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In 24 patients suffering from cerebrovascular diseases, alteration of the cerebral blood flow was investigated by means of the 133Xe clearance technique before and after the intravenous infusion of perfluorochemical suspension (Fluosol-DA, 20%, 10 ml/kg). Since perfluorochemicals exhibit high solubilities for not only oxygen but other kinds of gases, the partition coefficient of Xe (lambda tb) is considered to change depending on the amount of perfluorochemicals contained in the blood (Fct). The solubilities of Xe in the perfluorochemicals contained in the solution were then measured by gas chromatography to obtain an equation for lambda tb: lambda tb = 1.50/(Hct/100 + 12.48Fct/100 + 0.95). The cerebral blood flow was found to increase significantly by 10.1% in the lesional hemisphere and by 10.8% in the healthy one. The cortical small artery with a diameter between 0.1 and 0.2 mm appeared to dilate by 13% after its administration. From these results, the decrease of blood viscosity and some vasodilating effect of the solution might be responsible for the increase of the cerebral blood flow.

✓ Dissecting intracranial arterial aneurysms were identified in a 16-year-old girl and a 48-year-old man with moyamoya disease. Hemiplegia or tetraplegia rapidly developed. Angiography revealed bilateral stenoses or occlusion of the bifurcation of the internal carotid arteries (ICA's) and an unusual vascular network at the base of the brain. Autopsy confirmed massive hemorrhage from the thalamus and putamen, with intraventricular extension. The intracranial segments of both ICA's were markedly stenotic in both patients, due to eccentric fibroelastic intimal thickening. In one patient, a dissecting aneurysm was identified microscopically, involving the proximal segment of the left anterior cerebral artery. In the other patient, the right middle cerebral artery (MCA) was dissected beneath the internal elastic lamina along the entire length of the horizontal segment of the MCA. Thus, cerebral dissecting aneurysms may be present in patients with moyamoya disease.

A method for the heat treatment of human IgG solution at 60 degrees C for 10 h was established. Human immunodeficiency, mumps, vaccinia and 4 other viruses were added to the IgG solution in 33% sorbitol and heated at 60 degrees C. Those viruses were inactivated within 1 h. Heat-treated intravenous IgG (IVIG-H) was prepared by heat treatment and polyethylene glycol (PEG) fractionation. Conventional nonheated intravenous IgG (IVIG-C) was prepared from the same source paste by the fractionation method. No physicochemical or biological difference was observed between the heated and control IVIG preparations.

Corticosteroids which are incorporated in lipid emulsion are easily taken up by reticulo-endothelial system (RES) much more than free corticosteroids. In this study, the immunosuppressive effect of dexamethasone palmitate incorporated in lipid emulsion was compared with that of the free dexamethasone disodium phosphate. It showed that the antibody response in spleen to SRBC and DNP-Ficoll, the proliferative response of spleen cells to mitogens, DTH response to SRBC, ADCC activity of spleen cells and the effect on RES function in mice were strongly suppressed by dexamethasone palmitate incorporated in lipid emulsion when compared with the free corticosteroid. In addition, the effect in delaying mortality by preventing the spontaneous autoimmune disease of MRL/l mice was observed by the treatment with dexamethasone palmitate incorporated in lipid emulsion.From these results, dexamethasone palmitate incorporated in lipid emulsion is a potent long-acting immunosuppressant and is thought to be of value in the treatment of autoimmune disease such as idiopathic thrombocytopenic purpura (ITP) .

ペルフルオロオクチルブロミド(PFOB)は臭素原子を1個もつペルフルオロ化合物であり,X線遮蔽能をもつことから,造影剤としての応用が期待されている。Longらは,PFOB乳剤を担がん動物に投与し,腫瘍部位の造影に成功したと報告した。今回,著者らはAH130細胞とVX2 carcinomaの2種類の実験がんを用い,腫瘍造影剤としてのPFOB乳剤の可能性について検討した。AH130細胞を大腿部筋肉内に移植したラットにPFOB乳剤を投与し,投与後24時間目にX線撮影したところ,腫瘍の明瞭な造影籐が観察された。また,VX2 carcinomaを肝に移植した家兎に25w/v%PFOB乳剤を10ml/kg投与し,CT scanを行なった。肝正常組織にくらべ,腫瘍周辺部が高いdensityとして造影された。PFOB含量を測定した結果,周辺部に高濃度のPFOBが検出された。電子顕微鏡による組織学的検討からも,腫瘍周辺部に多数のマクロファージが存在し,そのマクロファージの中にPFOB粒子と思われる穎粒が多数散見され,特徴的な腫瘍のCT像がPFOB粒子の集積によることが明らかにされた。腫瘍造影剤としてのPFOBの有用性が確められた。

