Biomedical subjects

S Kudoh

Publications and source records attributed to S Kudoh.

At least 217 records · Page 12Linked to original sources

PubMed1995

[Endothelial metaplasia of the alveolar capillaries in experimental silicosis of rats].

We studied, by immunohistochemical and ultrastructural observations, the basic mechanism of interstitial fibrosis and endothelial metaplasia of alveolar capillaries in the lungs of Sprague-Dawley rats that received a single intratracheal infusion of silica particles. Immediately after silica administration, alveolar capillaries collapsed and their endothelial cells became necrotic over wide ranges. Alveolar myofibroblasts migrated into luminal silicaladen granulomas through defects in the alveolar linings. They proliferated and produced collagenous matrices that were incorporated into adjacent walls by coverage of regenerating epithelial cells. By day 4, endothelial cells of peribronchiolar small vessels had become positive for proliferating cell nuclear antigen. These endothelial cells apparently migrated along alveolar capillary tubes to replace injured endothelial cells through the processes of interdigitation of their cytoplasms. After one month, these alveolar endothelial cells, which were originally negative for factor VIII-related antigen (F-VIII) had become positive, especially in those segments in fibrotic scars. These endothelial cells developed numerous Weibel-Palade bodies containing F-VIII. Some endothelial cells formed specific ultrastructural fenestrations, which are unique to capillary endothelial cells that originated from bronchial arteries. The mechanism of endothelial metaplasia might consist of the following processes in endothelial cells that originated from broncho-pulmonary anastomoses: proliferation, migration, replacement, and differentiation of endothelial cells of bronchial arteries in the chronic fibrotic stages.

Animals↗

PubMed1994

Adrenomedullin, a newly discovered hypotensive peptide, is a potent bronchodilator.

The present study was designed to examine the effect of adrenomedullin (AM), a novel vasorelaxant peptide originally isolated from human pheochromocytoma, on histamine- or acetylcholine-induced bronchoconstriction in anesthetized guinea pigs in vivo. AM significantly inhibited acetylcholine-induced bronchoconstriction in a dose-dependent fashion. AM also significantly inhibited histamine-induced bronchoconstriction, but 10(-10) M AM had no significant inhibitory effect on this response. We also found that AM induced a long-lasting bronchodilator response, while isoproterenol induced transient bronchodilation. These preliminary findings suggest that AM may play important roles in airway function.

Acetylcholine↗

PubMed1994

Simultaneous determination of granisetron and 7-hydroxygranisetron in human plasma by high-performance liquid chromatography with fluorescence detection.

A highly sensitive high-performance liquid chromatographic method for the determination of granisetron, a novel antiemetic agent for cancer therapy, and its pharmacologically active and major metabolite in human plasma is described. Methylation of the metabolite with trimethylsilyldiazomethane was employed for sample pretreatment. As a result of this treatment, the originally non-fluorescent metabolite could be detected simultaneously with granisetron using fluorescence detection. Both the compounds and the internal standard added were isocratically well resolved from endogenous peaks in plasma on an ODS column. The concentrations of the compounds were proportional to the peak-area ratios over the practical determination ranges of 0.2-100 ng/ml for granisetron and 0.1-50 ng/ml for the metabolite. In tests, reproducibilities for granisetron at 1 ng/ml and the metabolite at 0.5 ng/ml as determined by the relative standard deviation (n = 3) were less than 3.98 and 7.23%, respectively, in a single run.

Chromatography, High Pressure Liquid↗

PubMed1994

Establishment of a human small-cell lung-cancer subline resistant to okadaic acid.

Okadaic acid (OA), a specific protein phosphatase inhibitor, has various biological functions. To elucidate the mechanism of OA resistance, we have established a small-cell lung-cancer subline (H69/OA100) resistant to the growth-inhibitory effect of OA; this was done by using the parental cell line (H69) and increasing the concentration of OA. H69/OA100 was about 8 times more resistant to OA than H69. Intracellular retention of the fluorescent OA derivative in H69/OA100 was the same as that in H69. The catalytic activity of protein phosphatase from H69/OA100 was significantly reduced compared with that from H69. The protein phosphatase from H69/OA100 was 3.6 times more resistant to OA than that from H69. We examined the effect of OA on the activity of the immunoprecipitated protein phosphatase type I (PPI) and type 2A (PP2A) from the 2 cell lines. The PPI and PP2A from H69/OA100 showed more resistance to OA than those from H69. We next examined the effect of OA on the cell cycle of H69 and H69/OA100. In H69, G2/M block was observed at an OA concentration of 30 ng/ml whereas in H69/OA100, no G2/M block was observed at concentrations up to 100 ng/ml OA. We finally evaluated the amount of p34cdc2 kinase expression and the phosphorylation status of p34cdc2. There was no difference in p34cdc2 expression between H69 and H69/OA100 at several concentrations of OA. However, dephosphorylation of p34cdc2 was observed at 30 ng/ml OA in H69, but not in H69/OA100 up to 100 ng/ml OA. These data suggest that the resistance to OA and the resistance of the cell-cycle block to OA in H69/OA100 might be due to alteration of protein phosphatase activity.

