Key Points

  • The deficiency of L cells, ISCs, and PCs due to GVHD can be overcome by GLP-2 treatment.

  • Lower L-cell numbers within the gastrointestinal tract are associated with a poorer outcome for patients suffering from GVHD.

Abstract

Acute graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). Although currently used GVHD treatment regimens target the donor immune system, we explored here an approach that aims at protecting and regenerating Paneth cells (PCs) and intestinal stem cells (ISCs). Glucagon-like-peptide-2 (GLP-2) is an enteroendocrine tissue hormone produced by intestinal L cells. We observed that acute GVHD reduced intestinal GLP-2 levels in mice and patients developing GVHD. Treatment with the GLP-2 agonist, teduglutide, reduced de novo acute GVHD and steroid-refractory GVHD, without compromising graft-versus-leukemia (GVL) effects in multiple mouse models. Mechanistically GLP-2 substitution promoted regeneration of PCs and ISCs, which enhanced production of antimicrobial peptides and caused microbiome changes. GLP-2 expanded intestinal organoids and reduced expression of apoptosis-related genes. Low numbers of L cells in intestinal biopsies and high serum levels of GLP-2 were associated with a higher incidence of nonrelapse mortality in patients undergoing allo-HCT. Our findings indicate that L cells are a target of GVHD and that GLP-2–based treatment of acute GVHD restores intestinal homeostasis via an increase of ISCs and PCs without impairing GVL effects. Teduglutide could become a novel combination partner for immunosuppressive GVHD therapy to be tested in clinical trials.

