BACKGROUND: Interleukin (IL)-12 and -23 share the p40 subunit and are crucial for the development of T helper (Th) 1- and Th17-cell responses in acute graft rejection. However, little is known about the impact of treatment with antagonistic anti-p40 antibody in inhibiting rejection of cardiac allografts. METHODS: C57BL/6 mice were transplanted with syngeneic or allogeneic (BALB/c) hearts and treated with 100 or 200 μg or 400 μg anti-P40 monoclonal antibody on postoperative days 1 and 3, respectively. The survival of grafts was monitored daily by abdominal palpation until the complete cessation of cardiac contractility (endpoint). The severity of acute rejection was evaluated by histology and immunohistochemistry. The expression of transcription factors within the grafts were measured by quantitative real-time polymerase chain reaction. Systemically, the lymphocytes were characterized by flow cytometry, and the serum levels of cytokines were determined by ELISA. RESULTS: In comparison with mice treated with isotype IgG or saline, treatment with anti-p40 significantly alleviated acute phase allograft rejection and resulted in prolonged survival of cardiac allografts (P<0.05). These changes were associated with reduced infiltration of inflammatory cells and down-regulation of Th1- and Th17-specific transcription factors and cytokines. Furthermore, treatment with anti-p40 significantly reduced the percentages of splenic Th1 and Th17 cells, but not Th2 and regulatory T cells (P<0.05), with concomitant reduction of serum interferon-γ and IL-17 levels (P<0.05). CONCLUSION: Our data indicated that treatment with anti-p40 inhibited Th1- and Th17-cell responses and prolonged the survival of cardiac allografts in mice.
BACKGROUND: Interleukin (IL)-12 and -23 share the p40 subunit and are crucial for the development of T helper (Th) 1- and Th17-cell responses in acute graft rejection. However, little is known about the impact of treatment with antagonistic anti-p40 antibody in inhibiting rejection of cardiac allografts. METHODS: C57BL/6 mice were transplanted with syngeneic or allogeneic (BALB/c) hearts and treated with 100 or 200 μg or 400 μg anti-P40 monoclonal antibody on postoperative days 1 and 3, respectively. The survival of grafts was monitored daily by abdominal palpation until the complete cessation of cardiac contractility (endpoint). The severity of acute rejection was evaluated by histology and immunohistochemistry. The expression of transcription factors within the grafts were measured by quantitative real-time polymerase chain reaction. Systemically, the lymphocytes were characterized by flow cytometry, and the serum levels of cytokines were determined by ELISA. RESULTS: In comparison with mice treated with isotype IgG or saline, treatment with anti-p40 significantly alleviated acute phase allograft rejection and resulted in prolonged survival of cardiac allografts (P<0.05). These changes were associated with reduced infiltration of inflammatory cells and down-regulation of Th1- and Th17-specific transcription factors and cytokines. Furthermore, treatment with anti-p40 significantly reduced the percentages of splenic Th1 and Th17 cells, but not Th2 and regulatory T cells (P<0.05), with concomitant reduction of serum interferon-γ and IL-17 levels (P<0.05). CONCLUSION: Our data indicated that treatment with anti-p40 inhibited Th1- and Th17-cell responses and prolonged the survival of cardiac allografts in mice.
Authors: Koichi Shimizu; Peter Libby; Viviane Z Rocha; Eduardo J Folco; Rica Shubiki; Nir Grabie; Sunyoung Jang; Andrew H Lichtman; Ayako Shimizu; Nancy Hogg; Daniel I Simon; Richard N Mitchell; Kevin Croce Journal: Circulation Date: 2011-12-05 Impact factor: 29.690
Authors: Yvonne R Chan; Kong Chen; Steven R Duncan; Kira L Lathrop; Joseph D Latoche; Alison J Logar; Derek A Pociask; Brendon J Wahlberg; Prabir Ray; Anuradha Ray; Joseph M Pilewski; Jay K Kolls Journal: J Allergy Clin Immunol Date: 2012-07-11 Impact factor: 10.793