Base Sequence↗

PubMed1994

T lymphocytes infiltrating renal cell carcinoma have a reduced expression of transferrin receptor.

T-cell responses have been reported to be impaired in cancer patients, and lymphocytes infiltrating human tumors (T-TIL) appear to be more affected than those in the peripheral blood. T-TIL display a poor proliferative response when compared to peripheral blood T (T-PBL) cells that show a strong response to all stimuli. Here we report that T-TIL from patients with renal cell carcinoma (RCC) also have a defect in transferrin receptor (TfR) expression that is not present in T-PBL cells. Immunocytometry studies (dual staining for CD3 epsilon and TfR) demonstrated that autologous T cells from the peripheral blood but not from the tumor expressed TfR following stimulation with IL2, anti-CD3 or PHA. Expression of TfR correlated with the capacity of T cells from the blood and tumor to proliferate. Gene expression studies using reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated that TfR mRNA levels in T-TIL were undetectable or low relative to T-PBL following stimulation. The failure to detect TfR mRNA in T-TIL after stimulation was not due to a shift in kinetics of mRNA accumulation since TfR mRNA was not detectable at any of the times tested (4, 12, 24 and 36 hr). The defect in TfR gene expression is selective since IL2R alpha gene expression was induced in T-TIL. Because IL2 binding to its receptor results in TfR expression, the defect in TfR induction in T-TIL appears to be distal to IL2R alpha expression. Our studies illustrate another alteration in T-TIL that is not observed in T cells from the peripheral blood. The absence of TfR gene expression may contribute to the poor proliferative response of T cells from the tumor.

Base Sequence↗

PubMed1994

Potentiation of long-term-cultured lymphokine-activated killer cell cytotoxicity against small-cell lung carcinoma by anti-CD3 x anti-(tumor-associated antigen) bispecific antibody.

Lymphokine-activated killer (LAK) cells exhibit a potent cytotoxicity to malignant cells in vitro. However, a satisfactory effect has not been obtained in many clinical studies except for a few cases. One of the most important reasons why cytolytic activity could not be exhibited in vivo is that LAK cells do not accumulate in the tumor tissue because of a lack of specificity. In the present study, we show the effect of a bispecific antibody (bsAb) on the accumulation of LAK cells around the small-cell lung carcinoma (SCLC) cell and the subsequent enhancement of LAK cell cytotoxicity against SCLC. When short-term(4 days)-cultured LAK cells were used, OKT3 x LU246 bsAb, which direct CD3+ T-LAK cells to the target cell, induced a similar level of cytotoxicity to that induced by 3G8 x LU246 bsAb, which directs CD16+ LAK cells. Long-term(21 days)-cultured LAK cells exhibited a reduced spontaneous cytotoxicity but retained high cytotoxic activity, which could be directed by OKT3 x LU246 or 3G8 x LU246 bsAb. The inhibitory effect of LAK cells on tumor cell clonogenicity in soft agar was also enhanced by both bsAb. These results indicate that application of the therapy with LAK cells and OKT3 x LU246 bsAb to SCLC patients might be a promising new method of adoptive immunotherapy.

Antibodies, Monoclonal↗

PubMed1994

Phase I study of irinotecan and cisplatin with granulocyte colony-stimulating factor support for advanced non-small-cell lung cancer.

