Correlation between IL-12 and IL-2 blood levels in the metastatic neoplastic disease: a possible inhibitory feedback system regulating their secretion

Despite the great importance of IL-2 and IL-12 in activating the anticancer immune response in humans, cancer-related physiopathology of their secretion needs to be better investigated. IL-2 blood levels have been proven to decrease in the advanced neoplastic disease, whereas preliminary data would suggest an enhanced secretion of IL-12 in metastatic cancer patients. This study was performed to analyze IL-2 levels in relation to those of IL-12 in metastatic solid neoplasms. The study included 40 untreated metastatic cancer patients. Serum levels of both IL-2 and IL-12 were measured by ELISA. Abnormally low blood levels of IL-2 and elevated values of IL-12 were observed in 16/40 and in 18/40 patients, respectively. Moreover, patients with IL-2 deficiency showed significantly higher mean levels of IL-12 than patients with normal values of IL-2. This preliminary result, by showing an increased secretion of IL-12 in advanced cancer patients with IL-2 endogenous deficiency, would suggest the existance of a possible feedback mechanism operating between macrophage release of IL-12 and T lymphocyte secretion of IL-2.     

Study on the relation between HPV and tumors of the throat and larynx

Several experiments have suggested that the pineal hormone melatonin (MLT) may regulate cancer growth by exerting both oncostatic and immunomodulating effects. In particular, MLT would stimulate the anticancer immunity induced by interleukin-2 (IL-2). Recent studies seem to suggest that the activation of the inflammatory response may counteract the anticancer efficacy of IL-2 immunotherapy because of the immunosuppressive action of inflammatory-related cytokines, mainly IL-6. At present, it is still unknown whether MLT may influence host immune antitumor defences by modulating the inflammatory response. To analyze this hypothesis, we have evaluated the effects of a chronic administration of MLT on some of the commonly used markers of inflammation, including erythrosedimentation rate (ESR), IL-6, neopterin and SIL-2R, in patients with evidence of activation of the inflammatory response due to advanced solid neoplasms or auto-immune diseases. The study included 14 patients (solid tumors: 9; autoimmune diseases: 5). MLT was given orally at 20 mg/day during the dark phase of the day for 7 consecutive days. Mean serum levels of IL-6, neopterin and SIL-2R significantly decreased in both groups of patients. ESR values also decreased on therapy, without, however, significant differences. This preliminary study shows that the pineal hormone MLT may inhibit the acute inflammatory reaction. Therefore, because of the immunosuppressive section of inflammation-related cytokines, this study could suggest that MLT may contribute to the generation of the immune reaction against cancer at least in part by removing the immunosuppression related to the activation of the inflammatory response.     

Prognostic value of serum IL-10 and soluble IL-2 receptor levels in aggressive non-Hodgkin's lymphoma

We investigated the prognostic significance of interleukin-10 (IL-10) and soluble interleukin-2 receptor (sIL-2r) levels in the pretreatment serum of 105 individuals with newly-diagnosed aggressive non-Hodgkin's lymphoma (NHL). Commercially available enzyme-linked immunoassay kits were used for cytokine and receptor measurements. Detectable levels of IL-10 were found in 42 (40%) patients at diagnosis, with no correlation with clinico-haematological parameters, but in no control samples (P < 0.001). Pretreatment concentrations of sIL-2r were markedly increased in individuals with NHL when compared to controls (2614 +/- 893 U/ml v 219 +/- 65 U/ml, P < 0.001), patients with stage III/IV presenting higher values than those with stage II disease (3885 +/- 1196 U/ml v 1732 +/- 646 U/ml, P < 0.001). No single parameter was associated with the achievement of complete remission, but the combination of elevated IL-10 and of sIL-2r greater than 3000 U/ml selected a subset of patients with a high probability of failing induction therapy (P < 0.001). Life-table analysis also indicated that patients with these characteristics have a significantly shorter event-free survival. In a multivariate analysis the combination of IL-10 with sIL-2r was found to have greater predictive strength than the combination of IL-10 with beta 2-microglobulin. We conclude that IL-10 and sIL-2r measurements can be expected to improve existing methods of risk assignment in aggressive NHL.     

