Effects Of Interleukin-2 Treatment Research Articles

Effect of Interleukin-2 Treatment Combined with Magnetic Fluid Hyperthermia on Lewis Lung Cancer-Bearing Mice

Objective: The study aimed to investigate the therapeutic effect of interleukin-2 (IL-2) treatment combined with magnetic fluid hyperthermia (MFH) on Lewis lung cancer-bearing mice. Materials and Methods: Magnetic fluids were prepared in vitro and directly injected into the tumors in the mice, which were subjected to an alternating magnetic field. The temperature in the tumor reached 43°C and was maintained by controlling the strength of magnetic field for 30 minutes. Twenty-four hours later, IL-2 was injected directly into the tumors. Mice were divided into four groups: group I (control), group II (MFH), group III (IL-2), and group IV (IL-2+MFH). Results: The tumor grew gradually in group II and group IV (both P<0.05) compared to the control group. Histological analysis showed that the tumor cells underwent apoptosis and necrosis. Immunohistochemistry results demonstrated that heat shock protein 70 (HSP70) and CD8-positive T cells were strongly expressed. Conclusion: The results have provided evidence that IL-2 treatment combined with MFH could improve the therapeutic effect on lung cancer-bearing mice.

Effects of Interleukin-2 Treatment on CD1d-Restricted Natural Killer T Cells

In Response: We thank our colleagues for their letter and discussion. Sandberg and Moll note that interleukin-2 (IL-2) combined with highly active antiretroviral therapy (HAART) administered over 1 year for human immunodeficiency virus infection results in increased iNKT cells ([1][1]) and suggest

Effects of Interleukin-2 Treatment on CD1d-Restricted Natural Killer T Cells

To the Editor: Interleukins (IL) are potent biomolecules used for immunotherapy in cancer and infectious diseases. The clinical benefit of cytokines is linked to their strong effects on immune cells, and these effects are important to study in patients undergoing treatment because the cellular

Immunotherapy of HIV-1 Infection

A number of lines of evidence suggest that immunotherapy with the cytokine interleukin-2 (IL-2) may boost the immune response to fight HIV infection. CD4 + T cells, the cells which orchestrate the immune response, are also the cells that become infected by the HIV virus. These cells use cytokines as signaling mechanisms for immune-response stimulation, growth and differentiation. Since CD4 + T cells are hampered due to HIV infection, normal signaling, and the resulting cascade, may not occur. Introduction of IL-2 into the system can restore or enhance these effects. We illustrate, through mathematical modeling, the effects of IL-2 treatment on an HIV-infected patient. With good comparison to existing clinical data, we can better understand what mechanisms of immune-viral dynamics are necessary to produce the typical disease dynamics.

Autologous bone marrow purging by in situ IL-2 activation of endogenous killer cells.

The major cause of treatment failure in hematologic malignancies is the development of resistance to chemotherapeutic agents and the presence of clonogenic tumor cells in remission bone marrow. In the present study, we tested the optimal conditions for activation by interleukin-2 (IL-2) of endogenous bone marrow effector cells to develop cytotoxicity against solid tumor and leukemia cells and the effects of IL-2 treatment on eradication of malignant cells from the marrow product while preserving hematopoiesis. Normal donor bone marrow was contaminated with 10% A549 lung cancer cells, MCF-7 breast cancer, or EM2 leukemia cells, and then combined with peripheral blood-derived lymphokine-activated killer (LAK) cells which had been incubated in the presence of IL-2, 6000 IU/ml, for 5 days. Eradication (A549 and MCF-7) or >90% reduction in tumor cell number (EM2) was achieved upon exposure of the marrow to LAK cells but not to control, non-IL-2-exposed PBMC. The non-cross-resistance of chemotherapy and cell-mediated cytotoxicity were tested by using chemoresistant target cells for LAK cytotoxicity assays. Ara-C-resistant K562 cells were sensitive to LAK cytotoxicity, similar to sensitive controls. Similar effects were seen in daunomycin-resistant HL60 leukemia cells and VP-16-resistant K562 cells. The daunomycin-resistant K562 cells were also sensitive to LAK cell killing similar to sensitive controls. Activation of bone marrow mononuclear cells (BMMC) with IL-2, 6000 IU/ml for 24 h, significantly enhanced cytotoxicity against the NK-resistant, LAK-sensitive Daudi cell line. This procedure did not result in significant loss of total BMMC or hematopoietic colony-forming units. We then studied the possibility that the effector cell activity of the IL-2-activated BMMC which is diminished after removal of the IL-2 at 24 h could be recovered upon re-exposure of the marrow to IL-2. We found that the optimum conditions for preserving cytotoxicity were prolonged continuous exposures to IL-2 but that re-exposure of the 24-h IL-2-activated BMMC to IL-2 after a 1- or 2-week IL-2 withdrawal was associated with full recovery of cytotoxicity. These experiments also demonstrated that the overall recovery of viable cells from the BMMC was over 100%, possibly due to a proliferative effect of the IL-2 exposure on BMMC. These results demonstrate that the use of IL-2-activated marrow in patients with acute leukemia in remission undergoing autologous bone marrow transplantation (aBMT) may overcome the obstacles of clonogenic, drug-resistant minimal residual disease. The effector cell activity and hematopoietic capacity of the activated bone marrow product can also be maintained even if optimal clinical care requires an interruption in the in vivo exposure to IL-2. This therapeutic approach is currently being tested in acute leukemia patients undergoing IL-2-activated aBMT followed by prolonged IL-2 treatment before and after hematologic reconstitution.