PURPOSE: Since leukopenia was one of the dose-limiting toxicities of the combination of irinotecan (CPT-11) and cisplatin in a previous trial, we conducted a phase I trial to investigate whether support with recombinant human granulocyte colony-stimulating factor (rhG-CSF) would permit further intensification of the CPT-11 dose in combination with a fixed cisplatin dose. PATIENTS AND METHODS: Twenty previously untreated patients with stage IIIB or IV non-small-cell lung cancer (NSCLC) were treated with CPT-11 on days 1, 8, and 15 in combination with cisplatin 80 mg/m2 intravenously on day 1. In addition, rhG-CSF (2 micrograms/kg/d) was administered on days 4 to 21, except on the days of CPT-11 treatment. The starting dose of CPT-11 was 70 mg/m2, and the CPT-11 dose was escalated in 10-mg/m2 increments until the maximum-tolerated dose was reached. RESULTS: Diarrhea was the dose-limiting toxicity at 90 mg/m2. Two of six patients experienced either grade 3 or 4 diarrhea or grade 3 leukopenia during the first course of therapy at this dose level. Modest escalation of the CPT-11 dose from 80 to 90 mg/m2 resulted in a marked increase in the plasma concentration of 7-ethyl-10-hydroxycamptothecin (SN-38). Occurrence of diarrhea was well correlated with the peak plasma concentration (Cmax) of SN-38 (P = .035). There were 10 partial responses (50%) among 20 patients. CONCLUSION: The recommended dose for phase II studies is 80 mg/m2 of CPT-11, and 80 mg/m2 of cisplatin plus rhG-CSF. With the use of rhG-CSF, the CPT-11 dose can be increased 33% above that in the original regimen (60 mg/m2 of CPT-11 and 80 mg/m2 of cisplatin).

Adult↗

PubMed1994

Phase I and pharmacologic study of irinotecan and etoposide with recombinant human granulocyte colony-stimulating factor support for advanced lung cancer.

PURPOSE: We conducted a phase I trial of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with etoposide, a topoisomerase II inhibitor, and recombinant human granulocyte colony-stimulating factor (rhG-CSF) support because of the overlapping neutrophil toxicity of both drugs. The aim was to determine the maximum-tolerated dose of CPT-11 combined with a fixed dose of etoposide in patients with advanced lung cancer, as well as the dose-limiting toxicities of this combination. PATIENTS AND METHODS: Twenty-five patients with stage III or IV lung cancer, 15 (60%) with prior chemotherapy, were treated at 4-week intervals using CPT-11 (90-minute intravenous infusion on days 1, 8, and 15) plus etoposide (80 mg/m2 intravenously on days 1 to 3). In addition, rhG-CSF (2 micrograms/kg/d) was given from day 4 to day 21, except on the days of CPT-11 administration. The starting dose of CPT-11 was 60 mg/m2, and it was escalated in 10-mg/m2 increments until the maximum-tolerated dose was reached. RESULTS: The maximum-tolerated dose of CPT-11 was 90 mg/m2, since two of the three patients developed grade 3 to 4 leukopenia or grade 3 to 4 diarrhea during the first cycle of treatment at this dose level. Diarrhea and leukopenia were the dose-limiting toxicities, while thrombocytopenia was only a moderate problem. Elimination of CPT-11 was biphasic, with a mean +/- SD beta half-life of 18.17 +/- 9.09 hours. The mean terminal half-life of 7-ethyl-10-hydroxycamptothecin (SN-38; the major metabolite of CPT-11) was 43.40 +/- 37.84 hours. There was one complete response (5%) and eight partial responses (38%) among 21 assessable patients, for an overall response rate of 43%. The response rates for small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) were 58% (seven of 12 patients) and 22% (two of nine patients), respectively. CONCLUSION: The combination of CPT-11 and etoposide with rhG-CSF support seems to be active against lung cancer, especially SCLC, with acceptable toxicity. The recommended dose for phase II studies in previously untreated patients is 80 mg/m2 of CPT-11 (days 1, 8, and 15) and 80 mg/m2 of etoposide (days 1 to 3) plus 2 micrograms/kg of rhG-CSF (days 4 to 21, except when CPT-11 is given). In addition, 70 mg/m2 of CPT-11 appears to be the appropriate dose for previously treated patients receiving this regimen.

Adult↗

PubMed1994

Serum neuron specific enolase level as a prognostic factor in non-small cell lung cancer.

In 93 patients with inoperable non-small cell lung carcinoma who underwent chemotherapy including cisplatin, the prognostic value of 9 factors were determined using Cox's proportional hazard model. Univariate analysis revealed that patients with a performance status of grade 2 (p < 0.01) or 3 (p < 0.05), those with stage IV disease (p < 0.05), those with a serum neuron specific enolase (NSE) level > 7.0 ng/ml (p < 0.001), and those with a low serum albumin level (p < 0.05) had a significantly worse prognosis. Multivariate analysis showed that a performance status of 2 or 3 and a high NSE serum level were associated with a significantly worse prognosis. More attention should be paid to the serum NSE level in patients with non-small cell lung carcinoma, because it not only reflects the tumor volume, but is also a prognostic factor which is dependent on individual tumor characteristics.

