PMID- 36578517
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230103
IS  - 1178-7031 (Print)
IS  - 1178-7031 (Electronic)
IS  - 1178-7031 (Linking)
VI  - 15
DP  - 2022
TI  - Effectiveness of Soluble CTLA-4-Fc in the Inhibition of Bone Marrow T-Cell 
      Activation in Context of Indoleamine 2.3-Dioxygenase (IDO) and CD4(+)Foxp3(+) 
      Treg Induction.
PG  - 6813-6829
LID - 10.2147/JIR.S359775 [doi]
AB  - BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease with 
      systemic inflammation finally resulting in damaged joints. One of the RA 
      development models suggests bone marrow (BM) as a place of inflammation 
      development further leading to disease progression. We aimed to investigate the 
      potential of CTLA-4-Fc molecule in inducing tolerogenic milieu in BM measured as 
      indoleamine 2,3-dioxygenase (IDO) expression, CD4(+)Foxp3(+) Treg induction, and 
      T cell activation control. The expression of IDO-pathway genes was also examined 
      in monocytes to estimate the tolerogenic potential in the periphery. METHODS: 
      Bone marrow mononuclear cells (BMMC) were stimulated by pro-inflammatory 
      cytokines and CTLA-4-Fc. Next IDO expression, CD4(+)CD69(+) and CD4(+)Foxp3(+) 
      percentage were estimated by PCR and FACS staining, respectively. Enzymatic 
      activity of IDO was confirmed by HPLC in BM plasma and blood plasma. Genes 
      expressed in IDO-pathway were analyzed by NGS in peripheral monocytes isolated 
      from RA patients and healthy controls. RESULTS: We found that CTLA-4-Fc and IFN-gamma 
      stimulation results in IDO production by BMMC. CTLA-4-Fc induced tryptophan 
      catabolism can inhibit mitogen-induced CD4(+) T cells activation without 
      influencing CD8(+) cells, but did not control CD25 nor Foxp3 expression in BM 
      cells. Significantly higher expression of selected IDO-pathway genes was detected 
      on peripheral monocytes isolated from RA as compared to healthy controls. 
      CONCLUSION: This study sheds light on some immunosuppression aspects present or 
      induced in BM. The potential of IDO-mediated pathways were confirmed in the 
      periphery, what may represent the promising candidates for therapeutic strategies 
      in RA.
CI  - (c) 2022 Massalska et al.
FAU - Massalska, Magdalena
AU  - Massalska M
AUID- ORCID: 0000-0002-2146-1100
AD  - Department of Pathophysiology and Immunology, National Institute of Geriatrics, 
      Rheumatology, and Rehabilitation (NIGRiR), Warsaw, 02-637, Poland.
FAU - Ciechomska, Marzena
AU  - Ciechomska M
AUID- ORCID: 0000-0002-0961-6130
AD  - Department of Pathophysiology and Immunology, National Institute of Geriatrics, 
      Rheumatology, and Rehabilitation (NIGRiR), Warsaw, 02-637, Poland.
FAU - Kuca-Warnawin, Ewa
AU  - Kuca-Warnawin E
AUID- ORCID: 0000-0001-9068-3885
AD  - Department of Pathophysiology and Immunology, National Institute of Geriatrics, 
      Rheumatology, and Rehabilitation (NIGRiR), Warsaw, 02-637, Poland.
FAU - Burakowski, Tomasz
AU  - Burakowski T
AD  - Department of Pathophysiology and Immunology, National Institute of Geriatrics, 
      Rheumatology, and Rehabilitation (NIGRiR), Warsaw, 02-637, Poland.
FAU - Kornatka, Anna
AU  - Kornatka A
AD  - Department of Pathophysiology and Immunology, National Institute of Geriatrics, 
      Rheumatology, and Rehabilitation (NIGRiR), Warsaw, 02-637, Poland.
FAU - Radzikowska, Anna
AU  - Radzikowska A
AUID- ORCID: 0000-0001-8647-8010
AD  - Department of Pathophysiology and Immunology, National Institute of Geriatrics, 
      Rheumatology, and Rehabilitation (NIGRiR), Warsaw, 02-637, Poland.
FAU - Pawlak, Dariusz
AU  - Pawlak D
AUID- ORCID: 0000-0002-3751-0608
AD  - Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, 
      15-222, Poland.
FAU - Muz, Barbara
AU  - Muz B
AUID- ORCID: 0000-0003-4125-4624
AD  - Department of Radiation Oncology, Cancer Biology Division, Washington University 
      School of Medicine, St. Louis, MO, 63108, USA.
FAU - Loniewska-Lwowska, Adrianna
AU  - Loniewska-Lwowska A
AUID- ORCID: 0000-0003-1423-0168
AD  - Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, 
      02-106, Poland.
FAU - Palucha, Andrzej
AU  - Palucha A
AD  - Genomed S.A. Ponczowa 12, Warsaw, 02-971, Poland.
FAU - Maldyk, Pawel
AU  - Maldyk P
AUID- ORCID: 0000-0002-9856-6998
AD  - Department of Rheumoorthopaedic Surgery, National Institute of Geriatrics, 
      Rheumatology, and Rehabilitation (NIGRiR), Warsaw, 02-637, Poland.
AD  - Clinical Department of Orthopaedic and Traumatology of Locomotor System, 
      Enfant-Jesus Clinical Hospital, Warsaw, 02-005, Poland.
FAU - Maslinski, Wlodzimierz
AU  - Maslinski W
AUID- ORCID: 0000-0001-5597-9373
AD  - Department of Pathophysiology and Immunology, National Institute of Geriatrics, 
      Rheumatology, and Rehabilitation (NIGRiR), Warsaw, 02-637, Poland.
LA  - eng
PT  - Journal Article
DEP - 20221222
PL  - New Zealand
TA  - J Inflamm Res
JT  - Journal of inflammation research
JID - 101512684
PMC - PMC9792113
OTO - NOTNLM
OT  - CD4+Foxp3+
OT  - CTLA-4-Fc
OT  - bone marrow
OT  - indoleamine 2,3- dioxygenase
OT  - monocytes
OT  - rheumatoid arthritis
COIS- The authors declare no conflict of interest.
EDAT- 2022/12/30 06:00
MHDA- 2022/12/30 06:01
PMCR- 2022/12/22
CRDT- 2022/12/29 02:25
PHST- 2022/01/27 00:00 [received]
PHST- 2022/09/06 00:00 [accepted]
PHST- 2022/12/29 02:25 [entrez]
PHST- 2022/12/30 06:00 [pubmed]
PHST- 2022/12/30 06:01 [medline]
PHST- 2022/12/22 00:00 [pmc-release]
AID - 359775 [pii]
AID - 10.2147/JIR.S359775 [doi]
PST - epublish
SO  - J Inflamm Res. 2022 Dec 22;15:6813-6829. doi: 10.2147/JIR.S359775. eCollection 
      2022.