Low-dose IL-2 prevents murine chronic cardiac allograft rejection: Role for IL-2-induced T regulatory cells and exosomes with PD-L1 and CD73.
Allografts
Animals
Autoantigens
/ metabolism
B7-H1 Antigen
/ metabolism
Disease Models, Animal
Exosomes
Forkhead Transcription Factors
/ metabolism
Graft Rejection
/ etiology
Graft Survival
Heart Transplantation
/ adverse effects
Interleukin-2
/ metabolism
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
MicroRNAs
T-Lymphocytes, Regulatory
alloantibody
animal models: murine
autoantibody
heart transplantation/cardiology
immunosuppression/immune modulation
translational research/science
Journal
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
ISSN: 1600-6143
Titre abrégé: Am J Transplant
Pays: United States
ID NLM: 100968638
Informations de publication
Date de publication:
09 2022
09 2022
Historique:
revised:
12
05
2022
received:
07
12
2021
accepted:
12
05
2022
pubmed:
24
5
2022
medline:
1
9
2022
entrez:
23
5
2022
Statut:
ppublish
Résumé
To determine the effects and immunological mechanisms of low-dose interleukin-2 (IL-2) in a murine model of chronic cardiac allograft rejection (BALB/c to C57BL/6) after costimulatory blockade consisting of MR1 (250 μg/ip day 0) and CTLA4-Ig (200 μg/ip day 2), we administered low-dose IL-2 (2000 IU/day) starting on posttransplant day 14 for 3 weeks. T regulatory (Treg) cell infiltration of the grafts was determined by immunohistochemistry; circulating exosomes by western blot and aldehyde bead flow cytometry; antibodies to donor MHC by immunofluorescent staining of donor cells; and antibodies to cardiac self-antigens (myosin, vimentin) by ELISA. We demonstrated that costimulation blockade after allogeneic heart transplantation induced circulating exosomes containing cardiac self-antigens and antibodies to both donor MHC and self-antigens, leading to chronic rejection by day 45. Treatment with low-dose IL-2 prolonged allograft survival (>100 days), prevented chronic rejection, and induced splenic and graft-infiltrating CD4+ CD25+ Foxp3 Treg cells by day 45 and circulating exosomes (Foxp3+) with PD-L1 and CD73. MicroRNA 142, associated with the TGFβ pathway, was significantly downregulated in exosomes from IL-2-treated mice. In conclusion, low-dose IL-2 delays rejection in a murine model of chronic cardiac allograft rejection and also induces graft-infiltrating Tregs and circulating exosomes with immunoregulatory molecules.
Identifiants
pubmed: 35603986
doi: 10.1111/ajt.17101
pii: S1600-6135(22)29912-2
doi:
Substances chimiques
Autoantigens
0
B7-H1 Antigen
0
Cd274 protein, mouse
0
Forkhead Transcription Factors
0
Interleukin-2
0
MicroRNAs
0
Mirn142 microRNA, mouse
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
2180-2194Subventions
Organisme : NIH HHS
ID : R21 AI123034
Pays : United States
Informations de copyright
© 2022 The American Society of Transplantation and the American Society of Transplant Surgeons.
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