Electrochemical fluorination of 2-methoxy-1,1,1-trifluoro-2-(F-methyl) octane gave the corresponding perfluorinated ether in 27% yield, along with cyclic by-products in 9%. A mixture of partly fluorinated tertiary amines, consisting of 1-dipropylamino-F-1-propene and 1-dipropylamino-2-hydryl-F-propane, did not afford a superior yield of tri(F-propyl)amine compared to the unfluorinated tripropylamine. 1-Diethylamino-2-(F-methyl)-F-1-pentene was fluorinated to give the corresponding F-tertiary amine in fairly good yields, together with 1-di(F-ethyl)amino-2-hydryl-2-(F-methyl)-F-pentane and their fragmented products. The study indicates that blocking of the α-carbon atom of an ether with F-methyl groups seems to reduce fragmentation, resulting in good yields of an unrearranged product. However, partial fluorination of a tertiary amine prior to electrochemical fluorination rather allows high yields of undesired by-products, as far as our experiments were concerned.

Two series of bis [2- (E-2-alkenoylamino) ethyl] disulfides (compds. I) and 2- (E-alkenoyl-amino) ethyl carbamoylmethyl sulfides (compds. II) were synthesized from 2-trans unsaturated fatty acids (C6 : 1-C14 : 1) and cystamine, and their effects on carrageenin-induced paw edema were studied. Several of compds. I and II showed significant anti-edema activity at a dose of 25 mg/kg, i. p. These derivatives were much more potent than the starting materials. The alkene chain length influenced the activity. The compounds (compds. I-3, I-8, II-3 and II-8) with C8 : 1 and C13 : 1 fatty acids showed the highest activity in both series. Compounds I-3 and II-3 with the C8 : 1 fatty acid were also effective when administered orally at a dose of 10 mg/kg.

Electrochemical fluorination of N-cyclopentylpyrrolidine gave the corresponding F-amine together with a ring-opened compound N-(F-pentyI)-F-pyrrolidine in the ratio of 1 to 1, in 55% yield. N-cyclohexylpyrrolidine, N-cyclopentylpiperidine, and N-cyclohexylpiperidine were also eletrochemically fluorinated in the same manner to give the corresponding F-amines, their isomers with rearranged structures, and ring-opened ones, in the ratio of ca - 4:2:1, and 2:1:1, respectively in 51 to 53% yields. Supporting spectral data are presented.

Three potent antiulcerogenic compounds, cassioside : (4S)-2,4-dimethyl-3-(4'-hydroxy-3'-hydroxymethyl-1'-butenyl)-4-( β-D-glucopyranosyl)methyl-2-cyc cinnamoside : (3R)-4- [(2'R, 4'S)-2'-hydroxy-4'-(β-D-apiofuranosyl-(1 →6)-β-D-glucopyranosyl)-2',6',6'-trimethylcyclo-hexylidene ] -3-buten-2-one and 3,4,5-trimethoxyphenol-β-D-apiofuranosyl-(1 →6)- β-D-glucopyranoside were isolated from a hot water extract of Cinnamomi Cortex ( the dried stem bark of Cinnamomun cassia Blume ) and their structures were determined.

Two active compounds that prevent serotonin-induced ulcerogenesis in rats were isolated from Chinese cinnamon (the stem bark of Cinnamomum cassia) and identified as 3-(2-hydroxyphenyl)-propanoic acid and its O-glucoside. The former compound, administered orally or parenterally to rats at a remarkably low dose (40 micrograms/kg body weight), also inhibited gastric ulcers induced by the other ulcerogens such as phenylbutazone, ethanol, and water immersion stress, although it failed to prevent indomethacin-induced ulcers. Pharmacological studies have shown that 3-(2-hydroxyphenyl)-propanoic acid hardly inhibited the secretion of gastric acid, but promoted the gastric blood flow. These results suggest that the antiulcerogenic effect of this compound is probably attributable to the potentiation of defensive factors through the improvement of the circulatory disorder and gastric cytoprotection.

