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At least 919 records · Page 51Linked to original sources

PubMed1999

The relationship of untreated borderline infiltrates by the Banff criteria to acute rejection in renal allograft biopsies.

The relationship of borderline infiltrates to acute rejection by Banff criteria in renal allografts of patients receiving only maintenance immunosuppression is not clear. Renal allograft biopsies with borderline lesions that were not treated with additional anti-rejection therapy were retrospectively studied. Sixty-five such biopsies were identified from 50 patients, and their outcome was determined by serum creatinine and/or histologic findings in subsequent biopsies, up to 40 d after the initial biopsy. In addition to the borderline infiltrates, there was evidence of acute cyclosporine or tacrolimus toxicity (58%), acute tubular necrosis (12%), and urinary obstruction (12%). Forty-day follow-up after 30 (46%) biopsies revealed serum creatinine < 110% of baseline, and repeat biopsies were not indicated. In 17 (26%), the serum creatinine initially decreased, then increased, and follow-up biopsies showed acute rejection in nine. In 18 (28%), the creatinine remained elevated and follow-up biopsies revealed acute rejection in nine. The untreated borderline infiltrates were thus nonprogressive after 47 biopsies (72%) and progressed to histologic acute rejection after 18 (28%). When there was increasing or persistently elevated creatinine after the initial biopsy, 51% of cases (18 of 35) progressed to acute rejection. Infiltrates that progressed to rejection had more frequent glomerulitis (7 of 18 versus 3 of 47, P = 0.003) and Banff acute score indices (i+t+v+g) >2 (16 of 18 versus 29 of 47, P = 0.03). A majority (72%) of borderline infiltrates not given additional anti-rejection therapy did not progress to acute rejection over 40 d of follow-up, suggesting that conservative management of these lesions, at least in the short term, may be more appropriate than routine treatment as acute rejection.

Adolescent↗

PubMed2001

Human glomerulonephritis accompanied by active cellular infiltrates shows effector T cells in urine.

Leukocyturia is associated with postinfectious glomerulonephritis (GN), interstitial nephritis, and renal allograft rejection. In addition, prominent infiltration of T cells and macrophages is commonly observed in the renal tissues of patients with GN, accompanied by cellular crescent formation and/or interstitial cell infiltration. Because these infiltrating T cells were thought to participate in the development of the diseases and to appear in the urinary space while functioning as effector cells in the renal inflammatory lesion, the study focused on the characterization of T cells that appeared in urine. Freshly voided urine cells were analyzed by flow cytometry to determine their phenotype and by reverse transcriptase-PCR to detect cytokine mRNA. In urine from patients with different forms of GN, including IgA nephropathy, Henoch-Schönlein purpura nephritis, and anti-neutrophil cytoplasmic antibody-associated GN, T cells appeared together with macrophages. The urine T cells were mainly CD45RA(-), CD45RO(+), and CD62L (L-selectin)(-), which are the phenotypic features of effector T cells. In agreement with this finding, T cells infiltrating glomeruli, crescents, and tubulointerstitial lesions were also effector type. Moreover, these urine cells expressed mRNA of the T helper lymphocyte 1 cytokines, interleukin-2, and/or interferon-gamma. These findings suggest that the appearance of effector T cells in urine may reflect the cellular immune reaction that occurs in the kidneys of patients with GN accompanied by active cell infiltration.

Adolescent↗

PubMed2000

Transrectal sonography of anal sphincter infiltration in lower rectal carcinoma.

