医学部 腎泌尿器外科学

深見 直彦

fukami naohiko

基本情報

所属
藤田医科大学 医学部 医学科 腎泌尿器外科学 講師
学位
博士(医学)

J-GLOBAL ID
201501003875118272
researchmap会員ID
7000012969

MISC

 4
  • N. Fukami, S. Ramachandran, M. Takenaka, J. Weber, V. Subramanian, T. Mohanakumar
    AMERICAN JOURNAL OF TRANSPLANTATION 12(4) 867-876 2012年4月  
    Using a murine model, we demonstrated that endobronchial administration of antibodies (Abs) to major histocompatibility complex (MHC) class I results in cellular infiltration, epithelial metaplasia, fibrosis and obstruction of the small airways (obliterative airway disease [OAD]) mediated predominantly by Th17 responses to self-antigens. This resembles bronchiolitis obliterans syndrome developed following human lung transplantation. Since B cells play a crucial role in induction of autoimmune responses, we defined the role of B cells and its antigen presenting properties in induction of OAD in this study. Anti-MHC class I was administered endobronchially in B-/- and wild-type mice. In contrast to wild type, B-/- animals did not demonstrate cellular infiltration, epithelial metaplasia and obstruction of airways following anti-MHC. Frequency of K-a1 tubulin and CollagenV-specific IL-17 cells was significantly decreased in B-/- mice. As expected, Abs against self-antigens and germinal center formation were not developed in B-/- mice. Thus, we conclude that B cells and its antigen presenting capacity play an important role in induction of immune responses to self-antigens and immunopathogenesis of OAD following the administration of anti-MHC. Therefore, strategies to block B-cell and its antigen presenting functions should be considered for preventing the development of chronic rejection.
  • Naohiko Fukami, Vijay Subramanian, Nataraju Angaswamy, Wei Liu, T. Mohanakumar, Kiyotaka Hoshinaga
    TRANSPLANT IMMUNOLOGY 26(2-3) 140-145 2012年3月  
    Introduction: Mizoribine (MZR) is an inosine monophosphate dehydrogenase inhibitor. It has been widely used in Japan in the treatment of autoimmune diseases and is known to inhibit T and B cell proliferation. The aim of this study was to evaluate the efficacy of MZR as an immunosuppressive agent and determine its ability to synergize with a commonly used calcineurin inhibitor Cyclosporine A (CsA) in prolonging survival of murine islet cells and heart transplanted across major histocompatibility barrier. Methods: Murine allogeneic islet cell transplantation between Balb/c donor mice and C57BL/6 recipient mice and heterotopic heart transplantation was done between C3H/Fle donor mice and Balb/c recipient mice. Recipients were divided into groups based on immunosuppression: Group 1-No immunosuppression, Group 2-MZR alone (20 mg/kg/day), Group 3-CsA alone (20 mg/kg/day), Group 4-MZR + CsA (20 mg/kg/day). Donor specific IFN-gamma, IL-10, IL-2, IL-4 secreting cells were enumerated by ELISpot. Serum cytokine and chemokine concentration was measured by Luminex. Results: Islet cell allograft recipients treated with CsA and MZR had prolonged islet function compared to other groups [normoglycemia (blood glucose <200 mg/dL) up to 32 +/- 4 days, p<0.05]. Similarly, heart allograft survival was significantly improved in mice treated with CsA and MZR compared to other groups (50% 30-day survival, p = 0.04). Donor specific IFN-gamma, IL-4, IL-2 secreting cells were significantly decreased in recipients treated with CsA and MZR with marked increase in IL-10 secreting cells (p<0.05). There was also an increase in serum IL-10 with decrease in IFN-gamma, IL-4, IL-2, MCP-1, and IL-6 in mice treated with CsA and MZR Conclusion: MZR and CsA when used in combination are potent immunosuppressive agents in murine islet cell and heart transplantation models. These agents lead to a decrease in donor specific IFN-gamma with increase in IL-10 secreting cells leading to improved allograft survival and function. (C) 2011 Elsevier B.V. All rights reserved.
  • Naohiko Fukami, Sabarinathan Ramachandran, Kishore Narayanan, Wei Liu, Dilip S. Nath, Martin Jendrisak, William Chapman, Thalachallour Mohanakumar