Commercially available human serum immunoglobulin G (IgG, native IgG) was separated into two fractions (Fr.I and II) using a diethylaminoethyl cellulose column. Heavy and light chains containing fractions were obtained from these two fractions after carboxamide-methylation. Thus, these fractions were subjected to an anti-inflammatory screening procedure and were shown to have a potent inhibitory activity against rat carrageenin induced paw edema, while no effect was observed in native IgG, Fr.I or II. The reduction and alkylation of the interchain disulfide bonds were essential to induce the anti-inflammatory activity. The anti-inflammatory activity of alkylated heavy and light chains of Fr.I (Fr.I-H and I-L) was also noted in subacute inflammation caused by the felt pellet and croton oil granuloma methods. Moreover, strong membrane stabilizing activities of Fr.I-H and I-L were demonstrated in vitro using rat red blood cell membrane and liver lysosomal membrane.

Before HBsAg screening of plasma was instituted, the preventive effect of immunoglobulin preparations (ISG) against Hepatitis B was not clearly defined. Since HBsAg screening became a requirement, all ISG has shown Anti-HBs and it further became clear that such preparations are effective in preventing Hepatitis B.Recently, cases of Hepatitis NANB associated with administration of intravenous immunoglobulin (IVIG) were reported. Since there is no NANB screening test presently available and IVIG tends to be administered in a large volume, a virus inactivation treatment should be performed on IVIG.Now that heat treatment at 60°C for 10 hours, which had previously been considered to be impossible or unnecessary for immunoglobulin, has become possible, an intravenous immunoglobulin preparation which is more ideal in stability and safety is available.

Immunoglobulin G from human serum was digested with papain to give an Fc fragment, which was carboxamidemethylated [carboxamidemethylated Fc (CM-Fc), M.W. about 25000].Types I, III and IV allergic reactions were significantly depressed by the administration of CM-Fc.

In order to study the relationship between the structure of pro-urokinase (pro-UK) and its clearance rate from circulation, three epidermal growth factor (EGF)-like domain deleted pro-UK mutants were constructed. Δ10–42, pro-UK, Δ10–45 pro-UK, and Δ10–49 pro-UK lacking Asn-10—Cys-42, Asn-10—Asp-45, and Asn-10—Thr-49, respectively, were compared with natural and recombinant pro-UKs (n-pro-UK and r-pro-UK) in terms of amidolytic activity and plasma clearance rate. Each pro-UK mutant gave almost the same enzymatic constants as n- and r-pro-UKs in terms of amidolytic activity. When 125I-labelled pro-UK and its derivatives were intravenously injected into rats, the clearance rate of pro-UK derivatives lacking EGF-like domain was significantly prolonged compared with those carrying intact EGF-like domain; for instance, the half-lives of Δ10–42 pro-UK, Δ10–45 pro-UK and Δ10–49 pro-UK were 8.2 ± 1.5 min, 6.3 ± 0.3 min and 7.1 ± 0.3 min, respectively, while those of n- and r-pro-UKs were 1.6 ± 0.1 min and 2.3 ± 0.0 min. Therefore, it is suggested that the pro-UK molecule is partially recognised and cleared by hepatic cells through EGF-like domain.

The effect of perfluorochemical (PFC) emulsion (25 w/v per cent of PFC concentration) on carbon monoxide poisoning was studied in rats exposed to 97 per cent O2 and three per cent CO. There was no significant difference in conversion rate of hemoglobin to carboxyhemoglobin (COHb) between PFC emulsion and saline groups. However, after re-exposure to pure oxygen, PFC emulsion group circulation reconverted to oxyhemoglobin (OXYHb) at a significantly faster rate than circulation in the control group. Survival time of rats was considerably affected by infusion of PFC emulsion and prolonged in proportion to increased injection dosage. Significant elevations in plasma glucose, lactate and aldolase levels and lactate/pyruvate ratio were found in the saline group and these levels remained well within normal range in the PFC emulsion group. These results indicate that PFC emulsion can function as an oxygen carrier in the presence of carbon monoxide and can deliver sufficient oxygen to peripheral tissues.