OBJECTIVE: The purpose of the study was to assess the accuracy of transrectal sonography in determining invasion by lower rectal cancer into the anal canal. SUBJECTS AND METHODS: Thirty-eight patients (14 women, 24 men; mean age, 65 years) with lower rectal cancer underwent transrectal sonography before surgery. Both depth of infiltration and tumor invasion into the anal canal were assessed, and results were compared with histopathology of the resected specimens. RESULTS: Infiltration into the anal canal was found histopathologically in 12 (32%) of 38 patients. Transrectal sonography revealed a true-positive diagnosis in 11 of these 12 patients. A false-positive diagnosis of anal canal infiltration was made in two patients for a sensitivity of 91%, a specificity of 85%, and an accuracy of 92%. In the 11 patients diagnosed correctly on transrectal sonography, the depth of tumor infiltration into the anal canal corresponded with histopathology. CONCLUSION: This study shows that transrectal sonography is an accurate method for assessment of anal canal infiltration in lower rectal cancer.

Adenocarcinoma↗

PubMed2002

Apoptosis and oxidative stress of infiltrated neutrophils obtained from mammary glands of goats during various stages of lactation.

OBJECTIVE: To examine apoptosis in infiltrated neutrophils during involution of mammary glands and compare them with those obtained during late and peak lactation, and to measure oxidative stress and activities of antioxidant enzymes and determine involvement of free radicals in apoptosis of infiltrated neutrophils. SAMPLE POPULATION: Neutrophils from mammary gland secretions of 8 goats at 4 stages (late and peak lactation and 1 and 2 weeks after end of lactation). PROCEDURE: DNA fragmentation was evaluated to characterize apoptosis. Concentration of thiobarbituric acid reactive substances (TBARS) was used to evaluate oxidative stress. Activities of superoxide dismutase and glutathione peroxidase were determined. RESULTS: Neutrophils from secretions obtained after end of lactation of all goats and from late-lactation milk of some goats underwent prominent apoptosis, whereas neutrophils from peak lactation secretions did not. Higher lipid peroxidation and lower antioxidant enzyme activities in neutrophils during involution were observed, compared with those during late and peak lactation. A significant negative correlation existed between TBARS concentrations and antioxidant enzyme activities during the nonlactating period. CONCLUSIONS AND CLINICAL RELEVANCE: Apoptosis is a feature of infiltrated neutrophils during involution of mammary glands in goats. This feature may allow prompt resorption and clearance of infiltrated neutrophils without damaging surrounding tissues. Increased oxidative stress in infiltrated neutrophils from secretions obtained after end of lactation is probably related to a deficiency in antioxidant enzyme activities. Understanding the relationship between apoptosis and oxidative stress will lead to new strategies for manipulating involution and reducing tissue damage.

Animals↗

PubMedDate not supplied

Immunofluorescent assessment of tumour infiltrating cells in laryngeal carcinoma. Application of monoclonal antibodies.

In order to gain some insight into host cell accumulations within primary tumour, frozen sections from surgical specimens of laryngeal carcinoma were subjected to indirect immunofluorescence using a panel of monoclonal antibodies against various human lymphocyte subsets as well as macrophages. In addition, polyclonal antibodies against Ig were used in order to trace B cells. Numerous host cell infiltrates seen at the tumour periphery were composed of T4 (helper) lymphocytes and macrophages. Lymphocytes of OKT8 (suppressor/cytotoxic) and Leu-7 (NK cells) series were intermingled with tumour cells in the case of scanty infiltrates. Infiltrating cells were also linked to the presence of metastases in regional lymph nodes. OKT4-positive abundant infiltrates were usually accompanied by uninvolved nodes, while scanty ones with OKT8 specificity were relatively frequently seen in the patients with evidence of nodal metastases. These differences were not statistically significant, however, B cells as well as plasma cells were infrequently observed and were encountered both in tumour samples with intensive cellular infiltrates as well as in those with scanty ones.

Adult↗

PubMed1990

Carcinoma of the nasopharynx. The significance of lymphocytic infiltration.

