Immunosuppressive Substance Research Articles

Fibronectin is an immunosuppressive substance associated with epithelial ovarian cancer.

Although the ascites of patients with ovarian cancer has been reported to contain immunosuppressive factors, the identity and source of this activity has not been determined. Previously, the authors showed that conditioned media from two of four epithelial ovarian cancer cell lines inhibits proliferation of mitogen-stimulated human lymphocytes. The physical characteristics of the inhibitory substance are unlike those of peptide growth factors but closely resemble those of fibronectin. In the current study, it was found that the two ovarian cancer cell lines that produce the inhibitory substance have more fibronectin on the cell surface and secrete significantly more immunoreactive fibronectin into their culture media than the other two ovarian cancer cell lines. In addition, the immunosuppressive activity was bound to a gelatin-Sepharose affinity column, known to bind fibronectin. Finally, in ascites from 20 patients with advanced epithelial ovarian cancer, fibronectin levels correlated with the ability to inhibit proliferation of lectin-stimulated lymphocytes (P < 0.001). Fibronectin is produced by some ovarian cancer cell lines and acts to inhibit proliferation of mitogen-stimulated lymphocytes. Additional studies are needed to clarify the role of fibronectin in ovarian cancer.

Cyclosporin A inhibits histamine release from human peripheral basophils and human skin mast cells

Cyclosporin A (CSA) is a strong immunosuppressive substance which is widely used for prevention of transplant rejection. Moreover, this compound is clinically active in different cutaneous inflammatory reactions. In the present study the effects of CSA on mediator release from activated human basophils and isolated human skin mast cells, as important effector cells of such skin diseases, were investigated. CSA exterted a dose-dependent inhibition of the IgE-mediated histamine release from both cell populations. The maximum inhibition was 64.4±9.3% and 85.8±14.2% for basophils and skin mast cells, respectively. Non-immunological histamine release induced by calcium ionophore A23817 was also inhibited. The present data suggest, therefore, that the anti-allergic properties of CSA on basophils and skin mast cells may be partially responsible for the strong anti-inflammatory effects of CSAin vivo.

Chronic cyclosporine therapy impairs endothelium-dependent relaxation in the renal artery of the rat.

Cyclosporine is an immunosuppressive substance that causes structural and functional alterations in endothelial cells. To examine the effects of chronic cyclosporine therapy on endothelial function, Wistar Kyoto rats received daily s.c. injections of saline, cyclosporine solvent, or cyclosporine (15, 30, or 50 mg/kg) for up to 2 wk. Blood pressure remained unchanged in all groups. Segments of the renal artery were suspended in organ chambers filled with physiological salt solution, and isometric tension was recorded. In rats treated with 30 or 50 mg/kg/day of cyclosporine, endothelium-dependent relaxations to acetylcholine of the renal artery were significantly impaired when compared with vessels obtained from rats injected with saline or solvent. The reduced acetylcholine-induced relaxation of cyclosporine-treated vessels was improved by preincubation of the preparations with the cyclooxygenase inhibitor indomethacin. Endothelium-independent relaxations in response to sodium nitroprusside were unimpaired in renal artery rings after 1 wk of cyclosporine but were reduced after 2 wk of treatment with 30 mg/kg/day. Contractions of the renal artery in response to norepinephrine and serotonin were not altered by cyclosporine. Thus, (1) high-dose cyclosporine therapy impairs endothelium-dependent relaxations in the renal artery of the rat; (2) an endothelium-derived cyclooxygenase product reduces the effects of endothelium-derived relaxing factor in cyclosporine-treated rats; and (3) chronic cyclosporine treatment slightly impairs vascular smooth muscle relaxation, whereas vascular contractility remains unaltered.

頭頚部癌に対するクレスチンの臨床効果 奈良県頭頚部癌免疫療法研究会成績

To evaluate the effectiveness of Krestin® (PSK), we conducted a clinical trial of head and neck cancer patients from 1987 to 1991. A total of 44 patients were included in this trial. To control the primary lesion and the metastasis, they received various treatments, i. e. surgery, radiation, or a combination of these treatments with or without chemotherapy. After the completion of these treatments, the patients were divided into two groups. One group (22 patients) received 3g/day of PSK orally.The 1-year disease-free rate of the PSK group was higher (generalized Wilcoxon test p=0.052) than that of the control group. The 2-year survival rate of the PSK group was also higher than that of the control group. The 2-year survival rate of the 15 patients with recurrence, was significantly higher (G. W. p=0.014) in the PSK group than in the control group.We also measured the level of immunosuppressive substance (IS) in the serum of 28 patients. It is thought that the IS level reveals the patients' immunosuppressive condition. The changes of the IS level suggested that PSK helped in the recovery of immunosuppressive function. The administration of PSK appears to be useful in the management of patients with head and neck cancer.