Interleukin-2 in neuroblastoma: clinical perspectives based on biological studies.

Stage IV neuroblastoma (NB) is a disease with a poor prognosis. Chemotherapeutical intensification and hematological rescue with autologous bone marrow transplantation (ABMT) achieve some complete remissions (CR), but most patients relapse during the first year. Immunotherapy could be an alternative in this situation of high risk of relapse due to residual disease and ABMT-related immunodepression. Ten stage IV NB patients in CR or very good partial remission have been treated with recurrent 5-day cycles of high doses of Interleukin-2 (IL2) after ABMT throughout one year (usually 5-6 cycles). Natural killer (NK) and lymphokine-activated killer (LAK) cytotoxic activities, as well as phenotype and number of circulating NK cells were determined, before and after each course of IL2 treatment. The effects promoted by IL2 varied during treatment: early cycles of IL2 induced a great extent of cell expansion, mainly on CD3-/CD16-/CD56+bright and CD8+dim cell phenotypes; conversely, late courses of IL2 promoted higher NK cytotoxic activity but a lesser increase on circulating NK cells. The induction of LAK activity did not significantly differ from early and late IL2 treatments. Clinical results are still inconclusive due to the small number of patients. The median follow-up of patients treated with IL2 is 24 months and the disease free survival (DFS) probability is 0.80 +/- 0.12 vs 0.16 +/- 0.15 from a historical control with identical treatment, but in the absence of IL2 treatment (p < 0.005). IL2 treatment-related toxicity was mild and no interruption of the treatment was required. Extremely accurate hydric control was carried out to avoid, as much as possible, the consequences of vascular leak syndrome, one of the most important toxic effects of IL2 treatment. The results presented here suggest an evolution of NK activity during IL2 treatment after ABMT, which should be taken into account for the designing of new immunotherapeutical protocols and opens a promising perspective in treatment of stage IV neuroblastoma.

Effects of IL-2 treatment on different compartments of the irradiated rat lung analysed by bronchoalveolar lavage and lung tissue morphology

In recent years, interleukin-2 (IL-2) has been used as an immunomodulatory agent in the treatment of various malignant tumours. However, this treatment has been limited by serious side-effects, including toxic reactions in the lung. The effects of IL-2 treatment on inflammatory cell populations in the normal and irradiated rat lung were investigated in this study. IL-2 was continuously administered as a subcutaneous infusion over a 6 week study period. Irradiation was given in a single dose (25 Gy) the day after starting IL-2 treatment. Evaluation with bronchoalveolar lavage fluid (BALF) analysis and lung tissue morphology was made 6 weeks after irradiation. In nonirradiated rats, IL-2 treatment induced significant increases in the total number of inflammatory cells in the perivascular, interstitial and peribronchial tissues as well as in the alveolar space. These increases were not reflected in BALF; on the contrary, a significant decrease of the total numbers of inflammatory cells was found in BALF. Irradiation alone caused a more pronounced inflammatory response was significant increases of all inflammatory cells in all lung compartments, which was also reflected in BALF. Concomitant treatment with IL-2 and irradiation induced an enhanced accumulation of inflammatory cells in the perivascular and peribronchial tissues compared with irradiation alone. Thus, both irradiation and IL-2 treatment induce inflammatory reactions in the lung, but there were signs of synergistic effects seen in this study. Furthermore, the results also emphasize the difficulties in making sophisticated conclusions from BALF analyses alone.

Electron microscopic observations on the accumulation of large granular lymphocytes (pit cells) and kupffer cells in the liver of rats treated with continuous infusion of interleukin-2

Treatment schedules were investigated for in vivo induction of lymphokine-activated killer cells in the rat liver. Treatment of rats with continuous systemic or regional infusion of recombinant human interleukin-2 with a dose of 4 to 8 x 10(4) U/day during 7 days, resulted in an increase in number of large granular lymphocytes or pit cells in the liver up to 43 times normal. Kupffer cells, nongranular lymphocytes, monocytes and neutrophils also increased in number, but with a maximal fivefold increase this was much less pronounced than for large granular lymphocytes. Kupffer cells showed morphological signs of activation and were frequently seen in mitosis. Frequent mitoses were also observed for large granular lymphocytes, but not for other leukocytes. This indicates that the effect of interleukin-2 treatment on hepatic (sinusoidal) cells was primarily directed to large granular lymphocytes and Kupffer cells. The large granular lymphocyte accumulation occurred mainly intrasinusoidally, but they were also frequently observed in the space of Disse where they are not found in control rats. This may be explained partly by the observed damage or gaps in the endothelial lining. The intrasinusoidal large granular lymphocytes adhered to the endothelium and to Kupffer cells. Higher responses, for all cell types, were found when interleukin-2 was administered regionally, that is, through the hepatic artery rather than through the systemic route (jugular vein), although the differences were not statistically significant. Doses below 4 x 10(4) U/day did not result in significant increases of large granular lymphocytes in the liver.