Production of and response to interleukin-2 in peripheral blood lymphocytes of cancer patients

Wanebo, Harold J.; Pace, Ronald; Hargett, Steve; Katz, Daniel; Sando, Julianne J.

doi:10.1002/1097-0142(19860201)57:3<656::aid-cncr2820570343>3.0.co;2-b

Cited by 63 publications

(13 citation statements)

References 16 publications

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“…Measurements of cytokine production in cell cultures have also been used to determine the immunological activity of breast cancer patients, but here the results were controversial. In one study, an impaired production of TNF was found (Zielinski et al, 1990) and a defective expression and release of the IL-2 receptors (Hakim, 1988), while in another study the production of IL-2 was not diminished (Wanebo et al, 1986). In lymphocyte cultures of patients with endometrial carcinomas a reduced IL-2 production has been described (Yron et al, 1986).…”

Section: Discussionmentioning

confidence: 97%

Impaired cytokine production in whole blood cell cultures of patients with gynaecological carcinomas in different clinical stages

Elsässer‐Beile

Kleist²,

Sauther³

et al. 1993

Br J Cancer

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Summary The production of the cytokines IFN-gamma, IL-1-alpha, IL-2 and TNF-alpha was investigated in mitogen-stimulated, whole blood cell culturs from 239 untreated patients with primary gynaecological carcinomas (breast, cervix, ovary, endometrium), and 191 healthy female controls.The cytokines were measured in the 4-day post-inductional supernatants by a sensitive enzymoimmunological assay. In the blood cell cultures of all four groups of cancer patients, significantly lower values of IFN-gamma (P < 0.001), IL-2 (P < 0.01) and IL-1 alpha (P < 0.01) were found as compared to the controls, although lymphocyte and monocyte counts were almost identical.Grouping the tumour patients into different clinical stages we could show in the four groups of carcinomas a gradual depression of the cytokine production according to growing tumour burden.The host's response to malignant tumours is usually considered to be primarily a function of the cellular immune system and various tests have been established to measure the integrity of this system in cancer patients, such as hypersensitivity skin tests (Bolton et al., 1975;Evans et al., 1977), or determination of mitogen-induced lymphocyte proliferation in vitro (Dean et al., 1977;Zembala et al., 1977;Fritze & Dystant, 1984).As the cell-mediated immune response is controlled by a series of soluble cytokines, in recent years the measurement of these substances has also been used to determine the cellular immunological potency of tumour patients (Rey et al., 1983;Santos et al., 1985;Elsasser-Beile et al., 1991a Blood samples Ten ml of heparinised blood was taken from each patient and control person between 9 and 11 a.m. The samples, kept at room temperature, were used within 2 h. A 0.5 ml aliquot was removed for total and differential leukocyte counts.Whole blood cell culture (WBCC) Cultures were performed as previously described with a system for which optimal conditions and kinetics of cytokine production were established (Elsasser-Beile et al., 1991b).In brief, heparinised venous blood was diluted 1/10 with RPMI 1640 (Seromed, Berlin FRG), which was supplemented with 50 U ml-' Penicillin (Seromed) and 50 Sg ml-' Streptomycin (Seromed) and distributed in 0.5 ml aliquots in 12 mm polystyrol tubes. For stimulation, 10 ig ml-' phytohaemagglutinin (PHA Wellcome, Burgwedel, FRG) and 0.5-5 g.g ml-' Pokeweed mitogen (PWM, Sigma, Deisenhofen, FRG) were added.Incubation of the cell cultures was performed at 37°C in a humidified atmosphere of 5% CO2. After 4 days of culture without changes of medium 320 ftl of supernatant was removed from each tube to be assayed for cytokine levels.Determination of cytokines Enzyme-linked immunoassays (ELISA) were applied for qualitative and quantitative determinations of cytokines.These tests are based on the sandwich principle and are performed in one step. Since a correlation was found between assay performance of the naturally occurring cytokines and their recombinant counterparts, the latter were used as standards.Interferon-gamma-ELISA IFN-gamma ...