Suppression of human lymphocyte proliferation and cytotoxic T lymphocyte generation by a soluble factor derived from K562 cells.

The human myeloid leukemia cell line, K562, secrets a lymphocyte growth-suppressive factor (LGSF). We report our investigation of the immunological and chemical features of this factor. LGSF showed no cytolytic effect on human peripheral blood mononuclear cells (PBMC). Nevertheless, LGSF adequately suppressed in vitro alloantigen- or mitogen (PHA, ConA, PWM)-stimulated human PBMC proliferation and alloantigen-induced cytotoxic T lymphocyte generation, in antigen-nonspecific and LGSF concentration-related manners. LGSF retained activity after filtration through a 0.22 microm filter membrane and storage at -80 degrees C for 6 months. Ultrafiltration experiments indicated that suppressive activity was retained in the higher molecular weight fraction (MW > 100,000) and that the activity was heat-labile at 56 degrees C for 30 min. These results strongly suggested that LGSF is a noncytotoxically immunosuppressive substance with a high molecular weight.

Evaluation of the serum level of immunosuppressive substance in oral cancer patients

The serum level of immunosuppressive substance (IS) was studied in 40 patients with primary oral cancer and in 79 patients without cancer. Its usefulness was evaluated as a parameter for monitoring therapy as well as recurrence of the tumors. Mean values for serum IS in patients with cancer and patients without were 687 ± 284 μg/mL and 464 ± 153 μg/mL, respectively. Normal healthy controls had a mean value of 431 ± 105 μg/mL, with the cutoff value set at 641 μg/mL (mean +2 SD). Patients without cancer who had a severe infectious disease showed conspicuously high serum IS levels, and these values were closely correlated with their C-reactive protein values. The positive rate of IS increased in all patients with oral cancer was 58%. The mean level of serum IS in cancer patients was significantly higher than that of the controls ( P < .01), and the level was found to be more elevated as the stage of the disease advanced (stage I to III, 48%; stage IV, 68%). Histologic analysis of the tumor cells in patients with squamous cell carcinoma (SCC) showed that the mean serum IS level of those who had poorly differentiated SCC was much higher (937 ± 181 μg/mL) than that of patients with well-differentiated SCC (616 ± 159 μg/mL). Patients who had recurrent or metastatic cancer, or those who died from the cancer exhibited marked elevation of the serum IS levels, whereas patients who remained free of cancer in the follow-up period showed significantly lower serum IS levels. The rise and fall of the serum IS level was closely correlated with the disease progression and/or remission. These data strongly suggest that serum IS is a useful parameter for monitoring the disease stage as well as the effect of therapy on patients with oral cancer.

口腔癌患者における血清中免疫抑制物質 (IS物質) の臨床的検討

口腔癌患者における血清中免疫抑制物質 (IS物質) の臨床的検討

The Increased Release of Prostaglandin E2 by Kupffer Cells from Burned Guinea Pigs

Prostaglandin E2 (PGE2) is a very important immunosuppressive substance that is synthesized and released by all macrophages including Kupffer cells (KCs). In this study the changes of PGE2 released by KCs were evaluated in a burned guinea pig model. Prostaglandin E2 was released by KCs from burned guinea pigs at a consistently and significantly high level when stimulated with endotoxin. On postburn day 8, KCs that were cocultured with hepatocytes released significantly less PGE2. There was also a significant decrease in antibody-dependent cell-mediated cytotoxicity on postburn day 1. Kupffer cells can mediate immune suppression in burn injury by a prolonged increased production of PGE2 that has immunosuppressive effects on other cells and by a decreased cytotoxic effect soon after burn injury.

Removal of immunosuppressive substance in cancer patients' serum.

Anemia-inducing substance (AIS) appears in plasma as cancer progresses. In this study, a non-coated charcoal column was used to remove AIS from the cachectic plasma obtained from patients with advanced cancer. AIS could be completely removed by 6 cycles of adsorption using this column. Similar data were obtained in an experiment using VX-2-transplanted rabbits. These observations raised the possibility that plasmapheresis with a non-coated charcoal column may be available as a new means of immunotherapy for advanced cancer.

Detection of Early Pregnancy Factor‐Like Activity in Human Amniotic Fluid

Early pregnancy factor (EPF), an immunosuppressive substance, appears in mammalian maternal serum at a very early stage after fertilization. To investigate the normal distribution of EPF in the human body, the rosette inhibition test has been used to detect EPF in human amniotic fluid. The mean value of rosette inhibition titer (RIT) was significantly higher (5.93 +/- 0.43 SE) in 52 amniotic fluid samples (16-30 weeks' gestation) than in 23 nonpregnant sera (3.54 +/- 0.11), indicating that something in amniotic fluid inhibits rosette formation. This inhibitory factor is recognized as EPF or EPF-like substance for its activity significantly correlated with that of EPF in serum from the same donor (r = 0.756: P less than 10(-6]. The immunological significance of the EPF-like substance in amniotic fluid may be important to the survival of semiallogeneic conceptus.

