Treatment of a MyD88 inhibitor alleviates rejection and inflammation in xenotransplantation by inhibiting dendritic cells activation and trained immunity in macrophages.
Int Immunopharmacol
; 130: 111664, 2024 Mar 30.
Article
in En
| MEDLINE
| ID: mdl-38377850
ABSTRACT
BACKGROUND:
Acute vascular rejection (AVR) and systemic inflammation in xenograft recipients (SIXR) negatively impact the xenografts survival, and novel immunosuppressants are required to improve survival outcomes. We previously reported that TJ-M2010-5, a myeloid differentiation factor 88 (MyD88) inhibitor, exerts excellent anti-rejection effects in allogeneic transplantation. The aim of the present study was to evaluate the efficacy of TJ-M2010-5 in preventing AVR and SIXR and to investigate whether combined treatment of TJ-M2010-5 with anti-CD154 antibody (MR1) could prolong xenograft survival furthermore.METHODS:
A model involving heart transplantation from Sprague-Dawley rats to BALB/c mice was established in vivo, and the xenografts developed typical AVR. Bone marrow-derived dendritic cells and macrophages were cultured to study the underlying mechanisms induced by rat cardiomyocyte lysate stimulation in vitro.RESULTS:
TJ-M2010-5 monotherapy prolonged xenograft survival, although combination treatment with MR1 further enhanced the anti-AVR and anti-SIXR effects with about 21 days graft survival, compared to monotherapy. TJ-M2010-5 reduced dendritic cell and macrophage activation induced by xenotransplantation, downregulated CD80/CD86 expression, suppressed B-cell activation and anti-donor antibody generation, reduced pro-inflammatory cytokine production and tissue factor expression, and attenuated epigenetic modifications underlying interleukin-6 and tumor necrosis factor-α production in macrophages by inhibiting nuclear factor kappa B nuclear translocation.CONCLUSIONS:
TJ-M2010-5 attenuated AVR and SIXR and contributed to xenograft survival by inhibiting dendritic cell and macrophage activation. A dual-system inhibition strategy combining TJ-M2010-5 with anti-CD154 antibody achieved better results in xenotransplantation.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Piperazines
/
Thiazoles
/
Heart Transplantation
/
Myeloid Differentiation Factor 88
Limits:
Animals
/
Humans
Language:
En
Journal:
Int Immunopharmacol
/
Int. immunopharmacol
/
International immunopharmacology
Journal subject:
ALERGIA E IMUNOLOGIA
/
FARMACOLOGIA
Year:
2024
Document type:
Article
Affiliation country:
China
Country of publication:
Netherlands