LAK activity tested on autologous tumour targets revealed that TIL were the best source of LAK cells. followed by PBL and LNL.

Antibody-dependent cell-mediated cytotoxicity in patients with chronic mononucleosis syndrome

Antibody-dependent cell-mediated cytotoxicity in patients with chronic mononucleosis syndrome

The prognostic significance of natural killer cytotoxicity in patients with colorectal cancer.

We evaluate the prognostic significance of preoperative natural killer (NK) cytotoxicity for K562 cells and its relationship to other prognostic factors in 102 patients with colorectal cancer who underwent curative resections between February 1984 and February 1985. The 18 patients who had recurrences within two years of surgery had significantly higher numbers of preoperative peripheral blood suppressor/cytotoxic and NK cells and significantly lower preoperative NK cytotoxicity than disease-free patients. Low preoperative NK cytotoxicity was predictive of recurrence independent of age, sex, hematocrit, procedure, blood loss, duration of surgery, Dukes' stage, specimen length, tumor size, tumor differentiation, and post-operative therapy. Low levels of in vitro NK-cell cytotoxicity may identify a subgroup of patients at high risk for recurrence.

Natural killer cell activity and antibody-dependent cellular cytotoxicity in patients under various immunosuppressive regimens

The influence of various modes of immunosuppression using cyclosporin A (CyA), corticosteroids (Cort), azathioprine (AZA), and antithymocyte globulin (ATG) alone or in combination with each other upon natural killer (NK) cell activity and antibody-dependent cellular cytotoxicity (ADCC) was assessed. CyA given alone did not influence either NK or ADCC activity; in contrast, the administration of Cort resulted in a significant decline ( P < 0.01) of ADCC but not of NK activity ( P > 0.1). The combination of the two drugs led to a significant impairment of NK activity ( P < 0.01). The combination of AZA and Cort was found to produce an even more pronounced reduction in NK activity compared to both healthy controls ( P < 0.001) as well as patients from the CyA + Cort group ( P < 0.001). A similar decrease was found also after the addition of ATG to CyA + Cort ( P < 0.001, compared both with patients on CyA + Cort and with controls). In these instances, ADCC showed an overall similar pattern. We conclude that the administration of either CyA or Cort does not influence NK activity, while the combination of CyA with Cort and of AZA with Cort leads to a decrease in both NK and ADCC activities. The monotherapy with Cort only leads to a reduction of ADCC. These findings may explain the higher incidence of malignancies in patients undergoing combined immunosuppressive treatment.

Natural killer cell activity in patients with urologic cancer.

Cell-mediated cytotoxicity in patients with urologic cancer was studied using the K562 cell line as target cell by a 4-hour chromium-51 release assay. Lysis of target cells by mononuclear cells of a healthy subject, over an 8-hour incubation period, demonstrated a linear function of incubation time and effector:target ratio. Natural killer (NK) cell activity was found decreased (mean 30.6%) in peripheral blood lymphocytes from 42 untreated patients with urologic cancer when compared to 20 healthy subjects (63.6%) and to 10 patients with varicocele, stone disease and benign prostatic hypertrophy (58.1%; p less than 0.05). There was no correlation between NK cell activity and the grade or stage status in bladder cancer patients. No age-dependent changes in NK cell activity could be found between young and aged groups of healthy subjects. Healthy male subjects have higher levels of NK cell activity (77.7%) than healthy female subjects (49.5%). Postoperative NK activity rose in 5 out of 6 cancer patients. It indicates that tumors may have an inhibitory effect on the surveillance activity of NK cells.

Effect of lymphokines on natural killer cytotoxicity in patients with high risk of developing the acquired immune deficiency syndrome

Regulation of natural killer (NK) activity of peripheral blood mononuclear cells (PBMC) from patients with the acquired immune deficiency syndrome (AIDS) and from individuals at high risk of developing AIDS (R-AIDS) was studied. The response of untreated PBMC to the interferon inducer polyinosinic polycytidilic acid (Poly I:C) was lower in AIDS and R-AIDS than in normal controls and PBMC from R-AIDS were more susceptible to stimulation with lymphokine rich supernatants (Con-A-SN, PHA-SN, lectin free IL-2) than AIDS and normal controls. To determine the role of the different T lymphocyte subsets in the regulation of NK activity, PBMC were selectively treated with monoclonal non-cytotoxic anti-Leu 2a and anti-Leu 3a anti-bodies and then stimulated with lymphokine rich supernatants. The results indicate that the effect of crude supernatants was the combination of opposite effects. Leu 2a-blocked R-AIDS-PBMC enhanced NK cytotoxicity when exposed to IL-2 rich supernatants whereas Leu 3a-blocked R-AIDS-PBMC suppressed the cytotoxic reaction.