REFERENCES

REFERENCES
1.
Zeiser
R
,
Blazar
BR
.
Acute graft-versus-host disease - biologic process, prevention, and therapy
.
N Engl J Med
.
2017
;
377
(
22
):
2167
-
2179
.
2.
Zeiser
R
,
Burchert
A
,
Lengerke
C
, et al
.
Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey
.
Leukemia
.
2015
;
29
(
10
):
2062
-
2068
.
3.
Zeiser
R
,
von Bubnoff
N
,
Butler
J
, et al;
REACH2 Trial Group
.
Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease
.
N Engl J Med
.
2020
;
382
(
19
):
1800
-
1810
.
4.
Drucker
DJ
,
Yusta
B
.
Physiology and pharmacology of the enteroendocrine hormone glucagon-like peptide-2
.
Annu Rev Physiol
.
2014
;
76
:
561
-
583
.
5.
Connor
EE
,
Evock-Clover
CM
,
Walker
MP
,
Elsasser
TH
,
Kahl
S
.
Comparative Gut Physiology Symposium: Comparative physiology of glucagon-like peptide-2: Implications and applications for production and health of ruminants
.
J Anim Sci
.
2015
;
93
(
2
):
492
-
501
.
6.
Rowland
KJ
,
Brubaker
PL
.
The “cryptic” mechanism of action of glucagon-like peptide-2
.
Am J Physiol Gastrointest Liver Physiol
.
2011
;
301
(
1
):
G1
-
G8
.
7.
Jeppesen
PB
,
Hartmann
B
,
Thulesen
J
, et al
.
Glucagon-like peptide 2 improves nutrient absorption and nutritional status in short-bowel patients with no colon
.
Gastroenterology
.
2001
;
120
(
4
):
806
-
815
.
8.
Harris
AC
,
Young
R
,
Devine
S
, et al
.
International, multicenter standardization of acute graft-versus-host disease clinical data collection: a report from the Mount Sinai Acute GVHD International Consortium
.
Biol Blood Marrow Transplant
.
2016
;
22
(
1
):
4
-
10
.
9.
Fine
JP
,
Gray
RJ
.
A proportional hazards model for the subdistribution of a competing risk
.
J Am Stat Assoc
.
1997
;
94
(
446
):
496
-
509
.
10.
Hayase
E
,
Hashimoto
D
,
Nakamura
K
, et al
.
R-Spondin1 expands Paneth cells and prevents dysbiosis induced by graft-versus-host disease
.
J Exp Med
.
2017
;
214
(
12
):
3507
-
3518
.
11.
Chiusolo
P
,
Metafuni
E
,
Paroni Sterbini
F
, et al
.
Gut microbiome changes after stem cell transplantation [abstract]
.
Blood
.
2015
;
126
(
23
).
Abstract 1953
.
12.
Holler
E
,
Butzhammer
P
,
Schmid
K
, et al
.
Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease
.
Biol Blood Marrow Transplant
.
2014
;
20
(
5
):
640
-
645
.
13.
Hülsdünker
J
,
Ottmüller
KJ
,
Neeff
HP
, et al
.
Neutrophils provide cellular communication between ileum and mesenteric lymph nodes at graft-versus-host disease onset
.
Blood
.
2018
;
131
(
16
):
1858
-
1869
.
14.
Rauch
I
,
Hainzl
E
,
Rosebrock
F
, et al
.
Type I interferons have opposing effects during the emergence and recovery phases of colitis
.
Eur J Immunol
.
2014
;
44
(
9
):
2749
-
2760
.
15.
Lindemans
CA
,
Calafiore
M
,
Mertelsmann
AM
, et al
.
Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration
.
Nature
.
2015
;
528
(
7583
):
560
-
564
.
16.
Mathew
NR
,
Baumgartner
F
,
Braun
L
, et al
.
Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD mutant leukemia cells
.
Nat Med
.
2018
;
24
:
282
-
291
.
17.
Levine
JE
,
Huber
E
,
Hammer
ST
, et al
.
Low Paneth cell numbers at onset of gastrointestinal graft-versus-host disease identify patients at high risk for nonrelapse mortality
.
Blood
.
2013
;
122
(
8
):
1505
-
1509
.
18.
Drucker
DJ
,
Habener
JF
,
Holst
JJ
.
Discovery, characterization, and clinical development of the glucagon-like peptides
.
J Clin Invest
.
2017
;
127
(
12
):
4217
-
4227
.
19.
Ehmann
D
,
Wendler
J
,
Koeninger
L
, et al
.
Paneth cell α-defensins HD-5 and HD-6 display differential degradation into active antimicrobial fragments
.
Proc Natl Acad Sci USA
.
2019
;
116
(
9
):
3746
-
3751
.
20.
Jenq
RR
,
Ubeda
C
,
Taur
Y
, et al
.
Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation
.
J Exp Med
.
2012
;
209
(
5
):
903
-
911
.
21.
Eriguchi
Y
,
Takashima
S
,
Oka
H
, et al
.
Graft-versus-host disease disrupts intestinal microbial ecology by inhibiting Paneth cell production of α-defensins
.
Blood
.
2012
;
120
(
1
):
223
-
231
.
22.
Yu
C
,
Jia
G
,
Deng
Q
, et al
.
The effects of glucagon-like peptide-2 on the tight junction and barrier function in IPEC-J2 cells through phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin signaling pathway
.
Asian-Australas J Anim Sci
.
2016
;
29
(
5
):
731
-
738
.
23.
Zhao
D
,
Kim
YH
,
Jeong
S
, et al
.
Survival signal REG3α prevents crypt apoptosis to control acute gastrointestinal graft-versus-host disease
.
J Clin Invest
.
2018
;
128
(
11
):
4970
-
4979
.
24.
Brubaker
PL
,
Izzo
A
,
Hill
M
,
Drucker
DJ
.
Intestinal function in mice with small bowel growth induced by glucagon-like peptide-2
.
Am J Physiol
.
1997
;
272
(
6 Pt 1
):
E1050
-
E1058
.
25.
Takashima
S
,
Kadowaki
M
,
Aoyama
K
, et al
.
The Wnt agonist R-spondin1 regulates systemic graft-versus-host disease by protecting intestinal stem cells
.
J Exp Med
.
2011
;
208
(
2
):
285
-
294
.
26.
Blazar
BR
,
Weisdorf
DJ
,
Defor
T
, et al
.
Phase 1/2 randomized, placebo-control trial of palifermin to prevent graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT)
.
Blood
.
2006
;
108
(
9
):
3216
-
3222
.
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