PMID- 22291191
OWN - NLM
STAT- MEDLINE
DCOM- 20120531
LR  - 20131121
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Linking)
VI  - 188
IP  - 5
DP  - 2012 Mar 1
TI  - Potently immunosuppressive 5-fluorouracil-resistant mesenchymal stromal cells 
      completely remit an experimental autoimmune disease.
PG  - 2207-17
LID - 10.4049/jimmunol.1101040 [doi]
AB  - We treated mice with 5-fluorouracil (5-FU) to isolate a quiescent and 
      undifferentiated mesenchymal stromal cell (MSC) population from the bone marrow. 
      We examined these 5-FU-resistant MSCs (5-FU-MSCs) free from hematopoietic 
      components for CFU fibroblasts (CFU-Fs) and assessed their immunosuppressive 
      potential in vitro and in vivo. We differentiated fibroblastic CFU-Fs 
      (Fibro-CFU-Fs) from mixed CFU-Fs, based on the absence of in situ expression of 
      CD11b and CD45 hematopoietic markers, as well as on their differentiation 
      capacity. Fibro-CFU-Fs were associated with increased numbers of large-sized 
      Fibro-CFU-Fs (>/=9 mm(2)) that displayed enhanced capacity for differentiation into 
      adipogenic and osteogenic mesenchymal lineages. Administration of these 
      5-FU-resistant CD11b(-)CD45(-) MSCs 6 d after myelin oligodendrocyte glycoprotein 
      (MOG) immunization completely remitted MOG-induced experimental autoimmune 
      encephalomyelitis after initial development of mild disease. The remission was 
      accompanied by reduced CNS cellular infiltration and demyelination, as well as a 
      significant reduction in anti-MOG Ab and splenocyte proliferation to MOG. 
      MOG-stimulated splenocytes from these mice showed elevated levels of Th2 
      cytokines (IL-4, IL-5, and IL-6) and decreased IL-17. Compared with untreated 
      MSCs, 5-FU-MSCs demonstrated potent immunosuppression of Con A-stimulated 
      splenocytes in vitro, even at a 1:320 MSC/splenocyte ratio. Immunosuppression was 
      accompanied by elevated IL-1ra, IL-10, and PGE(2). Blocking IL-1ra, IL-10, and 
      PGE(2), but not IL-6, heme oxygenase-1, and NO, attenuated 5-FU-MSC-induced 
      immunosuppression. Together, our findings suggested that immunosuppression by 
      5-FU-MSC is mediated by a combination of elevated IL-1ra, IL-10, and PGE(2), 
      anti-inflammatory Th2 cytokines, and decreased IL-17. Our findings suggested that 
      5-FU treatment identifies a population of potently immunosuppressive 5-FU-MSCs 
      that have the potential to be exploited to remit autoimmune diseases.
FAU - Oh, Ding Yuan
AU  - Oh DY
AD  - Centre for Inflammatory Disease, Monash University, Melbourne, Victoria 3163, 
      Australia.
FAU - Cui, Peng
AU  - Cui P
FAU - Hosseini, Hamid
AU  - Hosseini H
FAU - Mosse, Jennifer
AU  - Mosse J
FAU - Toh, Ban-Hock
AU  - Toh BH
FAU - Chan, James
AU  - Chan J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120130
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Immunosuppressive Agents)
RN  - U3P01618RT (Fluorouracil)
SB  - IM
MH  - Animals
MH  - Cell Differentiation/immunology
MH  - Cells, Cultured
MH  - Coculture Techniques
MH  - Disease Models, Animal
MH  - Down-Regulation/*immunology
MH  - Drug Resistance/immunology
MH  - Encephalomyelitis, Autoimmune, Experimental/*immunology/*pathology
MH  - Female
MH  - Fluorouracil/*pharmacology
MH  - Immunosuppressive Agents/*pharmacology
MH  - Lymphocyte Activation/immunology
MH  - Mesoderm/*immunology/pathology
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - Stromal Cells/drug effects/*immunology/pathology
EDAT- 2012/02/01 06:00
MHDA- 2012/06/01 06:00
CRDT- 2012/02/01 06:00
PHST- 2012/02/01 06:00 [entrez]
PHST- 2012/02/01 06:00 [pubmed]
PHST- 2012/06/01 06:00 [medline]
AID - jimmunol.1101040 [pii]
AID - 10.4049/jimmunol.1101040 [doi]
PST - ppublish
SO  - J Immunol. 2012 Mar 1;188(5):2207-17. doi: 10.4049/jimmunol.1101040. Epub 2012 
      Jan 30.