Blockade of TIM-1 on the donor graft ameliorates graft-versus-host disease following hematopoietic cell transplantation.
Animals
Antibodies, Blocking
/ therapeutic use
Antibodies, Monoclonal
/ therapeutic use
Biomarkers
Disease Models, Animal
Gene Expression
Graft vs Host Disease
/ diagnosis
Hematopoietic Stem Cell Transplantation
/ adverse effects
Hepatitis A Virus Cellular Receptor 1
/ antagonists & inhibitors
Humans
Immune Reconstitution
Immunohistochemistry
Immunophenotyping
Inflammation Mediators
/ metabolism
Lymphocyte Count
Mice
Mice, Knockout
Severity of Illness Index
Survival Rate
T-Lymphocytes
/ immunology
Transplantation, Homologous
Journal
Blood advances
ISSN: 2473-9537
Titre abrégé: Blood Adv
Pays: United States
ID NLM: 101698425
Informations de publication
Date de publication:
12 11 2019
12 11 2019
Historique:
received:
10
04
2019
accepted:
19
08
2019
entrez:
13
11
2019
pubmed:
13
11
2019
medline:
2
9
2020
Statut:
ppublish
Résumé
Acute graft-versus-host disease (GVHD) is a leading cause of mortality after allogeneic hematopoietic cell transplantation (HCT) mediated by dysregulated T-cell immune reconstitution. Given the role of the T-cell immunoglobulin and mucin 1 (TIM-1) surface protein in many immune processes, including organ transplantation tolerance, we asked if TIM-1 might drive post-transplant inflammation and acute GVHD. TIM-1 binds to phosphatidylserine (PtdSer), and agonism of TIM1 on immune cells is proinflammatory. HCT conditioning results in a significant supply of PtdSer from apoptosis and cellular debris. Using murine models, treatment with an antagonistic anti-TIM-1 monoclonal antibody (mAb) protects against acute GVHD while maintaining graft-versus-tumor effects. In contrast, the addition of exogenous free PtdSer worsened GVHD in a TIM-1-dependent manner. Importantly, TIM-1 blockade did not alter the expansion of donor T cells in vitro or in vivo. Instead, TIM-1 blockade reduces proinflammatory cytokines and promotes anti-inflammatory factors like carbonic anhydrase 1 and serum amyloid A1 in the gut tissue. This is mediated by TIM-1 on donor cells, as HCT of wild-type (WT) bone marrow (BM) and conventional T (Tcon) cells into TIM-1-/- knockout (KO) recipient mice showed little survival advantage compared with WT recipients, whereas WT recipients of TIM-1-/- KO Tcon cells or TIM1-/- KO BM had improved survival, in part due to the expression of TIM-1 on donor invariant natural killer T cells, which drives inflammation. Finally, in a humanized mouse xenograft GVHD model, treatment with anti-human TIM-1 antagonist mAb reduced GVHD disease burden and mortality. This supports TIM-1 as important for GVHD pathogenesis and as a target for the prevention of GVHD.
Identifiants
pubmed: 31714958
pii: 422757
doi: 10.1182/bloodadvances.2019000286
pmc: PMC6855109
doi:
Substances chimiques
Antibodies, Blocking
0
Antibodies, Monoclonal
0
Biomarkers
0
HAVCR1 protein, human
0
Hepatitis A Virus Cellular Receptor 1
0
Inflammation Mediators
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3419-3431Subventions
Organisme : NHLBI NIH HHS
ID : K08 HL119590
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK116074
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI089955
Pays : United States
Informations de copyright
© 2019 by The American Society of Hematology.
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