title: Interleukin-6 receptor signaling disruption prevents cardiac allograft deterioration in mice.
abstract: OBJECTIVE
  Interleukin-6, a pleiotropic cytokine that functions in both innate and adaptive immune responses, has been implicated in allograft rejection. We analyzed the efficacy of anti interleukin-6 receptor monoclonal antibody in delaying allograft rejection in a murine model of a heart.
  
  
  METHODS
  To investigate the role of interleukin-6 receptor signal transduction in acute and chronic allograft rejection, we blocked interleukin-6 receptor signaling to suppress the alloimmune response in C57BL/6 recipients of BALB/c cardiac allografts.
  
  
  RESULTS
  Administration of a high-dose α-interleukin-6 receptor monoclonal antibody prevented the intragraft infiltration of inflammatory cells and lymphocytes and prolonged allograft survival during the peritransplant period. However, all allografts were rejected by 23.5 days after transplant. In contrast, cardiac allograft recipients treated with a cytotoxic T-lymphocyte antigen 4-immunoglobulin plus continued administration of low-dose α-interleukin-6 receptor monoclonal antibody showed long-term graft survival compared with cytotoxic T-lymphocyte antigen 4-immunoglobulin monotherapy. A histologic analysis revealed that graft fibrosis was prevented in cytotoxic T-lymphocyte antigen 4-immunoglobulin plus high-dose α-interleukin-6 receptor monoclonal antibody group, but not in the cytotoxic T-lymphocyte antigen 4-immunoglobulin alone group. This suggests that deterioration of graft function associated with chronic rejection could be prevented by blocking interleukin-6 receptor signaling.
  
  
  CONCLUSIONS
  Disruption of interleukin-6 receptor signaling is an effective strategy for modulating proinflammatory immune responses and preventing chronic rejection.
authors: Department of Urology, Tokyo Women's Medical University, Tokyo, Japan. setogawacho@yahoo.co.jp
authors: Shoichi
authors: S
authors: Iida
authors: Kazuya
authors: K
authors: Omoto
authors: Izumi
authors: I
authors: Kanemitsu
authors: Kiyoshi
authors: K
authors: Setoguchi
authors: Hideki
authors: H
authors: Ishida
authors: Kazunari
authors: K
authors: Tanabe
authors: Toshihiro
authors: T
authors: Suzuki
authors: Yasuyuki
authors: Y
authors: Tashiro
authors: Hidehiro
authors: H
authors: Kishimoto
authors: Ryo
authors: R
authors: Abe
mesh_terms: D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002908:Chronic Disease; D005260:Female; D005355:Fibrosis; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000009:adverse effects / Q000276:immunology*; D018796:Immunoconjugates / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control; D015850:Interleukin-6 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000276:immunology* / Q000473:pathology; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; C113250:interleukin-6 receptor alpha; D000069594:Abatacept