Adult↗

PubMed1994

[Basic studies on the prevention of cyclosporin A induced nephrotoxicity].

Some studies were evaluated to examine how to prevent cyclosporin A (CsA) induced nephrotoxicity, using Wistar strain rats. First, three doses of CsA (10, 25 and 50 mg/kg) were orally administered and blood CsA levels were measured. In results, they were dose-dependent. Next CsA (25 mg/kg) and diltiazem (DIL), (1, 2, 10, 30 and 50 mg/kg), theophylline (TH), (10, 20 and 30 mg/kg) or ethylephrine (ET), (0.5 mg/kg) were administered and then blood CsA levels were measured. DIL (1 and 2 mg/kg) and TH (20 and 30 mg/kg) raised blood CsA levels, but ET failed to do. Second, CsA (10 and 25 mg/kg) was administered for 6 weeks and biochemical examination of the blood and urine and histopathology of the kidney were examined regularly. The ratio of Na and K (Na/K) in the urine was significantly decreased as compared with the control group and its decrease paralleled to the histopathological changes of the renal tubulus. Next, using urine Na/K as the indicator, the influence of DIL (2 mg/kg), TH (20 mg/kg) and ET (0.5 mg/kg) were examined. DIL and TH significantly raised the blood CsA levels, but ET had no effect on them, while DIL but TH and ET showed a tendency to prevent the decrease in urine Na/K. Finally, immunosuppressive effects of CsA and DIL were examined to make sure whether DIL could enhance the effects of CsA, using human lymphocytes in vitro. Proliferation assay showed both CsA and DIL were able to inhibit the proliferation of lymphocytes. 51Cr-release assay showed they inhibited the cytotoxic activity. DIL significantly enhanced this inhibition of CsA. These results suggested that CsA dosage could be reduced and the renal tubular damages could be lowered when DIL was used. It also seemed that DIL was able to enhance the immunosuppressive effect of CsA, therefore CsA dosage could be reduced when DIL was coadministered.

Animals↗

PubMed1994

Erythromycin promotes monocyte to macrophage differentiation.

Recent reports have suggested that long-term administration of erythromycin (EM) appears to ameliorate some of chronic inflammatory processes where macrophages and lymphocytes play important roles. Our study was initiated to examine the effect of EM on monocyte-macrophage lineage in vitro. EM (1 approximately 100 micrograms/ml) significantly increased the number of adherent monocyte-derived macrophages after 7 days of culture. The combination of EM and macrophage colony stimulating factor (M-CSF) synergistically increased the number of monocyte-derived macrophages, while the combination of EM and granulocyte-macrophage colony stimulating factor exerted an additive effect. Culture with EM induced the expression of a surface antigen CD71, one of the activation markers of macrophages as compared with control cultures. The combination of EM plus M-CSF significantly enhanced H2O2-producing capacity of those cells as compared with M-CSF alone. A differentiation process of monocytoid THP-1 cells was also augmented by EM. These results indicate that EM promotes differentiation of human monocyte-macrophage lineage, altering their functions.

Antigens, CD↗

PubMed1994

[Analysis of the preceding R-R interval and the coupling interval on premature ventricular contractions].

Premature Ventricular Contractions (PVCs) are one of the common arrhythmias. Although the analysis of the preceding R-R interval and the coupling interval on the Holter electrocardiogram, the Lorenz plotting method, has been used to characterize mature of PVC, this analysis has typically been performed without regard to the morphological classification of the electrocardiogram waveforms. Therefore, we performed the Lorenz plotting after a PVC classification. We analyzed 45 cases with more than 1,000 PVCs per day. Twenty-six of the cases with PVCs had no organic heart disease (idiopathic PVC); nineteen of the cases with PVCs had organic heart disease (PVC with disease). Each R-R interval was analyzed after classification based on the morphology of each QRS wave of the PVC. The computer generated a two-dimensional plot of the relationship between the preceding R-R interval of PVC and the following coupling interval. The forms of PVCs were monoform in idiopathic PVC and were mostly multiform in PVC with disease. The patterns on Lorenz plotting in idiopathic PVC had a tendency to be uniform with small standard deviations. In contrast, multiform PVCs tended to be highly variable with large standard deviations. The value of SD was 32.1 +/- 12.0 msec in idiopathic PVC, and that of the slope "a" was 0.048 +/- 0.051 in PVC with disease. Using the SD values and the slope "a" values, we were able to classify idiopathic PVC vs. PVC with disease with a 95% sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1994

[Clinical usefulness of the combined empirical therapy with flomoxef and fosfomycin for intractable respiratory tract infections. With a background of increasing MRSA incidence].

