PMID- 32681646
OWN - NLM
STAT- MEDLINE
DCOM- 20210518
LR  - 20210518
IS  - 1365-2249 (Electronic)
IS  - 0009-9104 (Print)
IS  - 0009-9104 (Linking)
VI  - 202
IP  - 3
DP  - 2020 Dec
TI  - Rapamycin-based graft-versus-host disease prophylaxis increases the 
      immunosuppressivity of myeloid-derived suppressor cells without affecting T cells 
      and anti-tumor cytotoxicity.
PG  - 407-422
LID - 10.1111/cei.13496 [doi]
AB  - The immunosuppressant rapamycin (RAPA) inhibits mammalian target of rapamycin 
      (mTOR) functions and is applied after allogeneic bone marrow transplantation 
      (BMT) to attenuate the development of graft-versus-host disease (GVHD), although 
      the cellular targets of RAPA treatment are not well defined. Allogeneic T cells 
      are the main drivers of GVHD, while immunoregulatory myeloid-derived suppressor 
      cells (MDSCs) were recently identified as potent disease inhibitors. In this 
      study, we analyzed whether RAPA prevents the deleterious effects of allogeneic T 
      cells or supports the immunosuppressive functions of MDSCs in a BMT model with 
      major histocompatibility complex (MHC) classes I and II disparities. RAPA 
      treatment efficiently attenuated clinical and histological GVHD and strongly 
      decreased disease-induced mortality. Although splenocyte numbers increased during 
      RAPA treatment, the ratio of effector T cells to MDSCs was unaltered. However, 
      RAPA treatment induced massive changes in the genomic landscape of MDSCs 
      preferentially up-regulating genes responsible for uptake or signal transduction 
      of lipopeptides and lipoproteins. Most importantly, MDSCs from RAPA-treated mice 
      exhibited increased immunosuppressive potential, which was primarily inducible 
      nitric oxide synthase (iNOS)-dependent. Surprisingly, RAPA treatment had no 
      impact on the genomic landscape of T cells, which was reflected by unchanged 
      expression of activation and exhaustion markers and cytokine profiles in T cells 
      from RAPA-treated and untreated mice. Similarly, T cell cytotoxicity and the 
      graft-versus-tumor effect were maintained as co-transplanted tumor cells were 
      efficiently eradicated, indicating that the immunosuppressant RAPA might be an 
      attractive approach to strengthen the immunosuppressive function of MDSCs without 
      affecting T cell immunity.
CI  - (c) 2020 The Authors. Clinical and Experimental Immunology published by John Wiley 
      & Sons Ltd on behalf of British Society for Immunology.
FAU - Scheurer, J
AU  - Scheurer J
AUID- ORCID: 0000-0002-0674-1059
AD  - Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, 
      Ulm, Germany.
FAU - Reisser, T
AU  - Reisser T
AD  - Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, 
      Ulm, Germany.
FAU - Leithauser, F
AU  - Leithauser F
AD  - Institute of Pathology, University Ulm, Ulm, Germany.
FAU - Messmann, J J
AU  - Messmann JJ
AD  - Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, 
      Ulm, Germany.
FAU - Holzmann, K
AU  - Holzmann K
AD  - Genomic-Core Facility, University Ulm, Ulm, Germany.
FAU - Debatin, K-M
AU  - Debatin KM
AD  - Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, 
      Ulm, Germany.
FAU - Strauss, G
AU  - Strauss G
AD  - Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, 
      Ulm, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200801
PL  - England
TA  - Clin Exp Immunol
JT  - Clinical and experimental immunology
JID - 0057202
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Histocompatibility Antigens Class II)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Allografts
MH  - Animals
MH  - *Bone Marrow Transplantation
MH  - Female
MH  - *Graft vs Host Disease/immunology/pathology/prevention & control
MH  - Histocompatibility Antigens Class I/immunology
MH  - Histocompatibility Antigens Class II/immunology
MH  - Immunity, Cellular/*drug effects
MH  - Mice
MH  - Myeloid-Derived Suppressor Cells/*immunology
MH  - *Neoplasms, Experimental/immunology/pathology/therapy
MH  - Sirolimus/*pharmacology
MH  - T-Lymphocytes/*immunology
PMC - PMC7670162
OTO - NOTNLM
OT  - GVHD
OT  - GVT effect
OT  - MDSCs
OT  - allogeneic bone marrow transplantation
OT  - rapamycin
COIS- All authors declare no competing financial and commercial interests.
EDAT- 2020/07/19 06:00
MHDA- 2021/05/19 06:00
PMCR- 2020/08/01
CRDT- 2020/07/19 06:00
PHST- 2020/03/30 00:00 [received]
PHST- 2020/06/30 00:00 [revised]
PHST- 2020/07/07 00:00 [accepted]
PHST- 2020/07/19 06:00 [pubmed]
PHST- 2021/05/19 06:00 [medline]
PHST- 2020/07/19 06:00 [entrez]
PHST- 2020/08/01 00:00 [pmc-release]
AID - CEI13496 [pii]
AID - 10.1111/cei.13496 [doi]
PST - ppublish
SO  - Clin Exp Immunol. 2020 Dec;202(3):407-422. doi: 10.1111/cei.13496. Epub 2020 Aug 
      1.