From 1974 to 1985, 76 patients with nasopharyngeal carcinoma (NPC) received irradiation with curative intent and 14 with palliative intent in our department. Of the 76 patients, 59 presented with UICC stage IV. The 5-year actuarial survival rate was 41% and the relapse-free survival rate (RFS) 45%. The slides were reviewed according to the World Health Organization (WHO) histologic classification, also taking into account the degree of lymphocytic infiltration according to its Cologne modification. Undifferentiated carcinoma and non-keratinizing carcinoma had similar 5-year RFS (47 and 44% respectively). Patients with major lymphocytic infiltration in the tumor presented with younger median age, with smaller primary tumors and with more advanced neck disease than the other patients. There was, however, no obvious association between the degree of lymphatic infiltration in the tumor and the prognosis. Patients with major lymphocytic infiltration had a 5-year RFS of 44%, versus 49% for patients without such infiltration.

Adolescent↗

PubMed1997

Profiles of pulp infiltrating lymphocytes at various times throughout feather regeneration in Smyth line chickens with vitiligo.

Smyth line (SL) chickens develop a spontaneous, autoimmune, posthatch loss of pigment cells (vitiligo) in regenerating feather tissue. Smyth line vitiligo (SLV) is associated with lymphocyte infiltrations prior to and throughout the development of the disorder. It was the purpose of this study to determine the type, relative amounts, and proportions of pulp-infiltrating lymphocytes at various times throughout the growth of regenerating feathers. Feathers were plucked from 8-week-old chickens with and without SLV. Feather pulp cell suspensions were prepared when the regenerating feathers were 2, 3, 4, and 6 weeks of age. Cells were fluorescently labeled using a panel of mouse monoclonal antibodies specific for chicken lymphocytes. Both T and B cells infiltrated the feather pulp of chickens with SLV. T cell levels remained elevated throughout the 6 weeks of feather growth, while B cell levels steadily declined to control levels over the same time. The pulp-infiltrating cells were primarily T cells with an alphabeta T cell receptor expressing the Vbeta1 gene (TCR2+). The ratio between CD4+ and CD8+ cells was 1.42 and 0.75 in 2- and 6-week-old regenerating feathers from chickens with autoimmune SLV, respectively. In non-vitiliginous chickens this ratio was always near 1. These data suggest that TCR2+ T cells play an important role in SLV. CD4+ cells may play a recruiting/activating role, whereas CD8+ cells may have cytotoxic activity specifically directed against melanocytes. Additionally, this is the first report demonstrating the infiltration of B cells into the feather pulp of vitiliginous chickens. These B cells may directly/indirectly contribute to melanocyte destruction in SLV.

Animals↗

PubMed1997

Resident and infiltrating cells in the rat iris during the early stages of experimental melanin protein-induced uveitis (EMIU).

Experimental melanin protein-induced uveitis (EMIU) is reported to be a model of anterior uveitis and choroiditis in which the retina is spared. In this study, we chose to compare EMIU with experimental autoimmune uveoretinitis (EAU), a well-recognised model of endogenous posterior uveitis, with regard to the nature and dynamics of the cellular infiltrate in the iris. Female Lewis albino rats were immunised with mixtures of crude retinal extract/complete Freund's adjuvant (CFA) (EAU), phosphate-buffered saline/CFA (controls), or iris melanin/CFA (EMIU) using established protocols. Animals were sacrificed on days 10 and 13 (around disease onset). Following whole body perfusion fixation, irides were dissected from the remainder of the globe. Iris wholemount preparations were then subjected to immunohistochemical analysis in order to investigate both the dynamics of infiltrating leukocytes and the effects of the inflammatory changes on resident immune cells in the iris. The nature of the cellular infiltrate in both EMIU and EAU models was essentially similar, namely there was a rich infiltrate of EDI+ mononuclear cells, Ox42+ neutrophils and T cells. Resident tissue macrophages (ED2+) were slightly below normal densities in the iris of EAU animals and marginally elevated in EMIU animals, MHC class II (Ia) staining, associated in the normal eye with dendritic cells (DC), was considerably elevated in EMIU. It is likely that this was due to both increased DC numbers and an influx of Ia+ exudate macrophages. No striking difference was found in the nature and phenotype of the cellular infiltrate in the iris at the onset of the disease in these two models of uveitis (EAU and EMIU). This suggests that the anterior segment inflammation in both models represents non-specific changes secondary to cytokine release associated with interaction of activated antigen-specific T cells and target antigens, namely retinal photoreceptors in EAU and uveal tract melanin-containing cells in EMIU. Alternatively, it may suggest that antigen-presenting cells resident in the iris and ciliary body in normal eyes have access to ocular antigens on both sides of the blood-ocular barrier and are capable of activating circulating antigen-specific T cells in these models.