We conducted a multicenter trial to determine the clinical usefulness of the combined therapy with flomoxef (FMOX) and fosfomycin (FOM) (FF therapy) as an empirical therapy in the treatment of intractable respiratory tract infections, because FF therapy has clinically been proved to be very useful for the treatment of severe infections including MRSA infections. The overall efficacy rate of FF therapy was 69.2%. The efficacy rate for "pneumonia/lung abscess," which occupy the largest portions of respiratory tract infections, was 70.0%, showing a statistically significant difference from the efficacy rate for FMOX alone (56.7%) found in a previous study (P = 0.09 by chi-squared test). Although MRSA was eradicated in only 3 cases (37.5%) including superinfection cases, of 8 patients, from whom MRSA had been isolated as causative organisms, none of our patients were superinfected with MRSA. Thus it has been concluded that FF therapy is clinically very useful when used as an empirical therapy in the treatment of respiratory tract infections.

Aged↗

PubMed1993

Loss of T-cell receptor zeta chain and p56lck in T-cells infiltrating human renal cell carcinoma.

Cancer patients and mice bearing tumors develop a progressive immunosuppression manifested by a decreased delayed-type hypersensitivity, decreased T-cell lytic activity, diminished production of lymphokines, and a reduced T-cell proliferative response. The mechanisms underlying these changes are incompletely understood. We recently reported the presence of marked alterations in signal transduction in T-cells from mice bearing long-term (28-day) tumours. We hypothesized that a soluble product produced by the tumor or resulting from the immune response to tumor might be responsible for inducing the changes in T-cells. Tumor-infiltrating lymphocytes from patients with renal cell carcinoma tested here showed, in 10 of 11 cases, a marked decrease in the expression of the T-cell receptor zeta chain and in p56lck tyrosine kinase. The presence of major alterations in the tumor-infiltrating lymphocytes with only minor changes in the peripheral blood leukocyte T-cells supports the notion that the defects are induced by exposure to tumor. These results suggest that tumor-infiltrating lymphocytes may be compromised in their antitumor efficacy in patients with renal cell cancer.

Carcinoma, Renal Cell↗

PubMed1993

T-cells infiltrating renal cell carcinoma display a poor proliferative response even though they can produce interleukin 2 and express interleukin 2 receptors.

The fact that progressing tumors contain a significant infiltrate of T-cells brings into question the competency of the infiltrating T-lymphocytes (T-TIL). We have examined the role of the T-cell receptor/CD3 complex and/or the interleukin 2 receptor (IL2R) in responsiveness of T-cells that infiltrate human renal cell carcinoma. T-TIL display a poor proliferative response to interleukin 2 (IL2) alone, IL2 in combination with antibody to CD3, or mitogen stimulation. The proliferative unresponsiveness was not related to low expression of CD3 or IL2R beta as the percentage of T-cells expressing CD3 and IL2R beta were comparable in both T-TIL and peripheral blood T-cells obtained from the same patient. In contrast to the lack of proliferative activity, stimulation of T-TIL or peripheral blood lymphocytes with phytohemagglutinin or anti-CD3 resulted in comparable levels of both IL2 and gamma-interferon mRNA and protein expression. While levels of IL2R alpha were low in unstimulated T-TIL and peripheral blood lymphocytes, anti-CD3 antibody or IL2 were capable of inducing surface expression of this protein in both cell populations. IL2R alpha mRNA levels were comparable in T-cells from the tumor and peripheral blood although in some experiments both the percentage of IL2R alpha-positive cells and the density of surface expression per cell were reduced in T-TIL. This reduced IL2R alpha expression on T-TIL was not responsible for the proliferative unresponsiveness since T-TIL that expressed both IL2R alpha and/or IL2R beta still failed to respond to high doses of IL2. Thus T-TIL display a selective loss of response to at least two well defined extracellular stimuli. While T-TIL exhibit a poor proliferative response regardless of the form of stimulation these cells remain sensitive to both anti-CD3 and IL2 in terms of IL2 and gamma-interferon or IL2R alpha expression, respectively. The fact that proliferative unresponsiveness exists even though T-TIL can produce IL2 and express IL2R alpha/beta suggests that T-TIL have a selective loss of a common intracellular signaling pathway which is requisite to proliferation but not other aspects of response to antigenic stimulation.

