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Costimulatory molecule-targeted immunotherapy of cutaneous graft-versus-host disease
Kim, Juyang,Kim, Hye J.,Park, Keunhee,Kim, Jiyoung,Choi, Hye-Jeong,Yagita, Hideo,Nam, Seok H.,Cho, Hong R.,Kwon, Byungsuk American Society of Hematology 2007 Blood Vol.110 No.2
<B>Abstract</B><P>Chronic graft-versus-host disease (cGVHD) is an increasingly frequent complication of allogeneic stem cell transplantation. Current therapies for cGVHD reduce symptoms but are not cures. The B10.D2→Balb/c (H-2d) minor histocompatibility antigen-mismatched model, which reflects clinical and pathological symptoms of human cGVHD, was used in this study. We demonstrated that a single injection of an agonistic monoclonal antibody (mAb) against CD137, a member of the tumor necrosis factor receptor superfamily, reverses skin fibrosis, ulceration, and alopecia, a dominant feature of cGVHD (cutaneous GVHD), ultimately improving general health conditions. The reversal is associated with markedly reduced CD4+ T-cell cytokines and increased apoptosis of donor CD4+ T cells. The Fas pathway is required for ameliorating cutaneous GVHD by anti-CD137 mAb. Taken together, these data indicate that the anti-CD137 mAb has a therapeutic effect on cutaneous GVHD by removing donor CD4+ T cells that cause cutaneous GVHD. Thus, our study demonstrates an agonistic mAb, specific for a costimulatory molecule, as a possible target for therapeutic intervention in cutaneous GVHD.</P>
Blockade of CD137 Signaling Counteracts Polymicrobial Sepsis Induced by Cecal Ligation and Puncture
Nguyen, Quang-Tam,Ju, Seong-A,Park, Sang-Min,Lee, Sang-Chul,Yagita, Hideo,Lee, In Hee,Kim, Byung-Sam American Society for Microbiology 2009 Infection and immunity Vol.77 No.9
<B>ABSTRACT</B><P>Sepsis, a leading cause of death worldwide, involves proinflammatory responses and inefficient bacterial clearance. Previously, we have shown that CD137 (4-1BB), a member of the tumor necrosis factor receptor superfamily, plays critical roles in eradicating infective<I>Listeria monocytogenes</I>, a gram-positive bacterium, and that stimulation of CD137 protects mice from sepsis-induced death. In this study, we unexpectedly found that CD137 activation aggravated polymicrobial sepsis due to mixed gram-positive and gram-negative bacterial infection induced by cecal ligation and puncture (CLP). CD137-deficient (CD137<SUP>−/−</SUP>) mice showed significantly lower mortality than CD137-sufficient (CD137<SUP>+/+</SUP>) mice in the CLP model. Administration of an agonistic anti-CD137 monoclonal antibody (MAb) to CD137<SUP>+/+</SUP>mice decreased their survival in this infection model, while administration of a blocking anti-CD137 ligand MAb (TKS-1) to such mice increased their survival. CD137<SUP>−/−</SUP>mice and TKS-1-treated CD137<SUP>+/+</SUP>mice had lower levels of chemokines/proinflammatory cytokines (monocyte chemoattractant protein 1, interleukin-6 [IL-6], tumor necrosis factor alpha, IL-12) and an anti-inflammatory cytokine (IL-10), exhibited improved bacterial clearance in the peritoneum, liver, and blood, and had greater numbers of infiltrated peritoneal neutrophils and macrophages in the CLP model than control mice. Our data suggest that CD137 activation aggravates polymicrobial sepsis induced by CLP.</P>
Suk, K,Kim, S,Kim, YH,Kim, K-A,Yagita H,Kayagaki N,Shong, M,Lee, M-S 이화여자대학교 세포신호전달연구센터 2000 고사리 세포신호전달 심포지움 Vol. No.2