Animals↗

PubMed1984

Mononuclear lymphoid populations infiltrating the microenvironment of primary CNS tumors. Characterization of cell subsets with monoclonal antibodies.

Mononuclear cell infiltrates are found to varying degrees in 30% to 60% of primary human central nervous system (CNS) gliomas. To explore the immunological importance of this, six operative glial tumors, eight non-glial tumors, and three normal brain specimens were studied. Utilizing an immunoperoxidase method, the authors examined frozen sections for lymphoid infiltrates expressing suppressor/cytotoxic and helper phenotypes, as identified with the Leu-1,2,3 monoclonal antibodies. Four of six gliomas demonstrated lymphoid infiltrates: three tumors exhibited a predominant suppressor/cytotoxic cell phenotype and the fourth showed mixed staining of suppressor/cytotoxic and helper cell phenotypes. Varying degrees of lymphoid infiltration characterized four out of eight non-glial primary CNS tumors. Two cases exhibited a prevalence of suppressor/cytotoxic phenotype cells, while two cases demonstrated a more heterogeneous pattern of phenotype expression. Normal brain sections revealed little or no evidence of mononuclear infiltrates. The immunobiological significance of these findings is discussed in the context of tumor-host interaction within the CNS.

Antibodies, Monoclonal↗

PubMed1994

Infiltration of the carotid artery by cavernous sinus meningioma.

Intracranial meningiomas are known to infiltrate surrounding structures such as the calvaria and dural sinuses, and the brain itself. The issue of whether meningiomas invade major intracranial arteries is of clinical importance, particularly in the case of meningiomas of the cavernous sinus. If a meningioma has not invaded the carotid artery wall, complete tumor removal may be accomplished with careful dissection from the carotid artery; however, if the tumor has infiltrated the wall of the carotid artery, complete removal may require sacrifice of the artery. To determine whether cavernous sinus meningiomas invade the carotid artery, the authors retrospectively reviewed the histopathology of 19 consecutively treated individuals whose carotid artery was sacrificed during removal of a meningioma involving the cavernous sinus. Patients were selected for carotid artery resection based on preoperative magnetic resonance imaging studies demonstrating complete encasement of the artery. Reconstruction of the carotid artery was planned depending on the results of preoperative balloon test occlusion with blood flow determinations. None of the 19 patients had pathological evidence of malignant tumor. Eight individuals (42%) were found to have infiltration of the carotid artery by meningioma. In five cases, focal involvement of the adventitia of the carotid artery wall was noted and, in three, the vessel was infiltrated up to the tunica muscularis. In no case was the tunica muscularis invaded by tumor. Thus, meningiomas of the cavernous sinus do infiltrate the internal carotid artery and, in order to completely resect these lesions and effect a surgical cure, it may be necessary to sacrifice the carotid artery with or without reconstruction.

Carotid Arteries↗

PubMedDate not supplied

Bilateral peripheral infiltrative keratitis after LASIK.