Serum interleukin-6 in relation to acute-phase reactants and survival in patients with renal cell carcinoma

Patients with malignancies often present with signs of inflammatory reactions such as elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Since interleukin-6 (IL-6) is a possible regulator of these reactions and has been proposed as a predictor of prognosis, the aim of the study was to analyse its clinical significance in patients with renal cell carcinoma. Serum samples were collected from 196 patients before any treatment. IL-6 was analysed by an enzyme-linked immunoassay and compared with tumour grade, stage, acute-phase reactants and survival. Patients with renal cell carcinoma had significantly higher IL-6 levels (mean 28.1 +/- 63.4 ng/l; median 8.3 ng/l) compared with controls (mean 1.7 +/- 2.6 ng/l; median 0.5 ng/l; P < 0.001). Serum IL-6 levels in patients with distant metastases were significantly higher than for patients with tumours confined to the kidney (P = 0.02). This difference was more pronounced when serum IL-6 levels in patients with poorly differentiated tumours were compared with well-differentiated tumours (P < 0.001). A significant correlation between the acute-phase reactants CRP, ESR and IL-6 levels was found. Survival time was significantly shorter (P = 0.001) for patients with IL-6 levels above the median serum level compared with patients with lower levels. Similar significant prognostic results were obtained in the group of patients with metastatic disease, but not in group of patients with stage I-III. Serum levels of IL-6 correlated to tumour stage, grade and acute-phase reactants. Increased levels were related to the presence of metastases and adverse survival. Serum IL-6 proved univariate prognostic information but this prognostic significance was lost using a multivariate analysis.     

IL-6 and IL-8 levels in plasma during hematopoietic progenitor transplantation

BACKGROUND AND OBJECTIVE: The relationship between cytokine concentrations and transplant-related complications has been studied in bone marrow transplant patients. The changes in TNF-alpha, IL-1 and IL-6 concentrations after transplantation are well documented in the literature but this is not the case for IL-8. The purpose of the present study was to investigate prospectively the plasma concentration of these cytokines and their relationship to transplant-related complications. DESIGN AND METHODS: Pro-inflammatory cytokine (TNF-alpha, IL-1, IL-6 and IL-8) levels in plasma were determined in a group of 53 patients undergoing hematopoietic progenitor transplantation. Plasma samples were collected weekly from day -7 to day +35 and stored at -70 degrees C until assayed by ELISA. The major transplant-related toxicities registered were: veno-occlusive disease (VOD), acute graft-versus-host disease (GVHD), infectious episodes, renal failure and mucositis. RESULTS: In spite of the great variability of plasma cytokine profiles between the different patients, we came to various conclusions. Patients' TNF-alpha and IL-1 concentrations correlated well over time. IL-6 and IL-8 profiles were similar and correlated well with febrile episodes. In some cases, an increase in IL-6 preceded hematologic recovery. In our study, increased levels of TNF-alpha, IL-6 and especially IL-8 correlated with hepatic or renal dysfunction as evaluated by increased bilirubin and creatinine in plasma, while pulmonary complications correlated only with increased IL-6 levels. Allogeneic transplant patients had a tendency to have higher TNF-alpha concentrations than autologous transplant patients, probably because an allogeneic transplant is associated with more transplant-related toxicity. Basal disease usually had no effect on cytokine profiles. INTERPRETATION AND CONCLUSIONS: IL-6 and IL-8 were the only cytokines studied whose increase correlated with febrile episodes. High IL-8 values may be a useful predictor of renal dysfunction and pulmonary disease and seems to trigger off high IL-6 levels. Plasma TNF-alpha and IL-1 concentrations during the posttransplant period have not been shown to be predictive of the development of transplant-related complications, and none of the profiles was recognized to be specific for a particular complication in this study.     

In vivo stimulation of IL-12 secretion by subcutaneous low-dose IL-2 in metastatic cancer patients

