Treg-inducing microparticles promote donor-specific tolerance in experimental vascularized composite allotransplantation.
Animals
Cell-Derived Microparticles
/ metabolism
Cytokines
/ metabolism
Drug Delivery Systems
Immunosuppression Therapy
/ methods
Immunosuppressive Agents
/ metabolism
Rats
T-Lymphocytes, Regulatory
/ cytology
Transplantation Tolerance
/ physiology
Vascularized Composite Allotransplantation
/ methods
biomaterials
controlled release
drug delivery
regulatory T cells
transplantation
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
17 12 2019
17 12 2019
Historique:
pubmed:
4
12
2019
medline:
14
4
2020
entrez:
4
12
2019
Statut:
ppublish
Résumé
For individuals who sustain devastating composite tissue loss, vascularized composite allotransplantation (VCA; e.g., hand and face transplantation) has the potential to restore appearance and function of the damaged tissues. As with solid organ transplantation, however, rejection must be controlled by multidrug systemic immunosuppression with substantial side effects. As an alternative therapeutic approach inspired by natural mechanisms the body uses to control inflammation, we developed a system to enrich regulatory T cells (Tregs) in an allograft. Microparticles were engineered to sustainably release TGF-β1, IL-2, and rapamycin, to induce Treg differentiation from naïve T cells. In a rat hindlimb VCA model, local administration of this Treg-inducing system, referred to as TRI-MP, prolonged allograft survival indefinitely without long-term systemic immunosuppression. TRI-MP treatment reduced expression of inflammatory mediators and enhanced expression of Treg-associated cytokines in allograft tissue. TRI-MP also enriched Treg and reduced inflammatory Th1 populations in allograft draining lymph nodes. This local immunotherapy imparted systemic donor-specific tolerance in otherwise immunocompetent rats, as evidenced by acceptance of secondary skin grafts from the hindlimb donor strain and rejection of skin grafts from a third-party donor strain. Ultimately, this therapeutic approach may reduce, or even eliminate, the need for systemic immunosuppression in VCA or solid organ transplantation.
Identifiants
pubmed: 31792185
pii: 1910701116
doi: 10.1073/pnas.1910701116
pmc: PMC6925993
doi:
Substances chimiques
Cytokines
0
Immunosuppressive Agents
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
25784-25789Subventions
Organisme : NIH HHS
ID : S10 OD011925
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL122489
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI074490
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA175294
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI131453
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI118777
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE021058
Pays : United States
Déclaration de conflit d'intérêts
The authors declare no competing interest.
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