PURPOSE: To report a case of peripheral infiltrate between the flap edge and limbus, which appeared on the first postoperative day after laser in situ keratomileusis (LASIK). METHODS: A 22-year-old man underwent uneventful bilateral simultaneous LASIK but developed a thick band of infiltrate between the flap margin and limbus extending from 2 o'clock to 9 o'clock in both eyes. The flap edge was not involved. The infiltrate was more concentrated at the periphery and faded centrally and progressed diffusely into the interface leading to typical diffuse lamellar keratitis. RESULTS: The infiltrate responded to topical prednisolone acetate 1% eye drops. CONCLUSIONS: This entity was referred to as LASIK-induced bilateral peripheral infiltrative keratitis with a probable immune-mediated etiology.

Administration, Topical↗

PubMed2006

Phenotypic and functional characterization of kidney-infiltrating lymphocytes in renal ischemia reperfusion injury.

T and B lymphocytes have been implicated in the pathogenesis of renal ischemia reperfusion injury (IRI). The trafficking of lymphocytes into kidneys during IRI has been postulated to underlie this effect, but has not been rigorously studied. We therefore characterized the lymphocyte populations infiltrating into mouse kidneys 3 and 24 h after renal IRI. Immunohistochemistry and flow cytometry staining of kidney lymphocytes showed increased trafficking of CD3+ T cells and CD19+ B cells in both sham-operated and IRI mice 3 h after renal IRI. In the IRI mice, increased infiltration of NK1.1+ and CD4+ NK1.1+ cells compared with normal and sham-operated mice was observed 3 and 24 h after renal IRI, respectively. After 24 h of renal IRI, the decreased percentages of CD3+, CD19+, and NK1.1+ populations in the IRI mice compared with control groups were observed. Increased TNF-alpha and IFN-gamma production of kidney infiltration CD3+ T cells in IRI mice but not sham-operated mice was found. Unexpectedly, isolation and transfer of kidney-infiltrating lymphocytes 24 h after renal IRI into T cell-deficient mice reduced their functional and histological injury after renal IRI, suggesting that kidney-infiltrating lymphocytes could have a protective function. These quantitative, qualitative, and functional changes in kidney lymphocytes provide mechanistic insight into how lymphocytes modulate IRI, as well as demonstrating that abdominal surgery alone leads to lymphocyte changes in kidney.

Animals↗

PubMed2004

[Function and prognostic significance of immune cells infiltrating human tumors].

The presence of a mononuclear infiltrate has prognostic importance in a variety of human cancers. The infiltration by different cell types, mainly T lymphocytes and dendritic cells has been correlated to tumor size, stage, metastatization, and patients' survival. Their pathophysiological role is influenced by the cell types, their localization (intra- or peritumoral), and by tumor characteristics or patient subgroups. The prognostic significance of the different cell populations in the individual tumor types is frequently controversial, which is due, in part, to their multiple functions; for example, tumor-associated macrophages are involved in the regulation of angiogenesis beside their immunologic functions. Moreover, the presence of immune cells in the tumor does not guarantee the development of an efficient immune reaction, consequently, the degree of infiltration does not necessarily correlate with the intensity of the immune response. Therefore, recent studies emphasize the importance of the assessment of the functional and activation state of tumor infiltrating lymphocytes. Here we summarize results on the prognostic role of infiltrating mononuclear cells in human neoplasms, and present our data on studies performed on cutaneous malignant melanoma.

B-Lymphocytes↗

PubMedDate not supplied

Fracture strength of glass infiltrated-magnesia core porcelain.

PURPOSE: This study determined the fracture strength of magnesia-core porcelain after using a glass infiltration firing technique. MATERIALS AND METHODS: Eighty refractory dies were replicated from a stainless steel master die milled to the dimensions of a maxillary premolar that had been prepared for a porcelain crown. The core porcelain was applied to the refractory dies using traditional condensation methods, and then formed into standardized copings using a centrifugal sculpturing device. The copings were vacuum-fired from 593 degrees C to 1 of 8 high temperatures. Five copings per temperature were then coated with a glass-infiltrate and ground back to a standard thickness. The finished copings were bonded to a duplicate die with an adhesive resin luting system and placed in an Instron testing machine and loaded to fracture. RESULTS: Analysis of variance and Student-Newman-Keuls tests demonstrated significant differences among treatments and temperatures (P < 0.05). A significant increase in fracture strength was observed after glass infiltration of the magnesia-core porcelain. Sintering the copings to 871 degrees C or 899 degrees C prior to glass infiltration gave the highest fracture load values. CONCLUSION: Glass infiltration significantly increased the fracture strength of the magnesia-core porcelain.

