PMID- 33058141
OWN - NLM
STAT- MEDLINE
DCOM- 20211130
LR  - 20221005
IS  - 1365-2249 (Electronic)
IS  - 0009-9104 (Print)
IS  - 0009-9104 (Linking)
VI  - 203
IP  - 3
DP  - 2021 Mar
TI  - CD40L-stimulated B cells for ex-vivo expansion of polyspecific non-human primate 
      regulatory T cells for translational studies.
PG  - 480-492
LID - 10.1111/cei.13537 [doi]
AB  - The therapeutic applications of regulatory T cells (T(regs) ) include treating 
      autoimmune diseases, graft-versus-host disease and induction of transplantation 
      tolerance. For ex-vivo expanded T(regs) to be used in deceased donor 
      transplantation, they must be able to suppress T cell responses to a broad range 
      of human leukocyte antigen (HLA). Here, we present a novel approach for the 
      expansion of polyspecific T(regs) in cynomolgus macaques that was adapted from a 
      good manufacturing practice-compliant protocol. T(regs) were isolated by 
      fluorescence-activated cell sorting (FACS) and expanded in the presence of a 
      panel of CD40L-stimulated B cells (CD40L-sBc). Prior to T(reg) culture, CD40L-sBc 
      were expanded in vitro from multiple major histocompatibility complex 
      (MHC)-disparate macaques. Expanded T(regs) expressed high levels of forkhead box 
      protein 3 (FoxP3) and Helios, a high percentage of T(reg) -specific demethylated 
      region (TSDR) demethylation and strong suppression of naive T cell responses in 
      vitro. In addition, these T(regs) produced low levels of inflammatory cytokines 
      and were able to expand post-cryopreservation. Specificity assays confirmed that 
      these T(regs) were suppressive upon activation by any antigen-presenting cells 
      (APCs) whose MHC was shared by CD40L-sBc used during expansion, proving that they 
      are polyspecific. We developed an approach for the expansion of highly 
      suppressive cynomolgus macaque polyspecific T(regs) through the use of a 
      combination of CD40L-engineered B cells with the potential to be translated to 
      clinical studies. To our knowledge, this is the first report that uses a pool of 
      MHC-mismatched CD40L-sBc to create polyspecific T(regs) suitable for use in 
      deceased-donor transplants.
CI  - (c) 2020 British Society for Immunology.
FAU - Alonso-Guallart, P
AU  - Alonso-Guallart P
AUID- ORCID: 0000-0002-8801-2457
AD  - Columbia Center for Translational Immunology, Department of Medicine, Columbia 
      University Medical Center, New York, NY, USA.
FAU - Llore, N
AU  - Llore N
AD  - Columbia Center for Translational Immunology, Department of Medicine, Columbia 
      University Medical Center, New York, NY, USA.
FAU - Lopes, E
AU  - Lopes E
AD  - Columbia Center for Translational Immunology, Department of Medicine, Columbia 
      University Medical Center, New York, NY, USA.
FAU - Kofman, S-B
AU  - Kofman SB
AD  - Columbia Center for Translational Immunology, Department of Medicine, Columbia 
      University Medical Center, New York, NY, USA.
FAU - Ho, S-H
AU  - Ho SH
AD  - Columbia Center for Translational Immunology, Department of Medicine, Columbia 
      University Medical Center, New York, NY, USA.
FAU - Stern, J
AU  - Stern J
AD  - Columbia Center for Translational Immunology, Department of Medicine, Columbia 
      University Medical Center, New York, NY, USA.
FAU - Pierre, G
AU  - Pierre G
AD  - Columbia Center for Translational Immunology, Department of Medicine, Columbia 
      University Medical Center, New York, NY, USA.
FAU - Bruestle, K
AU  - Bruestle K
AD  - Columbia Center for Translational Immunology, Department of Medicine, Columbia 
      University Medical Center, New York, NY, USA.
FAU - Tang, Q
AU  - Tang Q
AD  - Department of Surgery, University of California San Francisco, San Francisco, CA, 
      USA.
FAU - Sykes, M
AU  - Sykes M
AD  - Columbia Center for Translational Immunology, Department of Medicine, Columbia 
      University Medical Center, New York, NY, USA.
AD  - Department of Microbiology and Immunology, Columbia University Medical Center, 
      New York, NY, USA.
AD  - Department of Surgery, Columbia University Medical Center, New York, NY, USA.
FAU - Griesemer, A
AU  - Griesemer A
AD  - Columbia Center for Translational Immunology, Department of Medicine, Columbia 
      University Medical Center, New York, NY, USA.
AD  - Department of Surgery, Columbia University Medical Center, New York, NY, USA.
LA  - eng
GR  - U19 AI131474/AI/NIAID NIH HHS/United States
GR  - R01 OD017949/OD/NIH HHS/United States
GR  - S10 OD020056/OD/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20201228
PL  - England
TA  - Clin Exp Immunol
JT  - Clinical and experimental immunology
JID - 0057202
RN  - 0 (Cytokines)
RN  - 0 (Forkhead Transcription Factors)
RN  - 147205-72-9 (CD40 Ligand)
SB  - IM
MH  - Animals
MH  - Antigen-Presenting Cells/immunology
MH  - B-Lymphocytes/*immunology
MH  - CD40 Ligand/*immunology
MH  - Cell Line, Tumor
MH  - Cytokines/immunology
MH  - Flow Cytometry/methods
MH  - Forkhead Transcription Factors/immunology
MH  - Humans
MH  - Inflammation/immunology
MH  - K562 Cells
MH  - Primates/*immunology
MH  - T-Lymphocytes, Regulatory/*immunology
PMC - PMC7874833
OTO - NOTNLM
OT  - CD40L-stimulated B cells
OT  - non-human primates
OT  - regulatory T cells
OT  - tolerance
COIS- Q. T. is a co-inventor on two patents on regulatory T cell therapy and a 
      cofounder of Sonoma Biotherapeutics. The rest of the authors declare that they 
      have no competing interests.
EDAT- 2020/10/16 06:00
MHDA- 2021/12/01 06:00
PMCR- 2022/03/01
CRDT- 2020/10/15 17:40
PHST- 2020/04/20 00:00 [received]
PHST- 2020/08/31 00:00 [revised]
PHST- 2020/10/01 00:00 [accepted]
PHST- 2020/10/16 06:00 [pubmed]
PHST- 2021/12/01 06:00 [medline]
PHST- 2020/10/15 17:40 [entrez]
PHST- 2022/03/01 00:00 [pmc-release]
AID - CEI13537 [pii]
AID - 10.1111/cei.13537 [doi]
PST - ppublish
SO  - Clin Exp Immunol. 2021 Mar;203(3):480-492. doi: 10.1111/cei.13537. Epub 2020 Dec 
      28.