研究者詳細 - 丸山　彰一

論文 - 丸山　彰一

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Membranous glomerulopathy with Bowman's capsular and tubular basement membrane deposits. 査読有り

Markowitz GS, Kambham N, Maruyama S, Appel GB, Cohen DJ, Kim RC, Andres GA, D'Agati VD.

Clin Nephrol. 54 巻 ( 6 ) 頁： 478 - 486 2000年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Bowman's capsular and tubular basement membrane (TBM) deposits are an extremely unusual finding in non-lupus membranous glomerulopathy (MGN). We report three atypical cases of MGN with abundant Bowman's capsular and TBM deposits. In two cases, MGN was idiopathic; in the third case, MGN occurred in the renal allograft in the setting of HCV seropositivity. In addition to the usual glomerular capillary wall deposits, immunofluorescence and electron microscopy revealed extensive immune deposits within Bowman's capsule and TBMs, predominantly at the base of parietal and tubular epithelial cells. These cases suggest a potential pathomechanism of autoantibody to secreted epithelial antigens shared by visceral, parietal, and tubular epithelial cells. In all three cases, indirect immunofluorescence was unable to detect autoantibody to normal renal epithelial or matrix constituents. Furthermore, ELISA was unable to demonstrate circulating antibody to major extracellular matrix components. The implications of these findings for the pathogenesis of MGN are explored.

PubMed

Role of platelet-activating factor in functional alterations induced by xenoreactive antibodies in porcine endothelial cells. 査読有り

Biancone L, Cantaluppi V, Segoloni G, Boccellino M, Del Sorbo L, Conaldi PG, Tjoelker LW, Maruyama S, Cantu E, Stern D, Andres G, Camussi G.

Transplantation. 70 巻 ( 8 ) 頁： 1198 - 1205 2000年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Platelet-activating factor (PAF) is a phospholipid mediator of inflammation which has been implicated in rejection. The interaction of anti-alpha-galactosyl natural antibodies (anti-alpha gal Abs) with endothelial cells is the initial step for the development of xenograft rejection. In our study, we stimulated porcine aortic endothelial cells (PAEC) with anti-alpha gal IgG to investigate the synthesis of PAF from PAEC and its biological consequences. METHODS AND RESULTS: PAF was extracted and chromatographically purified from cultured PAEC stimulated with baboon anti-alpha gal Abs. The Abs induced a dose-dependent synthesis of PAF peaking after 30 min of incubation, and decreasing thereafter. Concomitant cell shape change, motility, and cytoskeleton redistribution were observed. These events were prevented by addition of a panel of PAF-receptor antagonists. An SV40 T-large antigen-immortalized PAEC line was engineered to express PAF acetyl-hydrolase (PAF-AH) cDNA, the major PAF-inactivating enzyme. These transfected cells exposed to anti-alpha gal Abs showed reduced cell contraction and motility compared with empty vector-transfected cells. Moreover, in PAEC stimulated with anti-alpha gal Abs, the synthesis of PAF promoted the adhesion of a monocytic cell line as shown by the inhibitory effect of PAF-receptor antagonists and of PAF-AH expression. Finally, studies on cell monolayer demonstrated an enhanced permeability 48 hr after exposure to anti-alpha gal Abs, and this increase was prevented by PAF-inactivation and by PAF-receptor blockade. CONCLUSIONS: These results demonstrate that on stimulation with anti-alpha gal Abs, PAEC synthetize PAF which can contribute to several vascular events involved in xenograft rejection.