Analysis of Variance↗

PubMed2000

Infiltrating polymorphonuclear leukocytes and apoptotic bodies derived from hepatocytes but not from ballooning hepatocytes containing Mallory bodies show nuclear DNA fragmentation in alcoholic hepatitis.

BACKGROUND: The mechanism of liver cell death in alcoholic hepatitis is still controversial. There is evidence that polymorphonuclear leukocytes (PMNs) which infiltrate liver parenchyma are involved in liver cell death. METHODS: We employed terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick end labeling (TUNEL) method to determine the cells that underwent apoptosis in liver specimens obtained from 1 normal liver, 23 livers with nonalcoholic liver disease, and 11 livers with alcoholic liver diseases (4 alcoholic hepatic fibrosis, 4 alcoholic hepatitis, and 3 alcoholic cirrhosis). The Fas, bcl-2, and CD15 antigens were immunolocalized to analyze the relationship between these antigens and apoptosis. RESULTS: Few TUNEL-positive reactions were found in normal liver. Apoptotic bodies in acute and chronic viral hepatitis were found to be TUNEL-positive. TUNEL-positive materials were also abundant in the cytoplasm of macrophages at the area of parenchymal collapse in viral liver diseases. Mononuclear cells that infiltrated liver parenchyma and portal tracts occasionally showed TUNEL-positive reactions, which reflected the activation-induced apoptosis of T lymphocytes. In alcoholic liver diseases, the incidence of apoptotic bodies derived from hepatocytes varied from 0 to 1.00/mm2. In addition, a considerable portion (0.2-16.5%) of infiltrating PMNs in alcoholic hepatitis were TUNEL-positive. In contrast, the nuclei of ballooning hepatocytes that contained Mallory bodies revealed few positive TUNEL reactions. Interestingly, the density of CD15-positive PMNs was well correlated with peripheral white blood cell counts (r = 0.842, p < 0.005). CONCLUSIONS: PMNs that infiltrate liver parenchyma show an activation-induced cell death-like phenomenon in alcoholic hepatitis, like activated T cells that infiltrate in viral hepatitis. This apoptosis phenomenon may follow the degranulation of PMNs, which may cause a necrosis of ballooning hepatocytes that contain Mallory bodies through satellitosis.

Apoptosis↗

PubMed1998

[Telomerase activity in infiltration ductal carcinoma of breast].

OBJECTIVES: To compare telomerase activity of infiltration ductal carcinoma of breast with that of benign breast changes and to analyze the significance of telomerase activity in diagnosis of malignancy. METHOD: Telomerase activity was detected in 61 cases of infiltration ductal carcinomas of breast and 14 cases of benign changed breast using TRAP assay. RESULTS: Telomerase activity was detected in 49 of 61 (80.3%) cases of infiltration ductal carcinoma. Telomerase activity in infiltration ductal carcinoma was not related tumor grades, tumor size, lymph node metastasis status, even tumor tissue estogen receptor(ER) and progesterone receptor(PR) status. Telomerase activity was not present in 5 cases of breast fibrocystic disease. Weak telomerase activity was detected in 4 of 9 cases of breast fibroadenoma. These suggested that telomerase activity acquires in very early stage of breast cancer. CONCLUSION: Telomerase activity is only detected in most of infiltration ductal carcinomas of breast and few cases of fibroadenoma. Telomerase activity may play an important role in the development of breast cancer.