Despite the well-demonstrated involvement of both interleukin 2 (IL-2) and interleukin 12 (IL-12) in the activation of host anti-cancer response, the knowledge of IL-2-IL-12 interactions has still to be better investigated. This study was performed to evaluate the effects of subcutaneous (s.c.) low-dose IL-2 on IL-12 secretion in metastatic cancer patients. The study included 19 evaluable metastatic renal cell cancer patients, who received s.c. low-dose IL-2 (6 MIU day(-1) for 6 days per week for 4 weeks) as a first-line immunotherapy of their metastatic disease. Serum levels of IL-12 were measured using an enzyme immunoassay on venous blood samples collected before the immunotherapy and at 1-week intervals. The clinical response consisted of partial response (PR) in four and stable disease (SD) in eight patients, whereas the other seven patients progressed. Mean serum levels of IL-12 observed in the overall patients significantly increased in response to IL-2 injection. Moreover, by evaluating IL-12 variations in relation to the clinical response, a marked significant increase in IL-12 mean values occurred in patients with response or SD, whereas the progressing patients showed a significant decline in IL-12 levels during IL-2 administration. Finally, IL-12 mean pretreatment values observed in patients who progressed were significantly higher than those seen in non-progressing patients. This study shows that low-dose IL-2 immunotherapy of cancer may stimulate the in vivo release of IL-12, and it would suggest that IL-2-induced IL-12 enhancement is associated with a favourable prognosis.     

The effects of IL-6 on cell adhesion and e-cadherin expression in breast cancer

Interleukin 6 (IL-6) is a pleiotropic inflammatory cytokine and its role in cancer is not yet clear. The effects of IL-6 on four breast cancer cell lines and normal mammary epithelium, cultured from milk were tested. Four different patterns of response to IL-6 were found depending on the differentiation status of the cells. In normal mammary epithelial cultures, the effects of IL-6 were mainly growth inhibitory, whereas in MCF-7, IL-6 had growth inhibitory and anti-adhesive effects. In T-47D and ZR-75-1 the anti-adhesive effects were prominent although the growth inhibitory effects were not. These anti-adhesive effects were associated with epithelioid to fibroblastoid morphological changes and a local decrease in E-cadherin expression. In the highly invasive cell line MDA-MB-231, which does not express E-cadherin, no effects of IL-6 were seen. IL-6 levels in the serum of 60 breast cancer patients were found to be increased in 27% (16/60) compared to 2% (1/50) in a control group. Furthermore, it was found that altered E-cadherin expression was seen in 69% of the primary tumours, although no significant association was found between raised serum IL-6 levels and altered E-cadherin expression. Finally IL-6 serum levels did not effect the survival of breast cancer patients. The authors therefore implicate IL-6 as a possible factor important in breast cancer progression and metastasis formation, although the clinical significance of this cytokine in breast cancer patients could not be established.     

Interleukin-10 in non-Hodgkin's lymphoma

Interleukin-10 (IL-10) is a pleiotropic cytokine produced by type 2 helper cells (Th2), as well as by monocytes and macrophages, and normal and neoplastic B lymphocytes. It is highly homologous to an open reading frame of Epstein-Barr virus (EBV) called BCRF1, and EBV infection of B-cells up-regulates IL-10. IL-10 production has strong immunosuppressive effects via inhibition of Th1 type cytokines, including interferon gamma and interleukin-2. On B-cells, IL-10 has a potent stimulating effect, inducing proliferation and differentiation. Interestingly, in cell lines derived from B-cell lymphomas, IL-10 production has been found to be up-regulated, and it serves as an autocrine growth factor. In patients with non-Hodgkin's lymphoma (NHL), serum IL-10 levels are significantly increased when compared to normal individuals and NHL patients in remission. The prognostic significance of these increased levels vary according to the assay used. Both human IL-10 and viral IL-10 are increased, and when specific assays for human IL-10 are used, there seems to be no prognostic significance, whereas when the assay cross-reacts with viral IL-10, high levels correlate with poor prognosis. These results suggest that viral IL-10 might have some pathogenic role in NHL.     