頭頸部悪性腫瘍患者におけるCEA,TA4,ISの動態

Between Feb.1987 and March 1989 the serum levels of tumor associated antigen (CEA, TA-4) and immunosuppressive substances (IS) were determined in 85 patients with head and neck epithelial malignancies. In the serum levels of CEA and TA-4, the positive ratios were low,23.2% and 22.5 respectively. They were high only stage IV prior to treatment. In the serum levels of immunosuppressive substance, the positive ratio was 32.4%, and the mean values were elevated reflecting clinical staging. Especially for the patients in stage IV, a 75.0% positive ratio was seen prior to treatment. After treatment, the serum levels of each marker were normal in cases with no evidence of disease, but in recurrent or uncontrolled cases, such serum levels were elevated.It seems that the serum levels of each m a rker is useful for monitoring the controlled or uncontrolled condition of malignancies.

Immunosuppressive substance in the sera of head and neck cancer patients : N Yamanaka, Y Harabuchi, et al. Cancer 1988; 62:1293–1298

Immunosuppressive substance in the sera of head and neck cancer patients : N Yamanaka, Y Harabuchi, et al. Cancer 1988; 62:1293–1298

Tumor growth-promoting effect of immunosuppressive substance in mice.

The effect of immunosuppressive (IS) substance obtained from cancerous ascitic fluid on tumor growth and host immunity in plasmacytoma X5563-bearing C3H/He mice is described. IS substance given in three injections, before and after tumor inoculation caused: (a) enhanced tumor growth, (b) marked reduction in survival times, (c) inhibition on Con-A response of spleen cells. Depressed natural killer (NK) activity was observed in normal and tumor-bearing mice treated with IS substance. The data presented here suggest that IS substance suppresses both humoral and cellular immunoresponsiveness and tumor cells evade immune surveillance or immunologically mediated removal.

Immunosuppressive Acidic Protein and Immunosuppressive Substance in Middle Ear Effusion (Report IV)

Immunosuppressive Acidic Protein and Immunosuppressive Substance in Middle Ear Effusion (Report IV)

Prevention of human helper T-cell clone activation by cyclosporin A also blocks secretion of granulocyte/macrophage colony stimulating activity

Cyclosporin A (CsA) blocks stimulation and growth of alloreactive T helper cell clones (Th-TCC), even in the presence of exogenous Interleukin-2 (IL-2). To examine whether this might reflect a generalised inhibition of cytokine production by these cells, their production of granulocyte/macrophage colony-stimulating factors (GM-CSF), thought not to be involved in the autocrine proliferation of the clones themselves, was investigated. Contrary to the prediction that only pathways relevant to T cell clonal expansion would be blocked by CsA, it was found that this immunosuppressive substance exerted a profound inhibitory activity on GM-CSF secretion, even in the presence of exogenous IL-2. Although a higher concentration of CsA was required to block GM-CSF secretion than to block proliferation, the former was not due to toxic effects on the cells, or permanently switching off the genes for GM-CSF, since upon further cultivation of the clones without CsA, alloantigen-specific responsiveness was restored. These results therefore show that clonal human T helper cell populations are sensitive to inhibition of GM-CSF secretion by CsA. Part of the immunosuppressive mechanism of action of CsA may therefore reside in this activity, since blockade of GM-CSF secretion by T helper cells would influence functional activities of antigen presenting cells.

Intrathecal synthesis of immunosuppressive acidic protein (IAP) in patients with multiple sclerosis and other inflammatory neurological diseases

Immunosuppressive acidic protein (IAP), an immunosuppressive substance produced mainly by macrophages, has previously been shown to increase in the serum of patients with inflammatory neurological diseases. In this study we assayed the IAP levels in cerebrospinal fluid (CSF) by a passive hemagglutination-inhibition test. CSF-IAP levels increased significantly in patients with multiple sclerosis (MS) during both the active and inactive stages and in patients with Guillain-Barré syndrome (GBS) or Miller Fisher syndrome (MFS) as compared with those of control patients, but not in patients with amyotrophic lateral sclerosis or spinocerebellar degeneration. During the active stage of MS, increased CSF-IAP levels together with the elevated IAP% (CSF-IAP/total CSF protein) and IAP index [(CSF-IAP/serum IAP)/(CSF albumin/serum albumin)] suggested the intrathecal synthesis of IAP. In contrast, in patients with GBS or MFS, increased CSF-IAP levels without elevation of IAP% could be attributed largely to increased total CSF protein levels. In patients with neuro-Behçet's disease, CSF-IAP levels and IAP% were elevated during the active stage, but remained normal levels during the inactive stage. Assaying CSF-IAP could provide useful information about inflammatory or immunopathological events within the central nervous system.

