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Biomedical subjects

N Mafune

Publications and source records attributed to N Mafune.

18 recordsLinked to original sources
PubMed2004

Adenovirus-mediated CTLA4 immunoglobulin G gene therapy in cardiac xenotransplantation.

BACKGROUND: CTLA4 immunoglobulin (CTLA4 Ig), which binds with high affinity to B7-1 and B7-2, interrupts T-cell activation by inhibiting the costimulatory signal. CTLA4Ig has been used to achieve antigen-specific tolerance induction in cardiac allografts. On the other hand, we have shown that short-term administration of deoxyspergualin (DSG) and daily cyclosporine (CsA) induces long-term survival of cardiac xenotransplants. We hypothesized that the combination therapy of DSG and adenovirus-mediated CTLA4IgG might induce long-term, survival or tolerance in cardiac xenotransplantation. OBJECTIVES: Syrian hamster hearts were transplanted heterotopically into Lewis rats. We compared the survival time and immunopathology of the following five groups: (1) no treatment; (2) DSG (5 mg/kg per day intramuscularly [IM], days -1 to +7) alone; (3) CsA (15 mg/kg per day IM, day 0 to rejection) plus DSG; (4) AdexLacZ (LacZ-adenovirus 1 x 10(9) (PFU intravenously [IV], day -7) plus DSG; and (5) AdexCTLA4IgG (CTLA4IgG-adenovirus 1 x 10(9) PFU IV, day -7) plus DSG. RESULTS: The survival times were: (1) no treatment, 3.7 days; (2) DSG alone, 12.4 days; (3) CyA plus DSG, >100 days; (4) AdexLacZ plus DSG, 11.0 days; and (5) AdexCTLA4IgG plus DSG, 23.6 days. Adenovirus-mediated CTLA4IgG therapy with DSG prolonged survival time significantly compared with DSG alone or AdexLacZ plus DSG, but CTLA4IgG therapy was not as effective as CsA. Immunopathology showed the deposition of C3 and IgM on the endothelium in the AdexCTLA4IgG plus DSG group. CONCLUSIONS: We showed that the effectiveness of adenovirus-mediated CTLA4IgG gene therapy in cardiac xenotransplantation in less than that of CsA. Combination therapy with inhibition of the B7/CD28 constimulatory signal and DSG administration might not be sufficient for long-term survival or tolerance in cardiac xenotransplantation.

Abatacept↗
PubMed2001

Proinflammatory cytokines in cerebrospinal fluid in repair of thoracoabdominal aorta.

BACKGROUND: Little is known about alterations of cytokine levels in cerebrospinal fluid (CSF) during thoracoabdominal aortic surgery. We measured perioperative CSF cytokine levels to determine their clinical significances. METHODS: Perioperative serum and CSF levels of cytokine were measured in 15 adult patients undergoing repair of the descending thoracic aorta (n = 4) or thoracoabdominal aorta (n = 11). All patients underwent prosthetic replacement and perioperative CSF drainage. Serum and CSF levels of tumor necrosis factor-alpha, Interleukin- (IL-) 1beta, IL-6, IL-8, IL-10, and IL-12 were measured before operation and at 0, 6, 12, 18, 24, 48, and 72 hours postoperatively using enzyme-linked immunosorbent assays. RESULTS: There were no hospital deaths, but 1 patient suffered paraplegia. Cerebrospinal fluid IL-8 levels peaked at immediately after operation (751.7 +/- 42.1 pg/mL versus preoperative levels, 54.9 +/- 24.6 pg/mL; p < 0.001), and the higher levels persisted for 72 hours. In contrast, serum IL-8 levels did not change and remained lower than CSF levels. The patient with paraplegia had the highest CSF IL-8 levels throughout the study period. Serum and CSF levels of tumor necrosis factor-alpha, IL-1beta, IL-6, and IL-12 did not significantly change. Serum and CSF levels of IL-10 were significantly elevated after operation compared with preoperative levels. In contrast to IL-8, serum IL-10 levels surpassed CSF levels. CONCLUSIONS: Cerebrospinal fluid IL-8 levels are significantly elevated in thoracoabdominal aortic operation, and may be the most sensitive to the inflammatory response in the ischemic spinal cord injury. Persistent elevation of CSF IL-8 levels may be predictive of further development of neurologic deficits, and a reduction of proinflammatory cytokine levels may be a beneficial effect of CSF drainage, but this requires further investigation.

Adult↗
PubMed1999

Autoantibody to the liver arginase present in sera of patients with autoimmune hepatitis and chronic hepatitis.