DOI： 10.1097/00007890-200010270-00013

PubMed

alpha-galactosyl epitopes on glycoproteins of porcine renal extracellular matrix. 査読有り

Maruyama S, Cantu E 3rd, Galili U, D'Agati V, Godman G, Stern DM, Andres G

Kidney Int. 57 巻 ( 2 ) 頁： 655 - 663 2000年2月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: The pig is the donor animal of choice for human xenotransplantation. In the most relevant pig-to-baboon model, pig organs transplanted into baboons are hyperacutely rejected by natural xenoantibodies, which mainly bind to alpha-galactosyl (alphaGal) epitopes expressed at the surface of endothelial cells. Recent advances in controlling hyperacute rejection have led to improved survival of these xenografts, and it is now important to identify alphaGal binding sites in other cells and tissues that may be subject to immunologic attack. To this end, we have studied whether alphaGal antibodies bind to glycated proteins of the extracellular matrix in the kidney and other organs most likely to be used for human xenotransplantation. METHODS: High-titer anti-alphaGal antibodies, similar to human natural xenoantibodies, were prepared in baboons, and their reactivity with components of pig extracellular matrix was tested by serology and immunohistology. RESULTS: The antibodies recognized epitopes of immobilized murine, bovine or porcine thyroglobulin, laminin, heparan sulfate proteoglycans, and fibronectin. In sections of pig tissue, the antibodies bound to endothelial and certain epithelial cells, as shown in previous studies, and also to mesenchymal cells, basement membranes, and extracellular matrices, in which they colocalized with matrix glycoproteins, especially laminin and heparan sulfate proteoglycans. CONCLUSIONS: These results suggest that when pig xenografts can be made to survive for prolonged periods, the reactivity of alphaGal antibody with matrix molecules can induce basement membrane and matrix lesions similar to those induced in laboratory animals by antilaminin and antiheparan sulfate proteoglycans antibodies.

DOI： 10.1046/j.1523-1755.2000.00887.x

PubMed

Differential expression of alpha-GAL epitopes (Galalpha1-3Galbeta1-4GlcNAc-R) on pig and mouse organs. 査読有り

Tanemura M, Maruyama S, Galili U

Transplantation. 69 巻 ( 1 ) 頁： 187 - 190 2000年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Expression of the alpha-gal epitope in mice can be completely eliminated by disruption of the alpha1,3 galactosyltransferase gene. As an initial step for assessing the feasibility of this approach in the pig, it was of interest to compare the expression of alpha-gal epitopes in pig and mouse organs. METHODS: Membranes from pig and mouse organ homogenates were analyzed for alpha-gal epitope expression by Western blots, enzyme-linked immunosorbent assay (ELISA), immunostaining of tissues, and ELISA inhibition assay. RESULTS: Immunostaining of Western blots with human anti-Gal detected alpha-gal epitopes on glycoproteins from pig organs but not on glycoproteins from the corresponding mouse organs. ELISA with membrane homogenates and immunostaining of tissue sections demonstrated a much higher binding of human anti-Gal to alpha-gal epitopes on pig membranes than on mouse membranes. ELISA inhibition assay with monoclonal anti-Gal indicated that alpha-gal epitope expression in pig organs is up to 500-fold higher than in mouse organs. CONCLUSION: Expression of alpha-gal epitopes in pig organs is many fold higher than in mouse organs. The abundance of these epitopes in pigs raises the question of whether pigs can properly develop without expression of alpha-gal epitopes.

DOI： 10.1097/00007890-200001150-00034

PubMed

Interaction of baboon anti-alpha-galactosyl antibody with pig tissues. 査読有り

Maruyama S, Cantu E 3rd, DeMartino C, Wang CY, Chen J, Al-Mohanna F, NakeebSM, D'Agati V, Pernis B, Galili U, Godman G, Stern DM, Andres G

Am J Pathol. 155 巻 ( 5 ) 頁： 1635 - 1649 1999年11月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