    TRANSPLANTATION 93(4) 364-372 2012年2月  
    Background. Presence of donor-specific antibodies (Abs) is detrimental to posttransplant allograft function. Some sensitized recipients have successfully undergone transplantation after pretransplant conditioning regimen using plasmapheresis and/or intravenous immunoglobulin therapy, but underlying mechanisms that confer such allograft protection are undefined. Methods. We developed a single human leukocyte antigen (HLA)-mismatched heterotopic murine heart transplant model (HLA-A2 into HLA-A2-sensitized-C57BL/6) to determine whether pretreatment of donors with low concentration of HLA class I (W6/32) or control Ab (C1.18.4) will confer protection. Expression levels of survival genes, Bcl-2 and heme oxygenase-1, were analyzed by gene array analysis and quantitative real-time polymerase chain reaction. Expression levels of cytokine panel were analyzed by Luminex. Role of Bcl-2 in the induction of allograft protection was analyzed by silencing the Bcl-2 expression in the donor hearts using a small hairpin (shRNA) specific for Bcl-2. Results. Control Ab-pretreated hearts were rejected in less than 5 days demonstrating hemorrhage, Ab, and C4 deposition. In contrast, W6/32-pretreated hearts were rejected at 15 days (P < 0.05) that was prolonged to 25 days with antilymphocyte serum treatment. W6/32-pretreated hearts on day 5 exhibited increased expression of Bcl-2 (5.5-folds), Bcl-xl (5.5-folds), and heme oxygenase-1 (4.4-folds); decreased expression of ICAM-1, VCAM-1 (3.2-fold), along with reduced levels of cytokines interleukin (IL)-1 beta (4.4-folds), tumor necrosis factor alpha (3.7-folds), IL-6 (7.5-folds), IL-12 (2.3-folds) and chemokines monocyte chemotactic protein 1 (4.5-folds), MIG (4.4-folds), MIP-1 alpha (3.4-folds), and IL-8 (3.1-folds). Silencing of Bcl-2 in accommodated hearts before transplant resulted in loss of protection with rejection (9 +/- 3 vs. 15 +/- 2days, P < 0.05). Conclusion. Pretreatment of hearts with low levels of anti-HLA Abs increases expression of antiapoptotic genes that inhibits caspases, leading to decreased inflammatory cytokines and chemokines, which promote allograft survival.
  • Nataraju Angaswamy, Naohiko Fukami, Venkataswarup Tiriveedhi, George J. Cianciolo, T. Mohanakumar
    CELL TRANSPLANTATION 21(6) 1285-1296 2012年  
    Inflammatory insults following islet transplantation (ITx) hinders engraftment and long-term function of the transplanted (Tx) islets. Using a murine model of ITx, we determined the role of LMP-420, a novel TNF-alpha inhibitor, both individually and in combination with the immunosuppressant cyclosporinc A (CSA) in islet engraftment and survival. Diabetic C57BL/6 mice were Tx with 500 BALB/c islets under the kidney capsule. Four cohorts were used: LMP-420 only, CSA only, combination of LMP-420 and CSA (LMP+CSA), and control (n = 12 per cohort). Serial monitoring of blood glucose levels revealed that LMP+CSA (35 +/- 5 days) prolonged stable blood insulin levels compared to control (6 +/- 4 days). Immunohistology demonstrated that coadministration (LMP+CSA) results in a significant decrease in CD8(+) T-cell infiltration (LMP+CSA: 31 18 vs. control: 224 +/- 51 cells, p < 0.001). Scrum cytolcine analysis revealed that LMP-420 administration resulted in an increase in the anti-inflammatory cytokine IL-10 (2.5-fold), and a decrease in TNF-alpha (three-fold) with no change in IL-2. However, coadministration resulted in a marked decrease in both IL-2 and TNF-alpha (threefold) along with increase in IL-10 (threefold). Coadministration also demonstrated increase of antiapoptotic SOCS-1 and Mn-SOD expression and significant reduction of donor-specific antibodies (p < 0.005). In conclusion. LMP-420 administration with CSA results in the upregulation of anti-inflammatory and antiapoptotic mechanisms which facilitate islet allograft engraftment and survival.

書籍等出版物

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講演・口頭発表等

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