Ascitic interleukin-12 is an independent prognostic factor in ovarian cancer

PURPOSE: The clinical impact of endogenous cytokines supplied with deterministic properties in the generation of either T helper (Th)1 -type or Th2-type immune response was investigated in patients with ovarian cancer. Whereas interleukin (IL)- 12 initiates the differentiation of naive Th0 cells toward Th1 phenotype, IL-4 and IL-10 mediate the development of Th2-type immunity. PATIENTS AND METHODS: Cytokines were determined before treatment by means of enzyme-linked immunosorbent assay (ELISA) in ascites fluid and serum of 76 patients with ovarian cancer. Cytokine levels were compared with each other and with standard clinicopathologic parameters. A stepwise logistic regression was calculated to rule out interdependence in the associations of the various variables. Survival analyses were performed with the Kaplan-Meier method and differences in survival were examined according to Mantel and Breslow. Cox proportional hazards analysis was used to identify independent prognostic factors. RESULTS: Whereas IL-10 and IL-12 were detectable in all ascites-fluid samples, IL-4 was measurable in only 43% of the specimens. With the exception of neopterin, macrophage colony-stimulating factor (M-CSF), and IL-4, determined cytokine levels were significantly elevated in ascites fluid compared with serum (P < .01). In univariate analyses, high ascitic-fluid concentrations of either neopterin, tumor necrosis factor-alpha (TNF-alpha), or IL-12 were associated with poor disease-free (P < .005) and overall (P < .01) survival. Multivariate Cox regression analysis showed ascitic-fluid IL-12 levels to be the only immunologic variable that retained independent prognostic significance (P < .03 for disease-free and P < .01 for overall survival), together with residual disease, Fédération Internationale de Gynécologie et d'Obstétrique (FIGO)-stage, and patient age. CONCLUSION: In ovarian cancer, high ascitic-fluid IL-12 levels, which may indicate a local Th1-generated immune response, are associated with disease progression.     

Soluble IL-6R in plasma cell dyscrasias

The understanding of the biology of multiple myeloma has advanced significantly in the past few years. The identification of the pivotal role of Interleukin-6 (IL-6), the soluble IL-6 receptor (sIL-6R), and how the ligand receptor complex interacts with the signal transducer gp130 has provided new biological insights into plasma cell disorders. Some studies have suggested that sIL-6R levels may have prognostic significance in MM, however this is not a consistent finding. Here the biology and function of IL-6 and sIL-6R are reviewed and the clinical significance of sIL-6R discussed.     

Neuroleptic treatment increases soluble IL-2 receptors and decreases soluble IL-6 receptors in schizophrenia

The cytokines interleukin-2 (IL-2) and interleukin-6 (IL-6) increase during immune activation, they are released from activated astrocytes and microglial cells in the central nervous system (CNS), and they are able to enhance the catecholaminergic neurotransmission. This study focused on the soluble receptors of IL-2 and IL-6 (sIL-2R, sIL-6R) as a part of the regulation system of IL-2 and IL-6. We studied serum levels of sIL-2R in 30 schizophrenic patients not under neuroleptic medication during an acute exacerbation of the disease and reexamined these patients under neuroleptic treatment after clinical improvement. The sIL-6R levels of 39 schizophrenic patients were estimated under the same conditions. The results were compared with the levels of sIL-2R and sIL-6R in 42 healthy controls. No difference was found between the schizophrenic patients before neuroleptic treatment and the healthy controls. During neuroleptic treatment, however, there was a significant increase of sIL-2R levels and a significant decrease of the sIL-6R levels between the pre- and post-conditions. In comparison with healthy controls, the treatment group also showed increased sIL-2R levels and decreased sIL-6R levels. These results suggest that treatment with neuroleptics is associated with increased sIL-2R and decreased sIL-6R. Since sIL-2R bind and inactivate IL-2, whereas sIL-6R form an active complex with IL-6, the increase of sIL-2R and the decrease of sIL-6R together may reflect a functional down regulation of these activating cytokines. This suggests that neuroleptic therapy has a differentiated immunomodulatory effect.     

Induction of interleukin-6 (IL-6) autoantibodies through vaccination with an engineered IL-6 receptor antagonist

Neutralization of cytokine activity by monoclonal antibodies or receptor antagonists is beneficial in the treatment of immune and neoplastic diseases, but the necessity for continuous parenteral delivery of these anticytokine agents poses considerable practical limitations. A viable alternative is to induce a neutralizing antibody response. Using transgenic mice with high circulating levels of human interleukin-6 (hIL-6), we show that injection of the hIL-6 receptor antagonist Sant1 (an IL-6 variant with seven amino-acid substitutions) induces a strong anti-hIL-6 antibody response. The elicited antibodies bind circulating hIL-6 with very high affinity, totally masking it, and neutralize hIL-6 bioactivity both in vitro and in vivo.     

