Introduction of novel pharmacodynamics in transplant medicine: Elucidation of the effect of immunosuppressive drugs on B cell

• Project/Area Number: 22590152
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Kinjo Gakuin University
• Principal Investigator: KURATA Yoko 金城学院大学, 薬学部, 助教 (80513928)
• Co-Investigator(Kenkyū-buntansha): KOBAYASHI Takaaki 名古屋大学, 医学(系)研究科(研究院), 教授 (70314010) ; AMIOKA Katsuo 金城学院大学, 薬学部, 教授 (50387594) ; KUZUYA Takafumi 名古屋大学, 医学部附属病院, 副部長 (00444406)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: B 細胞 / 薬力学解析 / 免疫抑制薬 / 感受性試験 / 免疫機能モニタリング / B細胞 / 免疫抑制学

Research Abstract

Recently, it has been revealed that the B cells related toanti-donor antibody production have an important role in chronic rejection after organtransplantation. Our attention has been directed towards detailed evaluation of variousimmunosuppressive drugs using pharmacodynamic (PD) analysis of B cell as well as T cell. We attempted to explore the useful combination of PD analysis of B cell andpreviously-established CFSE flow cytometry-based T cell proliferation assay. Obtained results were as follows, (i) calcineurin inhibitor (CNI) suppressedT-independent B cell proliferation through B cell receptor, but not T-dependent B cellproliferation through CD40-40L pathway, (ii) anti-metabolite and mTOR inhibitor (mTOR-I)suppressed T-dependent B cell differentiation, (iii) CNI, antimetabolite and mTOR-I suppressed T cell proliferation, (iv) renal transplant recipients with high sensitivityof CSA to T cell demonstrated high prevalence of viral reactivation, and (v) recipientswith low sens tivity exhibited high incidence of acute T cell mediated rejection.It was suggested that PD analysis of B cell and T cell might make it possible to selectthe optimum drug combination for transplant recipients, leading to individualizedimmunosuppression for prevention of chronic rejection.

Research Products

• [Journal Article] Kidney Volume Changes in Patients with Autosomal Dominant Polycystic Kidney Disease after Renal Transplantation (2012)
  • Author(s): Yamamoto T, Watarai Y, Kobayashi T,Matsuda Y, Tsujita M, Hiramitsu T, Nanmoku K, goto N, Katayama A, Tominaga Y, Uchida K.
  • Journal Title: Transplantation Volume: 93 Pages: 794-798
  • Peer Reviewed
• [Journal Article] Production of cloned pigs expressing human thrombomodulin in endothelial cells (2012)
  • Author(s): Yazaki S, Iwamoto M, Onishi A, Miwa Y,Hashimoto M, Oishi T, Suzuki S, Fuchimoto D, Sembon S, Furusawa T, Liu D, Nagasaka T, Kuzuya T,Ogawa H, Yamamoto K, Iwasaki K, Maruyama S, Kobayashi T.
  • Journal Title: Xenotransplantation Volume: 19 Pages: 82-91
  • Peer Reviewed
• [Journal Article] Clinical characteristics and outcomes of renal transplantation in elderly recipients (2012)
  • Author(s): Nanmoku K, Matsuda Y, Yamamoto T,Tsujita M, Hiramitsu T, Goto N, Katayama A, Watarai Y, Kobayashi T, Uchida K.
  • Journal Title: Transplant Proceedings Volume: 44 Pages: 281-3
  • Peer Reviewed
• [Journal Article] Potent immunosuppression for ABO-incompatible renal transplantation may not be a risk factor for malignancy. (2012)
  • Author(s): Yamamoto T, Kawaguchi T, Watarai Y,Tujita M, Hiramitsu T, Nanmoku K, Goto N,Katayama A, Kobayashi T, Uchida K.
  • Journal Title: Transplant Proceedings Volume: 44 Pages: 210-3
  • Peer Reviewed
• [Journal Article] Potent immunosuppression for ABO-incompatible renal transplantation may not be a risk factor for malignancy (2012)
  • Author(s): Yamamoto T, Kawaguchi T, Watarai Y, Tujita M, Hiramitsu T, Nanmoku K, Goto N, Katayama A, Kobayashi T, Uchida K.
  • Journal Title: Transplant Proc. Volume: 44 Issue: 1 Pages: 210-213
  • DOI: 10.1016/j.transproceed.2011.11.048
  • Peer Reviewed
• [Journal Article] Clinical characteristics and outcomes of renal transplantation in elderly recipients. (2012)
  • Author(s): Nanmoku K, Kobatashi T, et al.