T cell-mediated apoptosis is responsible for pancreatic β-islet cell death in autoimmune diabetes of NOD mice. Perforin, TNFα, FasL and IL-1 have been considered as effector molecule(s) leading to β-cell death, however, real culprit(s) in β-cell destruction have long been elusive despite intense investigation. Our previous studies demonstrated that FasL is not an effector in this process(1, 2), contrary to previous reports(3, 4). In the current work, we attempted to identify the final effector molecule(s) in β-cell death of autoimmune diabetes. The combination of IFNγ and TNFα, but not either cytokine alone, exerted a significant cytotoxicity on isolated islet cells as well as MIN6N8 cells, an SV40-transformed insulinoma cell line derived from NOD mice. IFNγ and TNFα synergistically induced MIN6N8 cell death by a caspase-dependent apoptosis. STAT-1 was activated by IFNγ followed by induction of IRF-1 and caspase-1, which rendered otherwise resistant islet cells susceptible to TNFα-mediated apoptosis. The β-cell death by IFNγ/TNFα was blocked by YVAD, a caspase-1-specific inhibitor. Transfection of IRF-1 cDNA sensitized MIN6N8 cells to TNFα-induced cytotoxicity, while phosphorylation-defective mutant of STAT1 abolished islet cell vulnerablity to IFNγ/TNFα. STAT1 and IRF-1 were up-regulated in pancreatic islet cells of diabetic NOD mice. Finally, anti-TNFα antibody significantly inhibited the development of diabetes after adoptive transfer of lymphocytes. Taken together, our results strongly indicated that IFNγ and TNFα synergistically act as the final effector molecules in autoimmune diabetes. Our data also suggest a novel mechanism of IFNγ/TNFα synergism: IFNγ renders otherwise resistant cells susceptible to TNFα-induced apoptosis through the induction of IRF-1. This cytokine synergism not only provides insight into the mechanism of islet destruction in autoimmune diabetes but also has relevance in other organ specific autoimmune diseases and anti-tumor effects of the cytokines where a similar cytokine synergism was reported.
Inhibitory receptor paired Ig-like receptor B is exploited by Staphylococcus aureus for virulence.
Nakayama, Masafumi,Kurokawa, Kenji,Nakamura, Kyohei,Lee, Bok Luel,Sekimizu, Kazuhisa,Kubagawa, Hiromi,Hiramatsu, Keiichi,Yagita, Hideo,Okumura, Ko,Takai, Toshiyuki,Underhill, David M,Aderem, Alan,Ogas American Association of Immunologists 2012 Journal of Immunology Vol. No.
<P>The innate immune system has developed to acquire a wide variety of pattern-recognition receptors (PRRs) to identify potential pathogens, whereas pathogens have also developed to escape host innate immune responses. ITIM-bearing receptors are attractive targets for pathogens to attenuate immune responses against them; however, the in vivo role of the inhibitory PRRs in host-bacteria interactions remains unknown. We demonstrate in this article that Staphylococcus aureus, a major Gram-positive bacteria, exploits inhibitory PRR paired Ig-like receptor (PIR)-B on macrophages to suppress ERK1/2 and inflammasome activation, and subsequent IL-6 and IL-1β secretion. Consequently, Pirb(-/-) mice infected with S. aureus showed enhanced inflammation and more effective bacterial clearance, resulting in resistance to the sepsis. Screening of S. aureus mutants identified lipoteichoic acid (LTA) as an essential bacterial cell wall component required for binding to PIR-B and modulating inflammatory responses. In vivo, however, an LTA-deficient S. aureus mutant was highly virulent and poorly recognized by macrophages in both wild-type and Pirb(-/-) mice, demonstrating that LTA recognition by PRRs other than PIR-B mediates effective bacterial elimination. These results provide direct evidence that bacteria exploit the inhibitory receptor for virulence, and host immune system counterbalances the infection.</P>
Blocking Fas Ligand on Leukocytes Attenuates Kidney Ischemia-Reperfusion Injury
Ko, Gang Jee,Jang, Hye Ryoun,Huang, Yanfei,Womer, Karl L.,Liu, Manchang,Higbee, Elizabeth,Xiao, Zuoxiang,Yagita, Hideo,Racusen, Lorraine,Hamad, Abdel Rahim A.,Rabb, Hamid American Society of Nephrology 2011 Journal of the American Society of Nephrology Vol.22 No.4