Breast Neoplasms↗

PubMed2000

Angiogenin expression in human colorectal cancer: the role of focal macrophage infiltration.

Tumor angiogenesis is essential for tumor growth and tumor metastasis, and it depends on angiogenic factors produced by tumor cells and/or infiltrating cells in tumor tissue. In this study, we evaluated the clinical significance of the expression of angiogenin, which is a potent angiogenic protein, and the relationship between its mRNA expression and focal macrophage infiltration in colorectal cancer. Furthermore, we investigated the induction of angiogenin mRNA expression by proinflammatory cytokines mainly produced by inflammatory cells in tumor tissues. When we examined the relationship between the mRNA expression of angiogenin, by semiquantitative reverse transcription-PCR, and clinicopathological features in 65 patients with colorectal cancer, there was a significant difference in the vascular involvement, lymph node metastasis, liver metastasis, and advanced stage in patients with high-expression of angiogenin compared with low expression (P < 0.05). With regard to prognosis, the survival time for subjects in the high angiogenin mRNA group (tumor:normal ratio >1.9) was significantly worse (P < 0.05). When we examined the localization of angiogenin in colorectal cancer, immunohistochemical analysis in 65 patients with colorectal cancer revealed that angiogenin was predominantly expressed in cancer cells compared with stromal cells or normal tissues. The intensity of staining of angiogenin was significantly correlated with microvessel counts and focal macrophage infiltration counts (P < 0.05). In an in vitro study, interleukin-1beta and tumor necrosis factor-alpha induced angiogenin mRNA expression in colon cancer cells in a dose- and time-dependent manner, and these cytokines significantly upregulated the expression of angiogenin mRNA, especially in colon cancer cells rather than in other cells in the stroma of tumor tissues (fibroblasts, tumor infiltrating lymphocytes, macrophages). These results suggest that tumor angiogenesis in colorectal cancer may be advanced, at least in part, by angiogenin induced by proinflammatory cytokines derived from infiltrating macrophages.

Colorectal Neoplasms↗

PubMed2000

Effect of a novel anti-inflammatory compound, YM976, on antigen-induced eosinophil infiltration into the lungs in rats, mice, and ferrets.

We evaluated the effects of YM976, a selective inhibitor of phosphodiesterase type 4, on antigen-induced eosinophil infiltration into the lungs in rats, mice, and ferrets. In rats, YM976 inhibited the accumulation of eosinophils at an oral ED(50) value of 1.7 mg/kg, and in C57Black/6 mice, exhibited a dose-dependent inhibition at an ED(50) value of 5.8 mg/kg. In the same dose range in the same mouse model, YM976 suppressed interleukin-5 production. We then compared the inhibitory effect of chronic administration with that of single administration in another rat model of eosinophilia induced by repeated antigen exposure. YM976 administered chronically offered more potent inhibition (ED(50) = 0.32 mg/kg p.o.) than a single dose (1.4 mg/kg p.o.). These results indicated that chronic administration is more effective in antigen-induced eosinophilia than a single administration. Emetogenicity is known to be a major adverse effect of phosphodiesterase type 4 inhibitors. We compared the anti-inflammatory activity of YM976 with its emetic activity in ferrets, in which it dose dependently suppressed eosinophil infiltration at an ED(50) value of 1.2 mg/kg, but induced no emesis at 10 mg/kg. This suggested that the compound exhibits a considerable dissociation between its anti-inflammatory and emetic effects. In summary, YM976 inhibited eosinophil infiltration in a dose-dependent manner in rats, mice, and ferrets. In ferrets, it suppressed antigen-induced eosinophil infiltration without emesis. Additionally, we demonstrated that the inhibitory effect on eosinophil infiltration was increased by chronic administration. In conclusion, YM976 is a promising drug for the treatment of diseases involving eosinophil activity, such as asthma.

Animals↗