  • Journal Title: Transplant Proceedings Volume: 44 Issue: 1 Pages: 281-283
  • DOI: 10.1016/j.transproceed.2012.01.006
  • Peer Reviewed
• [Journal Article] Comparative study on signal transduction in endothelial cells after anti-A/B and HLA antibody reaction : implication of accommodation (2012)
  • Author(s): Iwasaki K, Miwa Y, Ogawa H, Iwamoto M, Furusawa T, Onishi A, Kuzuya T, Haneda M, Watarai Y, Uchida K, Kobayashi T.
  • Journal Title: Transplantation Volume: 93 Issue: 4 Pages: 390-397
  • DOI: 10.1097/tp.0b013e3182424df3
  • Peer Reviewed
• [Journal Article] Adipose-derived stromal cells cultured in a low-serum medium, but not bone marrow-derived stromal cells,impede xenoantibody production. (2011)
  • Author(s): Saka Y, Furuhashi K, Katsuno T, Kim H,Ozaki T, Iwasaki K, Haneda M, Sato W,Tsuboi N, Ito Y, Matsuo S, Kobayashi T,Maruyama S.
  • Journal Title: Xenotransplantation Volume: 18 Pages: 196-208
  • Peer Reviewed
• [Journal Article] Clinical Significance of Regulatory T Cell-Related Gene Expression in Peripheral Blood After Renal Transplantation. (2011)
  • Author(s): H. Iwase, T. Kobayashi, Y. Kodera, Y.Miwa, T. Kuzuya, K. Iwasaki, M. Haneda, A.Katayama, A. Takeda, K. Morozumi, Y.Watarai, K. Uchida and A. Nakao.
  • Journal Title: Transplantation Volume: 91 Pages: 191-198
  • Peer Reviewed
• [Journal Article] Clinical Significance of Regulatory T Cell-Related Gene Expression in Peripheral Blood After Renal Transplantation (2011)
  • Author(s): H.Iwase, T.Kobayashi, et al
  • Journal Title: Transplantation Volume: 91 Issue: 2 Pages: 191-198
  • DOI: 10.1097/tp.0b013e3181ffbab4
  • Peer Reviewed
• [Journal Article] Significant Association Between Chronic Antibody-Mediated Rejection and Donor-Specific Antibodies against HLA-DRB rather than DQB in Renal Transplantation. (2010)
  • Author(s): Takaaki Kobayashi,Etsuko Maruya, Misao Niwa, Hiroh Saji, Setsuko Kohara, Akio Katayama, Yoshihiko Watarai, Asami TakedaKazuharu Uchida.
  • Journal Title: Human Immunology Volume: 72 Pages: 11-7
  • Peer Reviewed
• [Journal Article] Significance of HLA class I antibody-induced antioxidant gene expression for endothelial cell protection against complement attack. (2010)
  • Author(s): Kenta Iwasaki, Yuko Miwa, Masataka Haneda, Kazuharu Uchida, Akimasa Nakao, Takaaki Kobayashi.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 391 Pages: 1210-5
  • Peer Reviewed
• [Journal Article] Poten t ial value of human thrombomodulin and DAF expression for coagulation control in pig-to-human xenotransplantation (2010)
  • Author(s): Yuko Miwa, Koji Yamamoto, Akira Onishi,Masaki Iwamoto, Satoko Yazaki, Masataka Haneda, Kenta Iwasaki, De.Ge.Liu,Takaharu Nagasaka, Kazuharu Uchida,Akimasa Nakao, Kenji Kadomatsu,Takaaki Kobayashi.
  • Journal Title: Xenotransplantation Volume: 17 Pages: 26-37
  • Peer Reviewed
• [Presentation] Expansion of donor sources Hurdles of xenotransplantation. (2012)
  • Author(s): Takaaki Kobayashi
  • Organizer: The 42nd Annual Congress of the Korean Society for Transplantation & The 9th Korea-Japan
  • Place of Presentation: Transplantation Forum (Korea)
• [Presentation] Long-Term Outcome in Kidney Transplant Recipients with HTLV-1 Carriers. (2012)
  • Author(s): Goto N, Matsuda Y, Takada M, Yamamoto T,Tsujita M, Hiramitsu T, Nanmoku K, Watarai Y, Katayama A, Kobayashi T, Uchida K.
