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Peri-alloHCT IL-33 administration expands recipient T-regulatory cells that
protect mice against acute GVHD
#MMPMID27222477
Matta BM
; Reichenbach DK
; Zhang X
; Mathews L
; Koehn BH
; Dwyer GK
; Lott JM
; Uhl FM
; Pfeifer D
; Feser CJ
; Smith MJ
; Liu Q
; Zeiser R
; Blazar BR
; Turnquist HR
Blood
2016[Jul]; 128
(3
): 427-39
PMID27222477
show ga
During allogeneic hematopoietic cell transplantation (alloHCT), nonhematopoietic
cell interleukin-33 (IL-33) is augmented and released by recipient conditioning
to promote type 1 alloimmunity and lethal acute graft-versus-host disease (GVHD).
Yet, IL-33 is highly pleiotropic and exhibits potent immunoregulatory properties
in the absence of coincident proinflammatory stimuli. We tested whether
peri-alloHCT IL-33 delivery can protect against development of GVHD by augmenting
IL-33-associated regulatory mechanisms. IL-33 administration augmented the
frequency of regulatory T cells (Tregs) expressing the IL-33 receptor,
suppression of tumorigenicity-2 (ST2), which persist following total body
irradiation. ST2 expression is not exclusive to Tregs and IL-33 expands innate
immune cells with regulatory or reparative properties. However, selective
depletion of recipient Foxp3(+) cells concurrent with peri-alloHCT IL-33
administration accelerated acute GVHD lethality. IL-33-expanded Tregs protected
recipients from GVHD by controlling macrophage activation and preventing
accumulation of effector T cells in GVHD-target tissue. IL-33 stimulation of ST2
on Tregs activates p38 MAPK, which drives expansion of the ST2(+) Treg subset.
Associated mechanistic studies revealed that proliferating Tregs exhibit
IL-33-independent upregulation of ST2 and the adoptive transfer of st2(+) but not
st2(-) Tregs mediated GVHD protection. In total, these data demonstrate the
protective capacity of peri-alloHCT administration of IL-33 and IL-33-responsive
Tregs in mouse models of acute GVHD. These findings provide strong support that
the immunoregulatory relationship between IL-33 and Tregs can be harnessed
therapeutically to prevent GVHD after alloHCT for treatment of malignancy or as a
means for tolerance induction in solid organ transplantation.
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