PMID- 28361123
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220408
IS  - 2373-8731 (Print)
IS  - 2373-8731 (Electronic)
IS  - 2373-8731 (Linking)
VI  - 3
IP  - 3
DP  - 2017 Mar
TI  - Tocilizumab (Anti-IL-6R) Suppressed TNFalpha Production by Human Monocytes in an In 
      Vitro Model of Anti-HLA Antibody-Induced Antibody-Dependent Cellular 
      Cytotoxicity.
PG  - e139
LID - 10.1097/TXD.0000000000000653 [doi]
LID - e139
AB  - BACKGROUND: We previously demonstrated that natural killer (NK) cells activated 
      via FcgammaRIIIa (CD16) interactions with anti-HLA antibodies binding to peripheral 
      blood mononuclear cells (PBMCs) in the in vitro antibody-dependent cellular 
      cytotoxicity (ADCC) assay produced IFNgamma. Here we investigate if other CD16 
      bearing cells are responsive to alloantigen via alloantibody in the in vitro ADCC 
      and if the ADCC-induced cytokine reactions and cytotoxicity can be modified by 
      the anti-interleukin 6 receptor (IL-6R) monoclonal antibody, Tocilizumab (TCZ). 
      METHODS: Whole blood from a normal individual was incubated overnight with 
      irradiated allo-PBMCs pretreated with anti-HLA antibody positive (in vitro ADCC) 
      or negative sera (mixed lymphocyte reaction [MLR]), with or without TCZ or 
      control IgG. IFNgamma+, TNFalpha+ or IL-6+ cell% in NK cells, monocytes and CD8+ T cells 
      were enumerated by cytokine flow cytometry. ADCC using PBMCs (effector) and 
      Farage B cells (FB, target) with anti-HLA antibody positive sera, with or without 
      TCZ, was measured by flow cytometry. RESULTS: IFNgamma+ and/or TNFalpha+ cell% in NK 
      cells, monocytes and CD8+ T cells were elevated in the ADCC compared to the MLR 
      condition. IL-6+ cells were significantly increased in ADCC versus MLR (10.2 +/- 
      4.8% vs 2.7 +/- 1.5%, P = 0.0003), but only in monocytes. TCZ treatment 
      significantly reduced TNFalpha+ cell% in monocytes in ADCC, but had no effect on 
      other cytokine+ cells. TCZ showed no effect on cytotoxicity in ADCC. CONCLUSIONS: 
      IFNgamma, TNFalpha, and IL-6 production induced by HLA antibody-mediated CD16 bearing 
      cell activation in NK cells, monocytes, and CD8+ T cells suggests a potential 
      role for ADCC and these inflammatory cytokines in mediation of antibody-mediated 
      rejection. TCZ suppressed TNFalpha production in monocytes in the ADCC condition, 
      suggesting a role of IL-6/IL-6R pathway in monocytes activation. Inhibition of 
      this pathway could reduce the inflammatory cascade induced by alloantibody, 
      although the inhibitory effect on cytotoxicity is minimal.
FAU - Shin, Bong-Ha
AU  - Shin BH
AD  - Transplant Immunology Laboratory, Comprehensive Transplant Center, Cedars-Sinai 
      Medical Center/UCLA School of Medicine, Los Angeles, CA.
FAU - Ge, Shili
AU  - Ge S
AD  - Transplant Immunology Laboratory, Comprehensive Transplant Center, Cedars-Sinai 
      Medical Center/UCLA School of Medicine, Los Angeles, CA.
FAU - Mirocha, James
AU  - Mirocha J
AD  - Biostatistics Core, Research Institute, General Clinical Research Center, 
      Cardiothoracic Surgery, Cedars-Sinai Medical Center/UCLA School of Medicine Los 
      Angeles, CA.
FAU - Jordan, Stanley C
AU  - Jordan SC
AD  - Transplant Immunology Laboratory, Comprehensive Transplant Center, Cedars-Sinai 
      Medical Center/UCLA School of Medicine, Los Angeles, CA.
FAU - Toyoda, Mieko
AU  - Toyoda M
AD  - Transplant Immunology Laboratory, Comprehensive Transplant Center, Cedars-Sinai 
      Medical Center/UCLA School of Medicine, Los Angeles, CA.
LA  - eng
PT  - Journal Article
DEP - 20170216
PL  - United States
TA  - Transplant Direct
JT  - Transplantation direct
JID - 101651609
PMC - PMC5367756
COIS- The authors declare no funding or conflicts of interest.
EDAT- 2017/04/01 06:00
MHDA- 2017/04/01 06:01
PMCR- 2017/02/16
CRDT- 2017/04/01 06:00
PHST- 2016/07/14 00:00 [received]
PHST- 2017/01/05 00:00 [accepted]
PHST- 2017/04/01 06:00 [entrez]
PHST- 2017/04/01 06:00 [pubmed]
PHST- 2017/04/01 06:01 [medline]
PHST- 2017/02/16 00:00 [pmc-release]
AID - TXD50130 [pii]
AID - 10.1097/TXD.0000000000000653 [doi]
PST - epublish
SO  - Transplant Direct. 2017 Feb 16;3(3):e139. doi: 10.1097/TXD.0000000000000653. 
      eCollection 2017 Mar.