  • Organizer: 24th International Congress of The Transplantation Society
  • Place of Presentation: Berlin
• [Presentation] No Inhibitory Effect of Pre-Transplant Desensitization Treatment with Rituximab or Splenectomy on de Novo HLA Antibody Production in Renal Transplantation (2012)
  • Author(s): Kobayashi T, Yamamoto T, Kuroki K,Hiramitsu T, Tsujita M, Goto N, Nanmoku K,Nagasaka T, Ohtsuka S, Katayama A, WataraiY, Takeda A, Morozumi K, Uchida K
  • Organizer: 24th International Congress of The Transplantation Society
  • Place of Presentation: Berlin
• [Presentation] Polycystic Liver and Kidney Volume Changes in Patients with Autosomal Dominant Polycystic Kidney Disease after Renal Transplantation. (2012)
  • Author(s): T. Yamamoto, Y. Watrai, T. Kobayashi, Y.Matsuda, M. Tsujita, T. Hiramitsu, K.Nanmoku, N. Goto, K. Uchida.
  • Organizer: American Transplant Congress 2012
  • Place of Presentation: Boston
• [Presentation] Impacts of Intraoperative Transesophageal Echocardiaography on Hemodynamic Parameter during Operation in Pediatric Renal Transplantation with Less Than 20kg Body Weight. (2012)
  • Author(s): Y. Watarai, Y. Goto, Y. Kuroyanagi, T.Yamada, K. Mori, H. Takasu, T. Yamamoto,M. Tsujita, T. Hiramitsu, N. Goto, K.Nanmoku, T. Ueki, A. Katayama,T.Kobayashi, K. Uchida.
  • Organizer: American Transplant Congress 2012
  • Place of Presentation: Boston
• [Presentation] One Year Post-Transplant but Not Pre-Transplant DSA Levels Predict Subclinical AMR in HLA-Incompatible Renal Transplantation Using Risk-Stratified Desensitization Therapy. (2012)
  • Author(s): S. Yamanaga, Y. Watarai, T. Kobayashi,T. Yamamoto, M. Tsujita, T. Hiramitsu, K.Nanmoku, N. Goto, A. Takeda, K. Morozumi,A. Katayama, K. Uchida.
  • Organizer: American Transplant Congress2012
  • Place of Presentation: Boston
• [Presentation] Is There an Inhibitory Effect of Pre-Transplant Rituximab Therapy or Splenectomy on De Novo HLA Antibody Production after Renal Transplantation (2012)
  • Author(s): T. Kobayashi, T. Yamamoto, T. Hiramitsu,M. Tsujita, N. Goto, K. Nanmoku, T. Ueki,A. Katayama, A. Takeda, K. Morozumi, Y.Watarai, K. Uchida.
  • Organizer: American Transplant Congress 2012
  • Place of Presentation: Boston
• [Presentation] LongTerm Results of ABO-Incompatible Kidney Transplantation Using Cyclophosphamide and Splenectomy. (2012)
  • Author(s): Y. Watarai, A. Katayama, N. Goto,T.Kobayashi, T. Yamamoto, Y. Matsuda, M.Tsujita, T. Hiramitsu, T. Ueki, K. Nanmoku,A. Takeda, K. Morozumi, K. Uchida.
  • Organizer: American Transplant Congress 2012
  • Place of Presentation: Boston
• [Presentation] Desensitization Protocol UsingIntensified Dose of Mycophenolate Mofetil without Rituximab and Splenectomy for ABO-Incompatible Kidney Transplantation. (2012)
  • Author(s): Y. Watarai, A. Katayama, Y. Matsuda, T.Yamamoto, M. Tsujita, T. Hiramitsu, K.Nanmoku, N. Goto, T. Ueki, A. Takeda, K.Morozumi, T. Kobayashi, K. Uchida.
  • Organizer: American Transplant Congress 2012
  • Place of Presentation: Boston
• [Presentation] Potential Value of Post-Transplant DKB USA Monitoring for Early Diagnosis of Chronic Antibody-Mediated Rejection (2011)
  • Author(s): Takaaki Kobayashi, et al.
