PMID- 31556206
OWN - NLM
STAT- MEDLINE
DCOM- 20210514
LR  - 20230829
IS  - 1538-7836 (Electronic)
IS  - 1538-7836 (Linking)
VI  - 18
IP  - 1
DP  - 2020 Jan
TI  - Quantitative HLA-class-II/factor VIII (FVIII) peptidomic variation in dendritic 
      cells correlates with the immunogenic potential of therapeutic FVIII proteins in 
      hemophilia A.
PG  - 201-216
LID - 10.1111/jth.14647 [doi]
AB  - BACKGROUND: Plasma-derived (pd) or recombinant (r) therapeutic factor VIII 
      proteins (FVIIIs) are infused to arrest/prevent bleeding in patients with 
      hemophilia A (PWHA). However, FVIIIs are neutralized if anti-FVIII-antibodies 
      (inhibitors) develop. Accumulating evidence suggests that pdFVIIIs with von 
      Willebrand factor (VWF) are less immunogenic than rFVIIIs and that distinct 
      rFVIIIs are differentially immunogenic. Since inhibitor development is 
      T-helper-cell-dependent, human leukocyte antigen (HLA)-class-II (HLAcII) 
      molecules constitute an important early determinant. OBJECTIVES: Use dendritic 
      cell (DC)-protein processing/presentation assays with mass-spectrometric and 
      peptide-proteomic analyses to quantify the DP-bound, DQ-bound, and DR-bound 
      FVIII-derived peptides in individual HLAcII repertoires and compare the 
      immunogenic potential of six distinct FVIIIs based on their measured peptide 
      counts. PATIENTS/METHODS: Monocyte-derived DCs from normal donors and/or PWHA 
      were cultured with either: Mix-rFVIII, a VWF-free equimolar mixture of a 
      full-length (FL)-rFVIII [Advate((R)) (Takeda)] and four distinct B-domain-deleted 
      (BDD)-rFVIIIs [Xyntha((R)) (Pfizer), NovoEight((R)) (Novo-Nordisk), Nuwiq((R)) 
      (Octapharma), and Afstyla((R)) (CSL Behring GmBH)]; a pdFVIII + pdVWF [Beriate((R)) 
      (CSL Behring GmBH)]; Advate +/- pdVWF; Afstyla +/- pdVWF; and Xyntha + pdVWF. 
      RESULTS: We showed that (i) Beriate had a significantly lower immunogenic 
      potential than Advate +/- pdVWF, Afstyla - pdVWF, and Mix-rFVIII; (ii) distinct 
      FVIIIs differed significantly in their immunogenic potential in that, in addition 
      to (i), Afstyla + pdVWF had a significantly lower immunogenic potential than 
      Beriate, while the immunogenic potential of Beriate was not significantly 
      different from that of Xyntha + pdVWF; and (iii) rFVIIIs with pdVWF had 
      significantly lower immunogenic potentials than the same rFVIIIs without pdVWF. 
      CONCLUSIONS: Our results provide HLAcII peptidomic level explanations for several 
      important clinical observations/issues including the differential immunogenicity 
      of distinct FVIIIs and the role of HLAcII genetics in inhibitor development.
CI  - (c) 2019 International Society on Thrombosis and Haemostasis.
FAU - Diego, Vincent P
AU  - Diego VP
AD  - South Texas Diabetes and Obesity Institute, University of Texas Rio Grande 
      Valley, Brownsville, Texas.
AD  - Department of Human Genetics, School of Medicine, University of Texas Rio Grande 
      Valley, Brownsville, Texas.
FAU - Luu, Bernadette W
AU  - Luu BW
AD  - South Texas Diabetes and Obesity Institute, University of Texas Rio Grande 
      Valley, Brownsville, Texas.
AD  - Department of Human Genetics, School of Medicine, University of Texas Rio Grande 
      Valley, Brownsville, Texas.
AD  - Haplogenics Corporation, Brownsville, Texas.
FAU - Hofmann, Marco
AU  - Hofmann M
AD  - CSL Behring GmbH, Research, Marburg, Germany.
FAU - Dinh, Long V
AU  - Dinh LV
AD  - Haplogenics Corporation, Brownsville, Texas.
FAU - Almeida, Marcio
AU  - Almeida M
AD  - South Texas Diabetes and Obesity Institute, University of Texas Rio Grande 
      Valley, Brownsville, Texas.
AD  - Department of Human Genetics, School of Medicine, University of Texas Rio Grande 
      Valley, Brownsville, Texas.
FAU - Powell, Jerry S
AU  - Powell JS
AD  - CSL Behring, Med Affairs, King of Prussia, Pennsylvania.
FAU - Rajalingam, Raja
AU  - Rajalingam R
AD  - Immunogenetics and Transplantation Laboratory, Department of Surgery, School of 
      Medicine, University of California at San Francisco, California.
FAU - Peralta, Juan M
AU  - Peralta JM
AD  - South Texas Diabetes and Obesity Institute, University of Texas Rio Grande 
      Valley, Brownsville, Texas.
AD  - Department of Human Genetics, School of Medicine, University of Texas Rio Grande 
      Valley, Brownsville, Texas.
