Circular RNA MAP2K2‐modified immunosuppressive dendritic cells for preventing alloimmune rejection in organ transplantation

Long‐term patient and graft survival has been achieved in organ transplantation but at the expense of toxic side effects that are associated with long‐term use of nonspecific immunosuppressive drugs. Discovering new regulators of dendritic cells is the key for development of an ideal treatment to pr...

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Bibliographic Details
Published in:Bioengineering & translational medicine 2024-01, Vol.9 (1), p.e10615-n/a
Main Authors: Li, Shuailong, Abu Omar, Amal, Greasley, Adam, Wang, Bowen, Wang, Tan Ze, Chahal, Serina, Thapa, Raj Kumar, Quan, Douglas, Skaro, Anton, Liu, Kexiang, Zheng, Xiufen
Format: Article
Language:English
Subjects:
Animals
Antigens
Biocompatibility
Bone marrow
Cell growth
circMAP2K2
circular RNA
dendritic cell
Dendritic cells
Flow cytometry
Heart transplants
immune rejection
Immune system
immunosuppression
immunosuppressive DCs
Kinases
Laboratories
Leukocytes
Lymphocytes
Mass spectrometry
organ transplantation
Proteins
Rejection
Scientific imaging
Side effects
Surgery
Survival
Transplantation
Variance analysis
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Summary:Long‐term patient and graft survival has been achieved in organ transplantation but at the expense of toxic side effects that are associated with long‐term use of nonspecific immunosuppressive drugs. Discovering new regulators of dendritic cells is the key for development of an ideal treatment to prevent immune rejection. We hypothesized that knockdown of circMAP2K2 induces immunosuppressive DCs and that treatment with circMAP2K2 silenced‐DCs can prevent alloimmune rejection. DCs were cultured and transfected with siRNA for circMAP2K2. circMAP2K2 levels were measured by qRT‐PCR. DC's maturation and immune function were assessed by flow cytometry and mixed lymphocyte reactions. The function of circMAP2K2 was illustrated by a series of RIP and IP. The therapeutics of engineered DCs was tested in a mouse heart transplantation model. We found that circMAP2K2 was highly expressed in mature DCs. Knockdown of circMAP2K2 reduced expression of MHCII, CD40 and CD80, attenuated the ability of DCs to activate allogeneic naïve T cells, and enhanced CD4+CD25+FOXP3+ regulatory T cells (Treg). circMAP2K2‐induced immunosuppressive DCs by interacting with SENP3. Treatment with circMAP2K2‐knockdown DCs attenuated alloimmune rejection and prolonged allograft survival in a murine heart transplantation model. The immune suppression induced in vivo was donor‐antigen specific. In conclusion, knockdown of circMAP2K2 can induce immunosuppressive DCs which are able to inhibit overactive immune response, highlighting a new promising therapeutic approach for immune disorder diseases.
ISSN:2380-6761
2380-6761
DOI:10.1002/btm2.10615