Objectives To compare the significance of the two-compartment model, considering diffusional anisotropy with conventional diffusion analyzing methods regarding the detection of occult changes in normal-appearing white matter (NAWM) of multiple sclerosis (MS). Methods Diffusion-weighted images (nine b-values with six directions) were acquired from 12 healthy female volunteers (22–52 years old, median 33 years) and 13 female MS patients (24–48 years old, median 37 years). Diffusion parameters based on the two-compartment model of water diffusion considering diffusional anisotropy was calculated by a proposed method. Other parameters including diffusion tensor imaging and conventional apparent diffusion coefficient (ADC) were also obtained. They were compared statistically between the control and MS groups. Results Diffusion of the slow diffusion compartment in the radial direction of neuron fibers was elevated in MS patients (0.121 × 10−3 mm2/s) in comparison to control (0.100 × 10−3 mm2/s), the difference being significant (P = 0.001). The difference between the groups was not significant in other comparisons, including conventional ADC and fractional anisotropy (FA) of diffusion tensor imaging. Conclusion The proposed method was applicable to clinically acceptable small data. The parameters obtained by this method improved the detectability of occult changes in NAWM compared to the conventional methods. Key Points • Water diffusion was compared between the controls and multiple sclerosis patients. • A two-compartment model, considering diffusional anisotropy was selected for water diffusion analysis. • Axial and radial diffusion of fast and slow diffusion components were evaluated. • A new method was developed to obtain the metrics stably. • The metrics indicated high detectability of slight differences between the groups.

The present investigation was done to examine whether or not the presence of hydroxyproline in N-3-(4-hydroxyphenyl) propionyl Pro-Hyp-Gly-Ala-Gly (HP-5) is essential for the antiarrhythmic activity. Pretreatment of mice with 10 mg/kg of [Pro2]-HP-5 provided significantly better protection against calcium-induced arrhythmias than did pretreatment with HP-5. Thus, the prolyl residue was more favorable than the hydroxyprolyl residue for antiarrhythmic activity of these analogues.

Bis[2-[(E)-2-octenoylamino]ethyl] disulfide (compd. I-3) inhibited collagen- and arachidonic acid-induced rat platelet aggregation, although not adenosine 5'-diphosphate (ADP)-induced rat platelet aggregation. Based on these results, we then investigated the inhibitory effect of compd. I-3 on thromboxane B2 formation from arachidonic acid in rat platelets, and prostaglandin I2 formation in rat aortae. Compound I-3 inhibited both thromboxane B2 and prostaglandin I2 formation, suggesting that it has an inhibitory effect on cyclooxygenase. The inhibitory effect of compd. I-3 was confirmed in experiments using a crude preparation of sheep seminal vesicle microsomal prostaglandin synthetase. These findings suggested that compd. I-3 has an inhibitory effect on cyclooxygenase activity, like nonsteroidal anti-inflammatory drugs.

In order to increase the antiarrhythmic activity of Pro-Hyp-Gly-Ala-Gly (P-5), P-5 analogues with three different hydrophobic substituents, N-3- (4-hydroxyphenyl) propionyl (H), N-3-phenyl-propionyl (I) and N-3-phenylpropyl (P), were prepared and their activities were evaluated in CaCl2-induced arrhythmias in mice. HP-5 showed potent antiarrhythmic activity at 1 mg/kg, i.v. and its potency was much higher than that of P-5 at 10 mg/kg, i.v. IP-5 showed similar potency to P-5, but PP-5 was inactive. Pro-Hyp-Gly-Ala, Pro-Hyp-Gly and Pro-Hyp with the substituent, H, were also ineffective. Thus, 3- (4-hydroxyphenyl) propionylation of the imino nitrogen of Pro in P-5 led to increased potency.

Various caffeic acid derivatives were synthesized, and their effects on 5-lipoxygenase (5-LO), 12-lipoxygenase (12-LO) and prostaglandin (PG) synthase activities were investigated. Among them, caffeic acid octyl amide (5) and 1-(3,4-dihydroxyphenyl)-1-octen-3-one (11) showed very potent inhibitory activities toward 5-LO with IC50 values of 4.2 x 10(-8) and 3.5 x 10(-8) M, respectively. They were very selective inhibitors for 5-LO. Compound 11 showed non-competitive inhibition, and the two adjacent hydroxy groups attached to the benzene ring, as well as the hydrophobic alkyl side chain, were required for its strong binding to 5-LO.

Three potent antiulcerogenic compounds, cassioside : (4S)-2,4-dimethyl-3-(4'-hydroxy-3'-hydroxymethyl-1'-butenyl)-4-( β-D-glucopyranosyl)methyl-2-cyc cinnamoside : (3R)-4- [(2'R, 4'S)-2'-hydroxy-4'-(β-D-apiofuranosyl-(1 →6)-β-D-glucopyranosyl)-2',6',6'-trimethylcyclo-hexylidene ] -3-buten-2-one and 3,4,5-trimethoxyphenol-β-D-apiofuranosyl-(1 →6)- β-D-glucopyranoside were isolated from a hot water extract of Cinnamomi Cortex ( the dried stem bark of Cinnamomun cassia Blume ) and their structures were determined.

