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Published on: November 17, 2014
NF-κB c-Rel Is a Potential Therapeutic Target for Acute Corneal Transplant Rejection
Qian Zheng1,2, Ruiling Liu1, Bian Jiang3
1Eye Institute of Shandong First Medical University, State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Qingdao, China.
Purpose:
The purpose of this study was to determine the role of nuclear factor kappa B (NF-κB) c-Rel during acute corneal transplant rejection and whether targeting c-Rel can reduce corneal transplant rejection.
Methods:
Allogeneic corneal transplantation was performed in wild-type and c-Rel-deficient mice. Corneal graft survival rate, opacity, neovascularization, and edema were evaluated by slit-lamp microscopy. Adeno-associated virus 6 (AAV6) expressing c-Rel-specific small hairpin RNA (AAV6-shRel) and the small-molecule compound pentoxifylline (PTXF) were used to reduce c-Rel expression. Enzyme-linked immunosorbent assay was used to determine the expression of inflammatory cytokines. c-Rel expression was determined by quantitative RT-PCR and western blot. The effect of c-Rel inhibition on corneal transplant rejection was examined using a mouse model of acute allogeneic corneal transplantation. Tear production and corneal sensitivity were measured to determine the potential toxicity of AAV6-shRel and PTXF.
Results:
The expression of c-Rel and its inflammatory targets was increased in both mice and patients with corneal transplant rejection. Loss of c-Rel reduced corneal transplant rejection in mouse. Both AAV6-shRel and PTXF were able to downregulate the expression of c-Rel and its inflammatory targets in vitro. Treatment with AAV6-shRel or PTXF reduced corneal transplant rejection in mouse and downregulated the expression of inflammatory cytokines in peripheral blood mononuclear cells from patients with corneal transplant rejection. Treatment with AAV6-shRel or PTXF displayed no side effects on tear production or corneal sensitivity.
Conclusions:
Increased expression of c-Rel is a risk factor for acute corneal transplant rejection, and targeting c-Rel can efficiently reduce corneal transplant rejection.
Insights
Nuclear factor kappa B (NF-κB) c-Rel is a risk factor in corneal transplant rejection. Targeting c-Rel with AAV6-shRel or PTXF effectively reduces rejection and inflammation without side effects.
Area of Science:
- Immunology
- Ophthalmology
- Molecular Biology
Background:
- Acute corneal transplant rejection involves complex inflammatory pathways.
- Nuclear factor kappa B (NF-κB) signaling, particularly the c-Rel subunit, is implicated in immune responses.
- Understanding the role of c-Rel in corneal transplantation is crucial for developing new therapeutic strategies.
Purpose of the Study:
- To investigate the role of NF-κB c-Rel in acute corneal transplant rejection.
- To evaluate the efficacy of targeting c-Rel in reducing corneal transplant rejection.
Main Methods:
- Allogeneic corneal transplantation performed in wild-type and c-Rel-deficient mice.
- Evaluation of graft survival, opacity, neovascularization, and edema using slit-lamp microscopy.
- Inhibition of c-Rel using adeno-associated virus 6 (AAV6) expressing c-Rel-specific small hairpin RNA (AAV6-shRel) and pentoxifylline (PTXF).
Main Results:
- c-Rel expression and inflammatory targets were elevated in corneal transplant rejection.
- Loss of c-Rel significantly reduced corneal transplant rejection in mice.
- AAV6-shRel and PTXF treatments downregulated c-Rel and inflammatory cytokines, reducing rejection without toxicity.
Conclusions:
- Elevated c-Rel expression is a risk factor for acute corneal transplant rejection.
- Targeting c-Rel offers a promising therapeutic approach to mitigate corneal transplant rejection.
- Therapeutic inhibition of c-Rel demonstrates safety and efficacy in preclinical models.
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