Adult↗

PubMed1993

Phase I and pharmacologic study of irinotecan in combination with cisplatin for advanced lung cancer.

We have conducted a Phase I trial to determine the maximum tolerated dose of CPT-11 together with a fixed dose of cisplatin in patients with advanced lung cancer, and the dose-limiting toxicities of this combination. Fourteen previously untreated patients with stage IIIB or IV disease were treated with CPT-11 (90-min intravenous infusion on days 1, 8, and 15) plus cisplatin (60 mg m-2, intravenously on day 1). The starting dose of CPT-11 was 60 mg m-2, and diarrhea was the dose-limiting toxicity at the 90 mg m-2 dose level. All three patients (all four cycles) given 90 mg m-2 of CPT-11 experienced grade 3 diarrhea. Hematologic toxicity was relatively mild. Elimination of CPT-11 was biphasic with a mean (+/- s.d.) beta half-life of 11.36 +/- 7.26 h. The mean terminal half-life of the major metabolite (7-ethyl-10-hydroxycamptothecin; SN-38) was 22.13 +/- 13.28 (s.d.) h, and modest escalation of the CPT-11 dose from 80 mg m-2 to 90 mg m-2 resulted in a statistically significant apparent increase in the plasma concentrations of SN-38. There were one complete response (7%) and five partial responses (36%) among the 14 patients for an overall response rate of 43%. The recommended dose for Phase II studies is 80 mg m-2 of CPT-11 and 60 mg m-2 of cisplatin.

Adult↗

PubMed1993

Enhanced antitumor efficacy of a combination of CPT-11, a new derivative of camptothecin, and cisplatin against human lung tumor xenografts.

The objective of this study was to evaluate the antitumor efficacy of combined use of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and cisplatin (CDDP). The antitumor activities of CPT-11, CDDP and their combination against 3 human lung tumor xenografts were estimated using congenitally athymic BALB/c (nu/nu) mice. The doses were 47 mg/kg for CPT-11 and 6 mg/kg for CDDP on days 1, 5 and 9. In combination therapy, half of the single dosage of each agent was used. The doses were administered intraperitoneally. The antitumor activity and toxicity were evaluated in terms of the tumor volume and body weight change of mice, respectively. The combination therapy resulted in a statistically significant tumor regression compared to the use of only CPT-11 or CDDP in two tumor xenografts out of three. The toxicity of the combination therapy was no higher than that of CPT-11 or CDDP alone. These results suggest that the antitumor activity of the combination of CPT-11 and CDDP is superior to that of CPT-11 or CDDP alone.

Animals↗

PubMed1993

Antilymphocytic activity of erythromycin distinct from that of FK506 or cyclosporin A.

Erythromycin (EM), a macrolide antibiotic has been recently reported to depress the extent of inflammation irrespective of its antimicrobial action. Our study was initiated to examine the effect of EM on T cell proliferation in vitro, since other macrolide antibiotics FK506 and rapamycin (RAP) have been well known to possess strong immunosuppressive or anti-inflammatory potential. EM had a suppressive effect on the proliferative response of human lymphocytes stimulated with mitogens and antigens, while EM had no effect on concanavalin A (Con A)-induced interleukin-2 (IL-2) production or IL-2R alpha (CD25) expression. Delayed addition of EM after the first 48 hours of mitogenic stimulation did suppress IL-2-dependent proliferation of Con A blasts, whereas pretreatment with EM for the first 48 hours of stimulation did not impede the subsequent IL-2-dependent proliferation of obtained blast cells. The results indicate that EM suppresses T cell proliferation at a late stage in the activation process by impairing their response to IL-2. This antilymphocytic action of EM was quite distinct from that of FK506 or cyclosporin A (CsA) but was similar to that of RAP. Unlike RAP, however, EM did not antagonize FK506-induced suppression but potentiated the action of FK506 and CsA. The addition of an enteric hormone motilin, a receptor of which was previously found to be occupied by EM, unaffected the lymphocyte proliferation and the subsequent EM-induced suppression. These data suggest that EM operates through an undefined mechanism probably distinct from that of FK506, CsA, RAP or motilin.

Antigens↗