We have reported previously that immunization of rat liver arginase in rabbits induced autoantibody that is reactive with their own liver arginase and has cytotoxic activity to their hepatocytes. This promoted us to investigate whether or not such an autoantibody is present in sera of patients with certain hepatic disorders, since the liver arginase is dominant in the liver and highly homologous in structure among ureotelic animals. By Western blot analysis, sera from patients with chronic hepatitis and autoimmune hepatitis were shown to have an autoantibody reacting with purified human liver arginase. Since the autoantibody was also reactive with liver arginase of rat origin to almost the same extent as that of human origin, ELISA with rat liver arginase as a coating antigen was developed and used for the quantification of the autoantibody. Prominent increase of the anti-liver arginase autoantibody was found in autoimmune hepatitis, moderate increase in chronic liver diseases, and no increase in acute hepatitis or normal controls by the ELISA. These results suggest that the increased anti-liver arginase autoantibody might involve in some parts in the pathophysiology of the hepatitic disorders. Assay of the autoantibody can also be utilized as a marker for the differentiation of certain hepatitis.

Adolescent↗
PubMed1996

Secretory component, the receptor for polymeric immunoglobulin, has nothing to do with beta-galactosyltransferase in human milk.

Secretory component (SC) in external secretions is a soluble form of the polymeric immunoglobulin-receptor that is expressed on the cell membrane of mucosal epithelial cells. beta-(1-4)galactosyl transferase (beta-GT) is an enzyme that transfers galactose to non-reducing N-acetylglucosamine residues on various glycoproteins and is present in a soluble form in secretions as well as in a membrane-bound form. beta-GT is considered to have affinity for glycoproteins, including IgA in secretion. It has been claimed that these two proteins are related to or identical with each other. In the present study, we defined that the SC and the beta-GT are each independent molecules by the following facts; (1) both molecules are separable either by antibody-affinity chromatography, conventional ion-exchange or molecular exclusion chromatography, (2) conventionally purified SC from human milk contained neither enzymatic activity or antigenic determinants of the beta-GT, (3) recombinant beta-GT does not show reactivity with antibodies to SC, and (4) the SC showed no reactivity with antibody to beta-GT.

Antibodies, Monoclonal↗
PubMed1995

Co-localization of amyloid-associated proteins with amyloid beta in rat soleus muscle in chloroquine-induced myopathy: a possible model for amyloid beta formation in Alzheimer's disease.

Chloroquine, a potent lysosomotropic agent, induces myopathy in experimental animals similar to rimmed vacuole (RV) myopathy in humans. The abnormal accumulation of amyloid beta protein (A beta), which is the invariable pathological alterations in the brains affected by Alzheimer's disease (AD), has been demonstrated in denervated soleus muscle fibers in chloroquine-induced myopathy in rats. In AD affected brains, a variety of additional proteins are associated with the extracellular deposition of A beta, which leads to the intracellular accumulation of neurofibrillary tangles and finally to neuronal death. In this study, we demonstrate that amyloid-associated proteins, alpha 1-antichymotrypsin, apolipoprotein E, SP-40,40 and ubiquitin co-localize with A beta in vacuolated muscle fibers in chloroquine-induced myopathy. There are striking similarities in immunopathology between experimental RV myopathy and AD. Chloroquine-induced myopathy in rats provides a suitable model not only to obtain insight into the basic mechanisms underlying RV formation in muscle, but also to understand amyloid precursor protein processing into A beta, and the role of amyloid-associated proteins in terms of the pathogenesis of AD.

Alzheimer Disease↗
PubMed1989

Pre-clinical studies on boron neutron capture therapy.

The present report provides an overview of the multidisciplinary research effort on BNCT that currently is in progress at The Ohio State University. Areas under investigation include the preparation of boron containing monoclonal antibodies, the synthesis of boron containing derivatives of promazines and phathalocyanines, the development of a rat model for the treatment of glioblastoma by means of BNCT, the design of an accelerator-based neutron irradiation facility, and 10B concentration measurements using alpha track autoradiographic methods. Progress in each of these areas is described and the direction of future research is indicated.

Animals↗
PubMed1989

Boron neutron capture therapy: linkage of a boronated macromolecule to monoclonal antibodies directed against tumor-associated antigens.