Making the most of aid

The synovial fluid (SF) of rheumatoid arthritis (RA) patients contains a mixture of inflammatory mediators. In order to determine whether certain cytokine patterns locally in the joint are specifically related to the chronic inflammation in RA, the concentrations of interleukin (IL)-1alpha, IL-1beta, IL-6, IL-10, transforming growth factor-beta (TGF-beta), tumour necrosis factor-alpha (TNF-alpha) and IgG2b-inducing factor (IgG2bIF) were measured in SF from 22 patients with RA and 22 patients with other types of arthritic lesions. High levels of IL-10, latent and active TGF-beta and the presence of IgG2bIF are significantly correlated with RA when corrected for age. As these factors have the capacity to promote antibody production, they might contribute to the maintenance of local antibody production in RA synovial tissues. All RA-SF samples contained detectable levels of IL-10 and all except one contained IL-1beta, while concentrations in several non-RA-SF samples were below detection limits. IL-6 and TGF-beta were present in all SF samples from both RA and non-RA patients. The presence of IgG2bIF was strongly correlated with high levels of IL-10 and IL-1beta in SF. However, no distinct cytokine profile specific for the chronic inflammation characteristic of RA was found.     

Interleukin-6-type cytokines in vivo: regulated bioavailability

Investigators have traditionally thought of the class of inflammation- and injury-associated cytokines in large part as "free" entities in the peripheral circulation. In the case of interleukin-6 (IL-6), the cytokine can be found in blood in complexes of molecular mass 400-500, 150-200, and 25-35 kDa in association with binding proteins that can include soluble IL-6 receptor (sIL-6R), anti-IL-6, and anti-sIL-6R IgG, and others. Sustained high levels of different particular IL-6 complexes are observed in the human circulation in cancer patients subjected to particular active anticancer immunotherapy regimens. In the "chaperoned" state, circulating IL-6 complexes display differential immunoreactivity in different ELISAs and possess differential biological activity as assayed ex vivo. The discovery of "chaperoned" circulating IL-6 in humans points to a new level of modulation of cytokine function, that of regulated bioavailability of IL-6 in vivo.     

Differences in serum cytokine levels in acute and chronic autoimmune thrombocytopenic purpura: relationship to platelet phenotype and antiplatelet T-cell reactivity

Patients with both acute and chronic autoimmune thrombocytopenic purpura (AITP) have in vitro lymphocyte defects in the form of platelet-stimulated proliferation and cytokine secretion. A blinded study was performed to determine if these defects are related to serum cytokine levels and/or platelet antigen expression. Compared with controls, 53% of children with chronic AITP, but only 9% of those with acute AITP, had increased serum interleukin-2 (IL-2), interferon-gamma, and/or IL-10; however, none of the patients had detectible serum levels of IL-4 or IL-6, cytokine patterns suggesting and early CD4+ Th0 and Th1 cell activation. In children with chronic AITP, the levels of serum IL-2 correlated with in vitro platelet-stimulated IL-2 production. Few (17%) patients with AITP showed platelet activation, as measured by CD62 expression, or abnormal expression levels of platelet membrane glycoprotein (GP) IIbIIIa, but abnormal GPIb levels were observed in one-third of children with AITP. In contrast to normal controls and patients with nonimmune thrombocytopenia, a significant number of children with acute (80%), chronic (71%), or chronic-complex (55%) AITP and GPIb+ peripheral blood cells expressing HLA-DR. HLA-DR was variably coexpressed on distinct smaller and larger-sized GPIb+ cell populations with CD41, CD45, CD14, CD80, and/or glycophorin molecules. GPIb+ cells isolated from spleens of patients with chronic AITP had high expression (49% +/- 30%) of HLA-DR and splenic T cells had a high level of in vitro platelet-stimulated IL-2 secretion compared with controls. Platelet HLA-DR expression correlated inversely with platelet count, but not with therapy, serum cytokines, or in vitro lymphocyte antiplatelet reactivity. The results indicate that platelet HLA-DR expression is a common occurrence in patients with immune thrombocytopenia, whereas a large subpopulation of children with chronic AITP can be identified by increased serum cytokine levels and in vitro platelet-stimulated IL-2 secretion by lymphocytes, suggesting that differences exist in the immune pathogenesis of acute and chronic AITP, particularly at the level of platelet reactive T cells.     