Correlation between serum immunosuppressive substance and clinico-pathological findings in patients with gastric carcinoma.

Serum levels of immunosuppressive substance (IS) were determined in 99 patients with gastric cancer and in 32 healthy individuals. The serum IS levels in the patients (769.6 +/- 314.8 micrograms/ml) were significantly higher than those in the healthy individuals (549.7 +/- 104.7 micrograms/ml). A multivariate analysis on the correlation between serum IS levels and clinicopathological findings in the patients disclosed that there was a close correlation between the serum IS levels and the depth of invasion, in particular, the prognostic serosal invasion, metastasis to the distal lymph nodes and peritoneal dissemination. There was, however, no correlation between the serum IS level and hepatic metastasis. Serum IS levels were higher in patients with well-differentiated adenocarcinoma than in those with poorly differentiated adenocarcinoma or signet ring cell carcinoma. A serum IS level higher than 1000 micrograms/ml indicates the possibility that the tumor is only palliatively resectable because of involvement of the distal lymph nodes or peritoneal dissemination.

Immunosuppressive Acidic Protein and Immunosuppressive Substance in Middle Ear Effusion (third report)

Immunosuppressive Acidic Protein and Immunosuppressive Substance in Middle Ear Effusion (third report)

Immunosuppressive activity of culture supernatant from human decidual cells

To assess the role of decidual cells in direct contact with paternal antigens in maintenance of pregnancy, immunosuppressive action of the culture suprenatant of decidual cells were investigated. Desidual cells were obtained from artificially aborted healthy pregnants on 8 to 10 weeks of gestational age. Dispersed cell suspensions were prepared by enzyme digestion method (collagenase 1mg/ml and DNase 0.05mg/ml). Desidual cells were enriched by Ficoll-Hypaque® density gradient, following dish adherent method. 1×106/ml of decidual cells were cultured for 48 hours in RPMI-1640 medium supplemented with 10% fetal calf serum, and the supernatants were harvested.The supernatant added at a concentration of 50% inhibited the reactions of human peripheral blood lymphocytes (PBL) by polyclonal mitotic activities of phytohemagglutinin (PHA), mixed lymphocytes culture (MLC), and killer T cell induction of PBL against alloantigen by 40%, 35% and 50%, respectively. To diminish the contamination of macrophages (spectific gravity: 1.045_??_1.075), discontinuous density gradient method using Percoll® was performed. Desidual cells were enriched over 90% in the fraction of specific gravity of 1.033 to 1.044 (fraction 2; Fr 2). The culture supernatant of the desidual cells (Fr 2) suppressed not only the mitotic activities of PHA to PBL by 29.6% at a concentration of 50%, but also the MLC by 40%, 19% and 8.75% at concentrations of 50%, 25%, 12.5%, respectively. The culture supernatant also suppressed the killer T cell induction by 53.3% and 13.8% at concentrations of 50% and 25%, respectively.To dissect the mechanism of immunosuppressive action of the culture supernatant, the suppressive effect of the supernatant on IL-2 production or IL-2 receptor expression of PBL stimulated by PHA, were investigated. The supernatant suppressed not only IL-2 production (0u/ml) but also IL-2 receptor expression (32.2%) compared with controlls (9.4u/ml, 48.1%). The supernatant also suppressed the immunoglobulin (IgG and IgA) production from PWM stimulated B cells separated from PBL. Those results indicate that desidual cells play a role in the maintenance of pregnancy by producing immunosuppressive substance which inhibit both T cell and B cell immunity to fetus.

Tumor growth promoting activity of an immunosuppressive substance and its modulation by protein-bound polysaccharide PSK

The role of an immunosuppressive substance (IS), which is increased in the serum of tumor-bearing animals, was examined in rats. IS isolated from cancerous ascites fluid of rats was administered to Walker 256 tumor-bearing rats to examine changes in the serum level of IS, tumor growth and survival rate. PSK, an immunomodulator, was also administered. Serum IS increased with tumor growth. The administration of IS to tumor-transplanted rats caused the tumor to grow and shortened the animals' survival time. The administration of PSK, however, inhibited the increase in serum level of IS, resulting in the suppression of tumor growth and a prolongation of survival time. The findings suggested that IS is a useful parameter for predicting not only tumor growth but also the therapeutic effect of immunomodulators such as PSK.