Defective natural killing activity but retention of lymphocyte-mediated antibody-dependent cellular cytotoxicity in patients with the X-linked lymphoproliferative syndrome

Cellular mediated immune responses in vitro of six males with X-linked lymphoproliferative syndrome (XLP) were investigated. Impaired natural killing (NK) activity compared to seven controls ( P < 0.001) and interferon-α activation ( P < 0.011) were detected. However, normal numbers of lymphocytes expressing NK-associated antigens (Leu-7 and MO1) and large granular lymphocytes (LGL) were observed in all patients. Normal lymphocyte-mediated antibody-dependent cellular cytotoxicity (ADCC) ( P < 0.531) was found. NK and ADCC activities have been regarded as being mediated by the same subsets of lymphocytes, however, results of this study do not support this hypothesis: lymphocytes with impaired NK but normal ADCC functions ( NK − K + ) were found in males with XLP.

Natural killer cell response to regional lymph node metastases.

A determination of natural killer cell activity was performed in 67 individuals with advanced head and neck cancer. The mean activity of 28 patients clinically staged T3 NO or T4 NO was 81 +/- 11 lytic units (LU), significantly higher than 39 patients with palpable lymph node metastases (54 +/- 5 LU). Assessing patients by extent of nodal disease revealed that activity actually increased, though not significantly, with progressive N-staging. A major determinate of increased natural killer cell cytotoxicity in patients with lymph node metastases was extranodal cancer within the neck. The mean activity of nine patients whose tumor was fixed to underlying structures or adherent to skin was 87 +/- 15 LU, significantly higher than the 45 +/- 4 LU mean value of the remaining patients with clinically determined regional nodal disease. The potential clinical implications of these findings are discussed.

Study of cytotoxicity against adenovirally transformed cells in patients with tumours of the urinary tract.

Peripheral mononuclear cells of patients with tumours of the prostate and bladder and with papilloma of the bladder were studied for cytotoxicity against adenovirally transformed cell lines. The cytotoxicity of patients with carcinoma of the prostate or bladder revealed no significant changes compared with the control values. Patients with bladder papilloma having received immunostimulant therapy with levamisole over a year showed a significant rise of their cytotoxicity figures in the second 6-month period of study.

Selective Cytotoxicity of 25I-Labeled Monoclonal Antibody T101 in Human Malignant T Cell Lines

The radiolabeled anti-T cell antibody T101 can be used for specific tumor localization, but unlabeled T101 produces limited cytotoxicity in patients. We thus studied the in vitro cytotoxic effects of T101 labeled with 125I, a radionuclide known for its short-range, high-linear-energy electrons. We showed that 125I-T101 could be readily prepared at high specific activity with high immunoreactivity. Human malignant T cell lines HUT 102, MOLT-4, and HUT 78 were found to differ in the number of T65 determinants (the antigen recognized by T101) and the sensitivity to external x-ray radiation, which were of significance for the cytotoxicity of 125I-T101 in vitro. The cytotoxic effects of 125I-T101 were also found to be dose dependent and increased with exposure time under frozen conditions. As controls, unlabeled T101 had no cytotoxic effect, while free Na 125I or the 125I-labeled irrelevant antibody 9.2.27 exerted minor cytotoxicity. In HUT 102 and MOLT-4, more than 3 logs' cell killing was achieved within four weeks. Because considerable cytotoxicity was demonstrated in vitro by 125I-T101 on T65-positive malignant cells, and because low-dose 111In-T101 can be used successfully for tumor localization, future trials using 125I-T101 at high specific radioactivity may improve therapeutic results in patients with T65-positive malignancies.

Selective cytotoxicity of 125I-labeled monoclonal antibody T101 in human malignant T cell lines

The radiolabeled anti-T cell antibody T101 can be used for specific tumor localization, but unlabeled T101 produces limited cytotoxicity in patients. We thus studied the in vitro cytotoxic effects of T101 labeled with 125I, a radionuclide known for its short-range, high- linear-energy electrons. We showed that 125I-T101 could be readily prepared at high specific activity with high immunoreactivity. Human malignant T cell lines HUT 102, MOLT-4, and HUT 78 were found to differ in the number of T65 determinants (the antigen recognized by T101) and the sensitivity to external x-ray radiation, which were of significance for the cytotoxicity of 125I-T101 in vitro. The cytotoxic effects of 125I-T101 were also found to be dose dependent and increased with exposure time under frozen conditions. As controls, unlabeled T101 had no cytotoxic effect, while free Na 125I or the 125I-labeled irrelevant antibody 9.2.27 exerted minor cytotoxicity. In HUT 102 and MOLT-4, more than 3 logs' cell killing was achieved within four weeks. Because considerable cytotoxicity was demonstrated in vitro by 125I-T101 on T65- positive malignant cells, and because low-dose 111In-T101 can be used successfully for tumor localization, future trials using 125I-T101 at high specific radioactivity may improve therapeutic results in patients with T65-positive malignancies.