Heat-killed Listeria monocytogenes as an adjuvant converts established murine Th2-dominated immune responses into Th1-dominated responses

We investigated the capacity of heat-killed Listeria monocytogenes (HKL), a potent stimulator of the innate immune system, as a vaccine adjuvant to modify both primary and secondary Ag-specific immune responses. Mice immunized with the Ag keyhole limpet hemocyanin (KLH) mixed with HKL generated a KLH-specific primary response characterized by production of Th1 cytokines and large quantities of KLH-specific IgG2a Ab. Moreover, administration of KLH with HKL as an adjuvant reversed established immune responses dominated by the production of Th2 cytokines and high levels of KLH-specific IgE and induced a Th1-type response with high levels of IFN-gamma and IgG2a and low levels of IgE and IL-4. Neutralization of IL-12 activity at the time of HKL administration blocked the enhancement of IFN-gamma and reduction of IL-4 production, indicating that IL-12, induced by HKL, was responsible for the adjuvant effects on cytokine production. These results suggest that HKL as an adjuvant during immunization can successfully bias the development of Ag-specific cytokine synthesis toward Th1 cytokine production even in the setting of an ongoing Th2-dominated response. Thus, HKL may be clinically effective in vaccine therapies for diseases such as allergy and asthma, which require the conversion of Th2-dominated immune responses into Th1-dominated responses.     

Production of TNFalpha and IL-6 by activated whole blood from HIV-1 infected patients detected by a one-stage procedure: relationship with the phenotype of HIV-1 isolates

Diluted whole blood (WB) culturing may be the most appropriate milieu in which to study cytokine production in vitro. We tested TNFalpha and IL-6 production using small volumes of WB (25 microl) from HIV-1 positive patients with a one-step procedure that combines WB stimulation with LPS, PHA and cytokine measurement. We studied 49 patients without secondary infection or at distance of secondary infection staged according to the 1993 classification of the CDC and 12 healthy seronegative subjects. Heparinized blood from 5 control subjects had been collected sequentially during a period of 5 months. The individual variations of TNFalpha and IL-6 production were limited for all these individuals. In 1 out of 20 CDC group A patients, 6 out of 17 CDC group B patients and 3 out of 12 CDC group C patients, we obtained higher values of TNFalpha than the mean + 2 S.D. of the control group. In 3 out of 20 CDC group A patients, 1 out of 17 CDC group B patients without AIDS and 5 out of 12 CDC group C patients, the TNFalpha values were lower than the mean - 2 S.D. of the control group. Low IL-6 values were obtained in 1 out of 20 CDC group A patients and 1 out of 17 CDC group B patients and 3 out of 12 CDC group C patients. There was no correlation between TNFalpha production in vitro and plasma level of TNFalpha. We found no correlation between the levels of cytokines and monocyte count or between the levels of cytokines and CD4 T-cell count in peripheral blood. Our data point out a disarray in TNFalpha and IL-6 production by WB from HIV-1 infected patients. The relationship between the disarray of cytokine production and cytopathogenicity of HIV-1 isolates in the P4 cell line was investigated in this study. We found a correlation between the high level of TNFalpha produced by WB and the phenotype of HIV-1 isolates isolated from patients. The one-stage procedure used in this work is of potential value to investigate the activation status of cells for monitoring HIV-1 positive individuals and predicting HIV-1 phenotype.     

Changes in interleukin-1 beta and soluble interleukin-2 receptor levels in CSF and serum of schizophrenic patients

Some evidence points towards a possible autoimmune role in the aetiology of schizophrenia. Experimental findings provide contradictory results regarding abnormalities in cytokine production in this disorder. In the present study we tested the production of cytokines in CSF and serum in 16 schizophrenic patients and 10 healthy controls (tumor necrosis factor alpha - TNF alpha; interleukins IL-1 beta, IL-2, IL-6, soluble IL-2 receptor). Cytokine levels were evaluated by radioactively-labeled antibodies (IL-1 beta, IL-2, IL-6), by enzyme-linked immunoassay (TNF) and by a sandwich enzyme immunoassay (soluble IL-2 receptor). No significant differences were found in either CSF fluid or serum levels of TNF and IL-2 or IL-6. Interleukin-1 beta was significantly decreased in patients' CSF and serum as compared to controls. Soluble interleukin-2 receptor levels were decreased in CSF of patients, but highly increased in their serum in comparison with controls. Changes in various cytokine levels in CSF fluid and serum of schizophrenic patients probably reflect interrelated process of growth, degeneration or neuroimmunological abnormalities, which may all play a role in the pathophysiology of schizophrenia. The present study supports evidence for change in immune activation, probably of peripheral origin, in schizophrenic patients.