Two new protein-binding polyhedral boron derivatives, isocyanatoundecahydro-closo-dodecaborate(2-) (1) and isocyanato(trimethylamino)octahydro-closo-decaborate(1 -) (2), were synthesized. These anionic isocyanates have long hydrolysis half-lives at pH 7 and react readily with primary or secondary aliphatic amines resulting in spontaneous urea linkage. Utilizing 1, 1100 boron atoms (7.3% boron by weight) were incorporated per molecule of a polyclonal antibody directed against human thymocytes (anti-thymocyte globulin) without denaturation. However, immunoreactivity of the conjugates was lost. Reaction of 1 and 2 with polylysine yielded boronated macromolecules containing 21-28% boron by weight (up to 2000 boron atoms per molecule). Polylysine boronated with 2 was successfully linked to antibody molecules employing the heterobifunctional linking molecules N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP) and m-maleimidobenzoyl sulfosuccinimide ester (sulfo-MBS). Separation of the conjugated antibody from the free boronated macromolecules and unconjugated antibody molecules has been achieved by gel filtration on a Sephacryl S-300 column. By linking boronated polylysine to antibodies, greater than 10(3) boron atoms were incorporated with the attachment of this species to one or more sites on the antibody molecule. The resulting immunoconjugates contained greater than 10(3) boron atoms per molecule, retained their immunoreactivity, and potentially might be useful for the selective delivery of large numbers of boron atoms to tumor cells.

Animals↗
PubMed1985

Occurrence of cytotoxic autoantibody in rabbits by immunization with heterologous liver arginase: a possible implication in the mechanism of the autoimmune liver diseases.

Rat liver arginase was isolated from extracts of liver in a pure form. Monospecific antisera raised against the arginase reacted with arginase of liver but not with arginase of kidney, spleen, heart, lung, testis and brain. The antisera were, however, reactive with liver arginase of a variety of animals, including human, mouse, sheep, horse and cow as well as rabbit, a homologous animal used for immunization. The rabbit autoantibodies showed direct cytotoxic activity as well as antibody-dependent cell-mediated cytotoxicity to homologous rabbit hepatocytes. Immunocytochemical electron microscopic examination showed that the arginase was localized on the surfaces of rat hepatocytes and on intracellular organelles. These results suggest that liver arginase could be an important antigen of the liver with implications for the pathogenesis of autoimmune liver diseases.

Animals↗
PubMed1982

[Purification, characterization and clinical aspects of a liver specific antigen].

The early interest in the identification of human liver antigens relates to their potential value as serological markers of liver cell destruction and was confined mainly to those antigens which were tissue specific. Recently this interest has widened to include organ-specific antigens which could serve as possible targets of immune attack. In this respect, several liver-specific antigens have been reported. Those of current major interest are LSP (LP-I) and LP-II (Meyer zum Büschenfelde et al., 1972), LM-Ag (Meyer zum Büschenfelde et al., 1976) and F-antigen (Fravi et al., 1968). This investigation deals with the isolation, characterization and clinical aspects of a new liver specific antigen, the basic liver protein (BLP), which is different from those previously reported. Rat BLP has been purified from liver by a combination of ammonium sulfate fractionation, DEAE-cellulose column chromatography and affinity chromatography using the IgG fraction of rabbit anti-rat BLP serum. Human BLP has been also purified using essentially the same method. The purified rat and human BLP gave molecular weights of approximately 105,000 daltons on Sephadex G-200 gel filtration and 35,000 upon SDS-polyacrylamide gel electrophoresis. These results indicate that BLP exists as a trimer. Ammino acid analyses support this possibility. The isoelectric point of rat BLP was pH 8.5 and that of the human protein pH 8.1. The molecular weights, amino acid contents, isoelectric points and other biochemical characteristics of previously reported liver specific antigens differ significantly from those of rat and human BLP. Rabbit anti-rat BLP serum gave positive reactions with the liver extracts of other animals, including mouse, human, sheep, horse, cow and rabbit, but did not react with the extracts of other tissues. This indicates that rat and human BLP are organ specific proteins which are closely related to a similar protein in other species. BLP appeared within 6 hrs in the sera of rats following treatment CCl4, increased to a maximum at 36 hrs and disappeared within 72 hrs. These experiments suggest that serum BLP levels may serve as a measure of liver damage. The IgG fraction of rabbit anti-rat BLP serum inhibited the growth of fetal rat hepatocytes. Furthermore, rabbit antibody to rat BLP reacted with rabbit BLP. These latter results suggest that BLP may be involved in auto-immune liver disease. Thus, studies of BLP may serve to provide information on the extent of damage and the nature of auto-immune mechanisms in the liver.

Animals↗