Leptin Promotes Corneal Allograft Rejection In a Rat Model Via Enhancing Macrophage Activation And Cytokine Production

Obesity is closely related to exacerbated graft rejection and worse graft survival. High leptin levels, caused by excessive adipose cells in obese individuals, may exert a pivotal role in the pathogenesis of allograft rejection. However, the role and underlying mechanism of leptin in allograft rejection remains unclear. This study explored the role and potential mechanism of leptin in allograft rejection in rats. We performed allogeneic corneal transplantation in rats. The recipients were treated with subconjunctival injections of recombinant rat leptin after transplantation. Clinical evaluation, immunohistological assessment, real-time PCR and flow cytometry were administrated. RAW264.7 macrophages were handled with leptin (3 µg/mL) for 4 hours and then were treated with lipopolysaccharide (10ng/mL) for 24 hours. The culture supernatants were acquired for ELISA. NF-κBp65 activation in RAW264.7 macrophages was detected by western blot. Our results showed that the leptin-treated rats had a significantly reduced corneal graft mean survival time. The number of infiltrating F4/80+CD68+ macrophages increased in the leptin-treated corneal grafts. Monocyte chemoattractant protein-1(MCP-1), tumor necrosis factor-α (TNF-α) and interleukin 6(IL-6) mRNA expression level was higher in the leptin-treated corneal grafts than in the control allografts. Leptin treatment notably increased the frequency and number of T helper 1 (Th1) cells and T helper 17 (Th17) cells in rat ipsilateral cervical lymph nodes. Leptin enhanced NF-κBp65 activation and promoted MCP-1, TNF-α and IL-6 production in RAW264.7 macrophages. Leptin promoted corneal allograft rejection by enhancing the recruitment and activation of macrophages.

Tissue Engineering Meets Nanotechnology: Molecular Mechanism Modulations in Cornea Regeneration

Nowadays, tissue engineering is one of the most promising approaches for the regeneration of various tissues and organs, including the cornea. However, the inability of biomaterial scaffolds to successfully integrate into the environment of surrounding tissues is one of the main challenges that sufficiently limits the restoration of damaged corneal tissues. Thus, the modulation of molecular and cellular mechanisms is important and necessary for successful graft integration and long-term survival. The dynamics of molecular interactions affecting the site of injury will determine the corneal transplantation efficacy and the post-surgery clinical outcome. The interactions between biomaterial surfaces, cells and their microenvironment can regulate cell behavior and alter their physiology and signaling pathways. Nanotechnology is an advantageous tool for the current understanding, coordination, and directed regulation of molecular cell–transplant interactions on behalf of the healing of corneal wounds. Therefore, the use of various nanotechnological strategies will provide new solutions to the problem of corneal allograft rejection, by modulating and regulating host–graft interaction dynamics towards proper integration and long-term functionality of the transplant.

Corneal Lymphangiogenesis: Current Pathophysiological Understandings and Its Functional Role in Ocular Surface Disease

The cornea is a transparent and avascular tissue that plays a central role in light refraction and provides a physical barrier to the external environment. Corneal avascularity is a unique histological feature that distinguishes it from the other parts of the body. Functionally, corneal immune privilege critically relies on corneal avascularity. Corneal lymphangiogenesis is now recognized as a general pathological feature in many pathologies, including dry eye disease (DED), corneal allograft rejection, ocular allergy, bacterial and viral keratitis, and transient corneal edema. Currently, sizable data from clinical and basic research have accumulated on the pathogenesis and functional role of ocular lymphangiogenesis. However, because of the invisibility of lymphatic vessels, ocular lymphangiogenesis has not been studied as much as hemangiogenesis. We reviewed the basic mechanisms of lymphangiogenesis and summarized recent advances in the pathogenesis of ocular lymphangiogenesis, focusing on corneal allograft rejection and DED. In addition, we discuss future directions for lymphangiogenesis research.

Role of Immune Cell Diversity and Heterogeneity in Corneal Graft Survival: A Systematic Review and Meta-Analysis

Corneal transplantation is one of the most successful forms of solid organ transplantation; however, immune rejection is still a major cause of corneal graft failure. Both innate and adaptive immunity play a significant role in allograft tolerance. Therefore, immune cells, cytokines, and signal-transduction pathways are critical therapeutic targets. In this analysis, we aimed to review the current literature on various immunotherapeutic approaches for corneal-allograft rejection using the PubMed, EMBASE, Web of Science, Cochrane, and China National Knowledge Infrastructure. Retrievable data for meta-analysis were screened and assessed. The review, which evaluated multiple immunotherapeutic approaches to prevent corneal allograft rejection, showed extensive involvement of innate and adaptive immunity components. Understanding the contribution of this immune diversity to the ocular surface is critical for ensuring corneal allograft survival.