To choose a perfluorochemical as a candidate for the artificial erythrocyte or organ perfusate, screening of perfluorochemicals was performed from the standpoints of persistence of them in the circulation and deposition in the body tissues of rabbits, mice and rats. In view of elimination from the body, perfluorodecalin was found to be the most suitable compound among five different perfluorochemicals examined. As for emulsifiers, egg yolk phospholipid was found to be the first choice on account of its ability to sustain perfluorochemicals for an adequate period in the circulation as well as the feasibility for preparing emulsion among the three emulsifiers examined. It was found also that the smaller the particle size of emulsion, the better suited for an artificial erythrocyte of perfusate.

Adriamycin linked to oxidized dextran (ADM-OXD) via Schiff's base formation was compared with free adriamycin with regard to antitumor activity, acute toxicity and plasma pharmacokinetics in rats following i.v. administration. ADM-OXD showed higher activity against Walker carcinosarcoma 256 than free adriamycin. On the other hand, the acute toxicity of ADM-OXD was about three times less than that of free adriamycin. In contrast to free adriamycin, a very high plasma level of adriamycin was found after i.v. administration of ADM-OXD. The area under the plasma concentration curve with ADM-OXD was about 160-fold higher than with free adriamycin. Thus, the improvement of the therapeutic index in the case of ADM-OXD might be due to the difference in the disposition of ADM-OXD and free adriamycin in rats.

Using the xylene ear method in mice, it was demonstrated that the reduced and carboxamide-methylated fragments of human serum IgG (Fr. I-H and Fr. I-L) significantly suppressed capillary permeability. It was also shown that leucocyte emigration and protein leakage into and esterase activity of the pouch fluid, which was accumulated by carboxy-methyl cellulose injections, were suppressed by the administration of the fragments. Moreover, the lipid peroxide level was lowered by both Fr. I-H and Fr. I-L in the liver of either carrageenin-induced, paw edema-bearing or kaolin pouch inflammation in rats. The facts obtained in this study indicated the mechanisms of the anti-inflammatory effects of Fr. I-H and Fr. I-L were mainly caused by both the inhibitory effect on leucocyte emigration into the site of injury and stabilization of the membrane by inhibiting lipid peroxidation of the inflammatory tissue.

Distribution of plasma fibronectin in Yoshida sarcoma-bearing rats was studied. Fibronectin from human plasma labelled with 125I was administered intravenously to the tumor bearing-rats. The ratios of specific radioactivity (cpm/g) of the tumor to that of blood or liver increased in the time course after the administration. Consequently, 48 h later, the tumor/blood and the tumor/liver ratios were estimated to be 4.6 and 2.8, respectively. In contrast, the liver/blood ratio did not increase during the experimental period. Similar results were also obtained by the administration of fibronectin from rat plasma. Whole-body autoradiography also suggested such a selective distribution. However, 125I-labelled albumin was not localized in the tumor.

As a part of studies on perfluorochemicals for candidate as an artificial blood, the elimination of six kinds of the substance was studied to find the way and type of excretion in rats given their emulsions intravenously. (1) These compounds are solely excreted through expiration, none through urinary and biliary with an exception of FC-43 (perfluorotrifbutylamine. (2) The elimination curves of these compounds from the body appear to be exponential). (3) The elimination rate of each substance was fairly related to its vapor pressure, the higher, the more rapidly eliminated. (4) Within six compounds examined sofar, FDC (perfluorodecalin) is selected on account of its rapid elimination.

Further studies on the pharmacological effect of orally administered bis[2-(E-2-octenoyl-amino)ethyl] disulfide (compd. I-3) was examined by using several experimental models in vivo. Compound I-3 showed analgesic activity, inhibiting both acetic acid- and acetylcholine-induced writhings in mice. This compound also showed antipyretic activity against yeast-induced fever in rats, and significantly inhibited arachidonic acid-induced mortality in mice. However, it had no effect on serotonin-induced paw edema formation or platelet activating factor-acether-induced mortality in mice. The effects of compd. I-3 are suggested to be due to inhibition of prostaglandin biosynthesis.

