PMID- 27078882
OWN - NLM
STAT- MEDLINE
DCOM- 20160826
LR  - 20181113
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 11
IP  - 4
DP  - 2016
TI  - Immune Profiles to Predict Response to Desensitization Therapy in Highly 
      HLA-Sensitized Kidney Transplant Candidates.
PG  - e0153355
LID - 10.1371/journal.pone.0153355 [doi]
LID - e0153355
AB  - BACKGROUND: Kidney transplantation is the most effective treatment for end-stage 
      kidney disease. Sensitization, the formation of human leukocyte antigen (HLA) 
      antibodies, remains a major barrier to successful kidney transplantation. Despite 
      the implementation of desensitization strategies, many candidates fail to 
      respond. Current progress is hindered by the lack of biomarkers to predict 
      response and to guide therapy. Our objective was to determine whether differences 
      in immune and gene profiles may help identify which candidates will respond to 
      desensitization therapy. METHODS AND FINDINGS: Single-cell mass cytometry by 
      time-of-flight (CyTOF) phenotyping, gene arrays, and phosphoepitope flow 
      cytometry were performed in a study of 20 highly sensitized kidney transplant 
      candidates undergoing desensitization therapy. Responders to desensitization 
      therapy were defined as 5% or greater decrease in cumulative calculated panel 
      reactive antibody (cPRA) levels, and non-responders had 0% decrease in cPRA. 
      Using a decision tree analysis, we found that a combination of transitional B 
      cell and regulatory T cell (Treg) frequencies at baseline before initiation of 
      desensitization therapy could distinguish responders from non-responders. Using a 
      support vector machine (SVM) and longitudinal data, TRAF3IP3 transcripts and 
      HLA-DR-CD38+CD4+ T cells could also distinguish responders from non-responders. 
      Combining all assays in a multivariate analysis and elastic net regression model 
      with 72 analytes, we identified seven that were highly interrelated and eleven 
      that predicted response to desensitization therapy. CONCLUSIONS: Measuring 
      baseline and longitudinal immune and gene profiles could provide a useful 
      strategy to distinguish responders from non-responders to desensitization 
      therapy. This study presents the integration of novel translational studies 
      including CyTOF immunophenotyping in a multivariate analysis model that has 
      potential applications to predict response to desensitization, select candidates, 
      and personalize medicine to ultimately improve overall outcomes in highly 
      sensitized kidney transplant candidates.
FAU - Yabu, Julie M
AU  - Yabu JM
AD  - Department of Medicine, Stanford University School of Medicine, Palo Alto, CA, 
      United States of America.
FAU - Siebert, Janet C
AU  - Siebert JC
AD  - CytoAnalytics, Denver, CO, United States of America.
FAU - Maecker, Holden T
AU  - Maecker HT
AD  - Institute for Immunity, Transplantation, and Infection, Stanford University 
      School of Medicine, Palo Alto, CA, United States of America.
LA  - eng
GR  - K23 AI104401/AI/NIAID NIH HHS/United States
GR  - K23AI104401/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20160414
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Autoantibodies)
RN  - 0 (HLA-DR Antigens)
RN  - 0 (Immunoglobulins, Intravenous)
RN  - 0 (Microtubule-Associated Proteins)
RN  - 0 (TNF receptor-associated factor 3 interacting protein 3, human)
RN  - 4F4X42SYQ6 (Rituximab)
RN  - 69G8BD63PP (Bortezomib)
RN  - EC 3.2.2.6 (ADP-ribosyl Cyclase 1)
SB  - IM
MH  - ADP-ribosyl Cyclase 1/metabolism
MH  - Adult
MH  - Aged
MH  - Autoantibodies/analysis
MH  - B-Lymphocytes/immunology
MH  - Bortezomib/therapeutic use
MH  - CD4-Positive T-Lymphocytes/*immunology/metabolism
MH  - *Desensitization, Immunologic
MH  - Female
MH  - HLA-DR Antigens/*immunology
MH  - Histocompatibility Testing
MH  - Humans
MH  - Immunoglobulins, Intravenous/therapeutic use
MH  - Kidney Failure, Chronic/metabolism/pathology/*therapy
MH  - Kidney Transplantation
MH  - Longitudinal Studies
MH  - Male
MH  - Microtubule-Associated Proteins/genetics/metabolism
MH  - Middle Aged
MH  - Prospective Studies
MH  - Rituximab/therapeutic use
MH  - Transcriptome
PMC - PMC4831845
COIS- Competing Interests: JCS is an employee of a commercial company, CytoAnalytics. 
      This does not alter the authors' adherence to PLOS ONE policies on sharing data 
      and materials.
EDAT- 2016/04/15 06:00
MHDA- 2016/08/27 06:00
PMCR- 2016/04/14
CRDT- 2016/04/15 06:00
PHST- 2016/02/03 00:00 [received]
PHST- 2016/03/29 00:00 [accepted]
PHST- 2016/04/15 06:00 [entrez]
PHST- 2016/04/15 06:00 [pubmed]
PHST- 2016/08/27 06:00 [medline]
PHST- 2016/04/14 00:00 [pmc-release]
AID - PONE-D-16-05025 [pii]
AID - 10.1371/journal.pone.0153355 [doi]
PST - epublish
SO  - PLoS One. 2016 Apr 14;11(4):e0153355. doi: 10.1371/journal.pone.0153355. 
      eCollection 2016.