As barriers to xenotransplantation are surmounted, such as suppression of hyperacute rejection allowing improved graft survival, it becomes important to define longer-term host-xenograft interactions. To this end we have prepared in baboons high titer anti-alpha-Galactosyl (alphaGal) and anti-porcine aortic endothelial cell antibodies, similar to human natural xenoantibodies and reactive with epitopes of thyroglobulin, laminin, and heparan sulfate proteoglycans. When injected into pigs with a protocol similar to that used in the rat to show the nephritogenic potential of heterologous anti-laminin and anti-heparan sulfate proteoglycan antibodies, baboon immunoglobulins bound first to renal vascular endothelium, and later to interstitial cells, especially fibroblasts and macrophages, and to antigens in basement membranes and extracellular matrix, where they colocalized with laminin- and heparan sulfate proteoglycan-antibodies, and with bound Griffonia simplicifolia B4. A similar binding was observed in other organs. The pigs did not develop an acute complement-dependent inflammation, but rather chronic lesions of the basement membranes and the extracellular matrix. Incubation of renal fibroblasts with baboon anti-alpha-Galactosyl antibodies resulted in increased synthesis of transforming growth factor-beta and collagen, suggesting a possible basis for the fibrotic response. The results demonstrate that in this experimental model a consequence of alphaGal antibody interaction with porcine tissues, is immunoreactivity with alphaGal on matrix molecules and interstitial cells, priming mechanisms leading to fibrosis resembling that in chronic allograft rejection. The possibility that similar lesions may develop in long-surviving pig xenografts is discussed.

DOI： 10.1016/s0002-9440(10)65479-x.

PubMed

Membranous glomerulonephritis induced in the pig by antibody to angiotensin-converting enzyme: considerations on its relevance to the pathogenesis of human idiopathic membranous glomerulonephritis. 査読有り

Maruyama S, Cantu E 3rd, Demartino C, Vladutiu A, Caldwell PR, Wang CY,D'Agati V, Godman G, Stern DM, Andres G

J Am Soc Nephrol. 10 巻 ( 10 ) 頁： 2102 - 2108 1999年10月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

In the course of studies on the humoral consequences of swine to primate xenotransplantation, the investigators induced formation of glomerular subepithelial immune deposits and tubular lesions in pigs injected with heterologous antibody to angiotensin-converting enzyme. This study describes the morphology of the lesions, discusses their mechanism, explains their relevance for understanding the pathogenesis of human idiopathic membranous glomerulonephritis, and proposes future directions for investigations.

DOI： 10.1681/ASN.V10102102

PubMed

Alpha-galactosyl antibody redistributes alpha-galactosyl at the surface of pig blood and endothelial cells. 査読有り

Maruyama S, Cantu E3rd, Pernis B, Galili U, Godman G, Stern DM, Andres G

Transpl Immunol. 7 巻 ( 2 ) 頁： 101 - 106 1999年6月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

The interaction of antibodies with cell surface antigens may induce redistribution of immune complexes, followed by antigen depletion, with increased resistance to injurious effect of antibody and complement (antigenic modulation). Human natural antibodies to Gal alpha 1,3Gal beta 1,4GlcNAc-R (alpha Gal) epitopes expressed at the surface of pig cells are a major obstacle to xenotransplantation. Recent studies have shown that these antibodies do not modulate alpha Gal, but the morphological consequences of the antigen-antibody interaction are unknown. Pig blood and endothelial cells, were exposed to baboon alpha-Gal antibodies, and studied by immunofluorescence and phase contrast microscopy, flow cytometry, and inhibition enzyme-linked immunosorbent assay. In cells studied at 4 degrees C or fixed, alpha Gal was diffusely expressed at the surface. After cross-linking at 37 degrees C, antigenic modulation did not occur, but granular redistribution of alpha Gal immune complexes was seen in all cell types. In other systems a similar redistribution is known to induce perturbation of the plasma membrane/cytoskeletal structure with changes in adhesive properties, gene regulation, and T cell activation, which could be important if pig xenografts will be made to survive for prolonged periods.