Although clonal expansion of autoimmune T cells has been reported in multiple sclerosis (MS), very limited information is available on specificities, clonal size, or activation state of the expanded clones. Here we address the issue of clonal expansion by using a novel technique demonstrating clonotypes defined by single-strand conformation polymorphism of TCR β-chain cDNAs. Examination of activated T cells (CD3+CD25+) isolated from the peripheral blood of MS revealed limited numbers (20∼82) of expanded clones defined by single-strand conformation polymorphism clonotype. To estimate the Ag specificities of dominant clonotypes in the activated T cells, these samples were examined in parallel with Th1 T cell clones specific for myelin basic protein or proteolipid protein (PLP) derived from the same patients. Analysis of two patients demonstrated that the dominant clonotypes would contain those specific for myelin basic protein or PLP. Although the majority of the clonotypes could be detected only transiently, a PLP95–116-specific clonotype was found to persist for over 1 yr. Thus, single-strand conformation polymorphism clonotype analysis allows us to monitor the kinetics of given T cell clones in vivo and could provide useful information for designing clonotype (Id)-specific manipulation of human diseases such as MS.

BACKGROUND AND PURPOSE: T1 and T2 values and proton density can now be quantified on the basis of a single MR acquisition. The myelin and edema in a voxel can also be estimated from these values. The purpose of this study was to evaluate a multiparametric quantitative MR imaging model that assesses myelin and edema for characterizing plaques, periplaque white matter, and normal-appearing white matter in patients with MS. MATERIALS AND METHODS: We examined 3T quantitative MR imaging data from 21 patients with MS. The myelin partial volume, excess parenchymal water partial volume, the inverse of T1 and transverse T2 relaxation times (R1, R2), and proton density were compared among plaques, periplaque white matter, and normal-appearing white matter. RESULTS: All metrics differed significantly across the 3 groups (P < .001). Those in plaques differed most from those in normal-appearing white matter. The percentage changes of the metrics in plaques and periplaque white matter relative to normal-appearing white matter were significantly more different from zero for myelin partial volume (mean, −61.59 ± 20.28% [plaque relative to normal-appearing white matter], and mean, −10.51 ± 11.41% [periplaque white matter relative to normal-appearing white matter]), and excess parenchymal water partial volume (13.82 × 10(3) ± 49.47 × 10(3)% and 51.33 × 10(2) ± 155.31 × 10(2)%) than for R1 (−35.23 ± 13.93% and −6.08 ± 8.66%), R2 (−21.06 ± 11.39% and −4.79 ± 6.79%), and proton density (23.37 ± 10.30% and 3.37 ± 4.24%). CONCLUSIONS: Multiparametric quantitative MR imaging captures white matter damage in MS. Myelin partial volume and excess parenchymal water partial volume are more sensitive to the MS disease process than R1, R2, and proton density.

To the Editor.— Trouble with object naming has been associated with alexia without agraphia, 1 but has received only limited attention. 2 We report a typical case of alexia without agraphia but with transient anomia for visually presented objects. Report of a Case.— A 58-year-old, righthanded, diabetic man was admitted to the hospital because of blurred vision and difficulty in reading. There was dense, rightsided hemianopsia of the left eye. Visual acuity was 10/20 OS with blindness in the right eye because of traumatic cataract. His conversational speech was almost normal. Reading ability was completely impaired. His writing was substantially superior to reading. Kinesthetic reading was considerably better. Half of all visually presented objects were semantically misnamed, but periphrased and appropriately defined. Once objects were handled, he could name almost all. Six months later, object naming greatly improved, but the alexia remained. The patient died a year later of pontine

Programmed death-1 (PD-1) is a known immunoinhibitory receptor that contributes to immune evasion of various tumor cells and pathogens causing chronic infection, such as bovine leukemia virus (BLV) infection. First, in this study, to establish a method for the expression and functional analysis of bovine PD-1, hybridomas producing monoclonal antibodies (mAb) specific for bovine PD-1 were established. Treatment with these anti-PD-1 mAb enhanced interferon-gamma (IFN-γ) production of bovine peripheral blood mononuclear cells (PBMC). Next, to examine whether PD-1 blockade by anti-PD-1 mAb could upregulate the immune reaction during chronic infection, the expression and functional analysis of PD-1 in PBMC isolated from BLV-infected cattle with or without lymphoma were performed using anti-PD-1 mAb. The frequencies of both PD-1+ CD4+ T cells in blood and lymph node and PD-1+ CD8+ T cells in lymph node were higher in BLV-infected cattle with lymphoma than those without lymphoma or control uninfected cattle. PD-1 blockade enhanced IFN-γ production and proliferation and reduced BLV-gp51 expression and B-cell activation in PBMC from BLV-infected cattle in response to BLV-gp51 peptide mixture. These data show that anti-bovine PD-1 mAb could provide a new therapy to control BLV infection via upregulation of immune response.