FAU - Kumar, Satish
AU  - Kumar S
AD  - South Texas Diabetes and Obesity Institute, University of Texas Rio Grande 
      Valley, Brownsville, Texas.
AD  - Department of Human Genetics, School of Medicine, University of Texas Rio Grande 
      Valley, Brownsville, Texas.
FAU - Curran, Joanne E
AU  - Curran JE
AD  - South Texas Diabetes and Obesity Institute, University of Texas Rio Grande 
      Valley, Brownsville, Texas.
AD  - Department of Human Genetics, School of Medicine, University of Texas Rio Grande 
      Valley, Brownsville, Texas.
FAU - Sauna, Zuben E
AU  - Sauna ZE
AD  - Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and 
      Advanced Therapeutics, Center for Biologics Evaluation and Research, U.S. Food 
      and Drug Administration, Silver Spring, Maryland.
FAU - Kellerman, Roberta
AU  - Kellerman R
AD  - Division of Hematology, Department of Medicine, University of North Carolina at 
      Chapel Hill, North Carolina.
FAU - Park, Yara
AU  - Park Y
AD  - Department of Laboratory Medicine and Pathology, University of North Carolina at 
      Chapel Hill, North Carolina.
FAU - Key, Nigel S
AU  - Key NS
AD  - Division of Hematology, Department of Medicine, University of North Carolina at 
      Chapel Hill, North Carolina.
AD  - Department of Laboratory Medicine and Pathology, University of North Carolina at 
      Chapel Hill, North Carolina.
FAU - Escobar, Miguel A
AU  - Escobar MA
AD  - Division of Hematology, Department of Medicine, McGovern School of Medicine, 
      University of Texas Health Sciences Center at Houston, Texas.
FAU - Huynh, Huy
AU  - Huynh H
AD  - CSL Limited Research, Bio21 Institute, Melbourne, Australia.
FAU - Verhagen, Anne M
AU  - Verhagen AM
AD  - CSL Limited Research, Bio21 Institute, Melbourne, Australia.
FAU - Williams-Blangero, Sarah
AU  - Williams-Blangero S
AD  - South Texas Diabetes and Obesity Institute, University of Texas Rio Grande 
      Valley, Brownsville, Texas.
AD  - Department of Human Genetics, School of Medicine, University of Texas Rio Grande 
      Valley, Brownsville, Texas.
FAU - Lehmann, Paul V
AU  - Lehmann PV
AD  - Department of Pathology, Case Western Reserve University School of Medicine, 
      Cleveland, Ohio.
AD  - Department of Neurology, Case Western Reserve University School of Medicine, 
      Cleveland, Ohio.
AD  - Cellular Technology Ltd, Shaker Heights, Ohio.
FAU - Maraskovsky, Eugene
AU  - Maraskovsky E
AD  - CSL Limited Research, Bio21 Institute, Melbourne, Australia.
FAU - Blangero, John
AU  - Blangero J
AD  - South Texas Diabetes and Obesity Institute, University of Texas Rio Grande 
      Valley, Brownsville, Texas.
AD  - Department of Human Genetics, School of Medicine, University of Texas Rio Grande 
      Valley, Brownsville, Texas.
FAU - Howard, Tom E
AU  - Howard TE
AD  - South Texas Diabetes and Obesity Institute, University of Texas Rio Grande 
      Valley, Brownsville, Texas.
AD  - Department of Human Genetics, School of Medicine, University of Texas Rio Grande 
      Valley, Brownsville, Texas.
AD  - Haplogenics Corporation, Brownsville, Texas.
AD  - Department of Pathology and Lab Medicine, VA Valley Coastal Bend Healthcare 
      Center, Harlingen, Texas.
LA  - eng
GR  - 1RC2-HL101851/National Heart, Lung and Blood Institute/International
GR  - HL-71130/National Heart, Lung and Blood Institute/International
GR  - HL-72533/National Heart, Lung and Blood Institute/International
GR  - CO6 RR020547/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Thromb Haemost
JT  - Journal of thrombosis and haemostasis : JTH
JID - 101170508
RN  - 0 (HLA Antigens)
RN  - 839MOZ74GK (F8 protein, human)
RN  - 9001-27-8 (Factor VIII)
SB  - IM
MH  - Dendritic Cells
MH  - *Factor VIII
MH  - HLA Antigens
MH  - *Hemophilia A/drug therapy
MH  - Humans
MH  - Proteomics
OTO - NOTNLM
OT  - blood coagulation factor inhibitors
OT  - factor VIII
OT  - hemophilia A
OT  - histocompatibility antigens class II
OT  - peptide
OT  - quantitative peptidomics
OT  - sequence analysis
EDAT- 2019/09/27 06:00
MHDA- 2021/05/15 06:00
CRDT- 2019/09/27 06:00
PHST- 2019/06/04 00:00 [received]
PHST- 2019/09/23 00:00 [revised]
PHST- 2019/09/23 00:00 [accepted]
PHST- 2019/09/27 06:00 [pubmed]
PHST- 2021/05/15 06:00 [medline]
PHST- 2019/09/27 06:00 [entrez]
AID - S1538-7836(22)01577-X [pii]
AID - 10.1111/jth.14647 [doi]
PST - ppublish
SO  - J Thromb Haemost. 2020 Jan;18(1):201-216. doi: 10.1111/jth.14647.