DOI： 10.1016/s0966-3274(99)80026-4

PubMed

Role of complement in acute tubulointerstitial injury of rats with aminonucleoside nephrosis. 査読有り

Nomura A, Morita Y, Maruyama S, Hotta N, Nadai M, Wang L, Hasegawa T, Matsuo S

Am J Pathol. 151 巻 ( 2 ) 頁： 539 - 547 1997年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

The present work was designed to elucidate the in vivo role of complement in the proteinuria-associated tubulointerstitial injury. Rats were intravenously injected with puromycin aminonucleoside, and massive proteinuria was observed within 5 days. Prominent tubulointerstitial injury characterized by proximal tubular degeneration, tubular dilatation, and leukocyte infiltration were observed 7 days after injection. C3 and C5b-9 were observed in the luminal side of proximal tubular cells. Renal function, assessed by inulin and para-aminohippurate clearance, was significantly decreased. To-assess the role of complement in this model, rats were injected with either cobra venom factor or soluble recombinant human complement receptor type 1 starting at day 3. These manipulations significantly improved tubulointerstitial pathology and para-aminohippurate clearance without affecting the degree of proteinuria. Deposition of C3 and C5b-9 was not detected in the kidney of rats depleted of complement by cobra venom factor. In rats treated with soluble complement receptor, C3 was still detected in the tubules, but deposition of C5b-9 was not observed. Soluble complement receptor was detected at the site of C3 deposition and in the urine. These data strongly suggest that complement plays a pivotal role in proteinuria-associated tubulointerstitial injury and that systemic complement depletion or inhibition of complement in the tubular lumen may diminish the tubulointerstitial damage.

PubMed

Detection of ret homodimers in MEN 2A-associated pheochromocytomas. 査読有り

Wada M, Asai N, Tsuzuki T, Maruyama S, Ohiwa M, Imai T, Funahashi H, Takagi H, Takahashi M

Biochem Biophys Res Commun 218 巻 ( 2 ) 頁： 606 - 609 1996年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Using transfection of NIH 3T3 cells, we have recently demonstrated that multiple endocrine neoplasia (MEN) 2A mutations activate the c-Ret protein by inducing its disulfide-linked homodimerization on the cell surface. To investigate whether the homodimers are present in original tumors, the expression of the c-Ret protein was analyzed in eight sporadic and two MEN 2A-associated pheochromocytomas, the latter two of which contained mutations in cysteine 618 or 634 of Ret. The c-Ret protein was expressed at variable levels in all pheochromocytomas examined. By labeling the c-Ret protein immunoprecipitated from tumor tissues with [gamma-32P]ATP in vitro, its homodimers were detected in pheochromocytomas from MEN 2A patients but not in a sporadic tumor. This result represents the first demonstration of Ret homodimers in original tumors.

DOI： 10.1006/bbrc.1996.0107

PubMed

Germ line mutations of the ret proto-oncogene in Japanese patients with multiple endocrine neoplasia type 2A and type 2B. 査読有り

Maruyama S, Iwashita T, Imai T, Funahashi H, Ceccherini I, Luo Y, Romeo G, Matsuo S, Matsuyama M, Takahashi M

Jpn J Cancer Res 85 巻 ( 9 ) 頁： 879 - 882 1994年9月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

We investigated mutations of the ret proto-oncogene in Japanese patients with multiple endocrine neoplasia (MEN) type 2A and type 2B. DNAs from pheochromocytomas and/or medullary thyroid carcinomas (MTCs) of five MEN 2A and three MEN 2B patients were amplified by a polymerase chain reaction (PCR) and analyzed. Tumors of four MEN 2A patients had missense mutations in Cys 634 in the extracellular domain of the ret proto-oncogene. The same mutations were detected in normal tissues of the patients, indicating that the mutations had arisen in the germ line. Using a reverse transcriptase(RT)-PCR, both normal and mutant transcripts of the ret proto-oncogene were detected in a tumor of one patient with MEN 2A mutation. In addition, three MEN 2B patients examined had the same point mutation (ATG-->ACG) at codon 918 in the tyrosine kinase domain of the ret proto-oncogene. Since all mutations identified in this study generated new restriction enzyme sites or eliminated a restriction site, the mutant alleles of affected family members could be readily detected without sequencing.

DOI： 10.1111/j.1349-7006.1994.tb02962.x

PubMed

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