  • Organizer: AMERICAN TRANSPLANT CONGRESS 2011
  • Place of Presentation: Philadelphia (USA)
  • Year and Date: 2011-05-01
• [Presentation] Functional difference between membrane-bound and soluble human thrombomodulin. (2011)
  • Author(s): Yuko Miwa, Satoko Yazaki, Masaki Iwamoto,Kenta Iwasaki, Koji Yamamoto, Masataka Haneda, Akira Onishi, Kazuharu Uchida, Takaaki Kobayashi
  • Organizer: CTS-IXA 2011 Joint Congress
  • Place of Presentation: Miami
• [Presentation] Complement andthrombin block endothelial cellaccommodation. (2011)
  • Author(s): Kenta Iwasaki, Yuko Miwa, MasatakaHaneda, Takaaki Kobayashi
  • Organizer: CTS-IXA 2011 JointCongress
  • Place of Presentation: Miami
• [Presentation] Difference in signal transduction between anti-A/B and anti-HLA antibody binding to endothelial cells. (2011)
  • Author(s): Kenta Iwasaki, Yuko Miwa, Masataka Haneda, Takaaki Kobayashi
  • Organizer: CTS-IXA 2011 Joint Congress
  • Place of Presentation: Miami
• [Presentation] Successful production and breeding of cloned pigs expressing human thrombomodulin in endothelial cells. (2011)
  • Author(s): Masaki Iwamoto, Satoko Yazaki, Akira Onishi, Yuko Miwa, Michiko Hashimoto,Takatsugu Oishi, Shunichi Suzuki,Dai-ichiro Fuchimoto, Shoichiro Sembon,Takaharu Nagasaka, DaGe Liu, Kenta Iwasaki,Masataka Haneda, Koji Yamamoto, Shoichi Maruyama, Takaaki Kobayashi
  • Organizer: CTS-IXA 2011 Joint Congress
  • Place of Presentation: Miami
• [Presentation] The Presence and Strength of IgG3 Subclass Is Associated with Graft Function in DSA-Positive Kidney Transplant Patients. (2011)
  • Author(s): M. Taniguchi, P.I. Terasaki, L.M.Rebellato, T. Kobayashi, P.G.Catrou, K.P. Briley.
  • Organizer: AMERICAN TRANSPLANT CONGRESS 2011
  • Place of Presentation: Philadelphia
• [Presentation] Potential Value of Post-Transplant DRB DSA Monitoring for Early Diagnosis of Chronic Antibody-Mediated Rejection. (2011)
  • Author(s): T. Kobayashi, E.Maruya, M.Taniguchi,M.Niwa, H.Saji, A. Katayama, A.Takeda,Y.Watarai, P.I.Terasaki, K.Uchida.
  • Organizer: AMERICAN TRANSPLANT CONGRESS 2011
  • Place of Presentation: Philadelphia
• [Presentation] Close Relation Between Chronic Antibody Mediated Rejection and Donor Specific Antibody Against Hla Class II DRb, But Not DQb. (2010)
  • Author(s): Takaaki Kobayashi, et al.
  • Organizer: International Congress of The Transplantation Society
  • Place of Presentation: Vancouver (Canada)
  • Year and Date: 2010-08-19
• [Presentation] Pharmacodynamic Evaluation of Cyclosporine in B-Cell. (2010)
  • Author(s): Takafumi Kuzuya, et al.
  • Organizer: International Congress of The Transplantation Society
  • Place of Presentation: Vancouver (Canada)
  • Year and Date: 2010-08-18
• [Presentation] Comparative Study of HLA Antibody Detection Between Elisa and Luminex Assay, and Its Clinical Relevance in Renal Transplantation. (2010)
  • Author(s): Takaaki Kobayashi, et al.
  • Organizer: International Congress of The Transplantation Society
  • Place of Presentation: Vancouver (Canada)
  • Year and Date: 2010-08-17
• [Presentation] The Implication of AMP-Activated Protein Kinase As A Target To Suppress Lymphocyte Proliferation. (2010)
  • Author(s): Iwasaki K, Hirabayashi A, Kato M,Kuzuya T, Miwa Y, Haneda M, Uchida K, Nakao A, Kobayashi T.
  • Organizer: International Congress of The Transplantation Society
  • Place of Presentation: Vancouver
• [Presentation] Comparative Study of HLA Antibody Detection Between ELISA and Luminex Assay,and Its Clinical Relevance in Renal Transplantation. (2010)
  • Author(s): Kobayashi T, Maruya E, Niwa M, Kohara S,Katayama A, Watarai Y, Saji H, Uchida K
  • Organizer: International Congress of The Transplantation Society
  • Place of Presentation: Vancouver
• [Presentation] Is There an Inhibitory Effect of Pre-Transplant Rituximab Therapy or Splenectomy on De Novo HLA Antibody Production after Renal Transplantation?
  • Author(s): Takaaki Kobayashi, et al.
  • Organizer: American Transplant Congress 2012
  • Place of Presentation: Boston (USA)