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Section: Discussionmentioning

confidence: 97%

Impaired cytokine production in whole blood cell cultures of patients with gynaecological carcinomas in different clinical stages

Elsässer‐Beile

Kleist²,

Sauther³

et al. 1993

Br J Cancer

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“…Studies on human cancer patients have revealed defects in both IL-1 production (38) and IL-2 production (39), in some patients. In some, lymphocyte responsiveness to IL-2 seemed to be impaired (39). Factors of the sort described here might well be responsible.…”

Section: Discussionmentioning

confidence: 99%

Festschrift Inhibition of cell‐mediated immunity by tumour cell products: Depression of interleukin‐2 production and responses to interleukin‐2 by mouse spleen cells

Nelson

Nelson²

1988

Immunol Cell Biol

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Summary Supernatants from cultures of mouse and human tumour cells inhibited the production of interleukin‐2 (IL‐2) by stimulated mouse spleen cells. The tumour cells tested, all of which were active, included a mouse and a human melanoma, three methylcholanthrene‐induced fibrosarcomas of mice, and human HeLa cells. Supernatants from normal mouse and human fibroblasts were inactive. Inhibition was dose‐dependent. Spleen cells from aged mice were more susceptible to inhibition than spleen cells from young mice. When tumour cell culture supernatants were fractionated on Sephacryl S‐300, two peaks of activity were found, with apparent molecular weights of approximately 50 and 18 kD. Supernatants from tumour cell and fibroblast cultures caused variable, but generally weak, inhibition of responses of lymphoblasts to IL‐2. It is suggested that inhibition of IL‐2 production may be an important mode of action of tumour cell products that inhibit cell‐mediated immunity.

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“…PGE2 is a short-lived lipid-based signaling molecule with potent localized paracrine and autocrine functions that is particularly important for tumor development. PGE2 has been shown to promote tumor angiogenesis (38,71), drug resistance (36), invasion and migration (35), immune suppression (24,72,73), and the inhibition of apoptosis (34). PGE2 is generated by tumors and tumor-associated immune cells from arachidonic acid, with the rate-limiting step being the enzymatic activity of cyclo-oxygenase 2 (COX-2).…”

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confidence: 99%

Oncolytic Herpes Simplex Virus 1 Encoding 15-Prostaglandin Dehydrogenase Mitigates Immune Suppression and Reduces Ectopic Primary and Metastatic Breast Cancer in Mice

Walker¹,

Sehgal

Kousoulas³

2011

J Virol

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Oncolytic human herpes simplex viruses (HSV) have been genetically engineered to limit neurovirulence and the establishment of latency and reactivation and to replicate exclusively in cells with deficient apoptotic mechanisms (i.e., cancer cells) (5, 6, 37). These genetic changes are fundamental to the safety and efficacy of oncolytic herpesviruses but often result in rapid clearance of the virus by the host immune response, thus limiting its therapeutic potential. It is precisely the antiviral immune response, however, that is thought to help overcome tumor-induced immune suppression, allowing for antitumor immunity to develop. In this regard, HSV-1 infections within tumors may function as in situ vaccines, providing the necessary inflammatory signals that engage innate and adaptive immune responses to tumor antigens. Thus, oncolytic HSV-1 may be effective both directly as a cancer killing agent and indirectly as an immunological enhancer, or in situ cancer vaccine (13,49). Previously, we reported that the novel fusogenic oncolytic herpesvirus OncSyn (OS) was effective at treating primary solid breast tumors in mice (25,26). Moreover, treatment of primary 4T1 tumors in syngeneic BALB/c mice with OS led to a substantial reduction in the formation of metastatic foci within multiple organs and in some cases eliminated lung metastasis, suggesting the development of effective antitumor immunity (43).The HSV-1 vhs gene product encoded by the UL41 open reading frame (ORF) has multiple functions that are known to suppress antiviral immune responses. (i) vhs is an RNase that degrades viral and cellular mRNAs, limiting host and viral antigen production (3,32,33,45,48,51,56,59,61,65,75). (ii) UL41 (vhs) with ICP47 is known to inhibit major histocompatibility complex I (MHC-I) antigen presentation (59), while vhs alone has also been implicated in the reduction of MHC-II expression (69). (iii) vhs has been reported to suppress production of cytokines and chemokines and inactivate dendritic cells (7,59). In agreement with these reports, deletion of the vhs gene prevented HSV-1-mediated inactivation of antigen presentation by dendritic cells (DC) (54) and improved the immunogenicity of a candidate replication-defective HSV-1 vaccine strain (16,55). Furthermore, deletion of the vhs gene causes substantial reduction in neurovirulence (48, 60, 64).

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Production of and response to interleukin-2 in peripheral blood lymphocytes of cancer patients

Cited by 63 publications

References 16 publications

Impaired cytokine production in whole blood cell cultures of patients with gynaecological carcinomas in different clinical stages

Impaired cytokine production in whole blood cell cultures of patients with gynaecological carcinomas in different clinical stages

Festschrift Inhibition of cell‐mediated immunity by tumour cell products: Depression of interleukin‐2 production and responses to interleukin‐2 by mouse spleen cells

Oncolytic Herpes Simplex Virus 1 Encoding 15-Prostaglandin Dehydrogenase Mitigates Immune Suppression and Reduces Ectopic Primary and Metastatic Breast Cancer in Mice

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