Lymphatic Trafficking in the Eye: Modulation of Lymphatic Trafficking to Promote Corneal Transplant Survival

Abstract

(Lymph)angiogenesis into the cornea prior to and after corneal transplantation is a critical risk factor for allograft rejection. Lymphatic vessels even more than blood vessels seem important in mediating immune responses, as they facilitate allograft sensitization in the draining lymph nodes. Thus, the concept of modulating lymphatic trafficking to promote corneal graft survival seems promising. A variety of approaches has been developed to inhibit progressive lymphangiogenesis in experimental settings. Recently, additionally to pharmacological approaches, clinically available techniques such as UVA-based corneal collagen crosslinking and fine needle diathermy were reported to be effective in regressing lymphatic vessels and to experimentally promote graft survival. Clinical pilot studies also suggest the efficacy of blocking antigen presenting cell trafficking to regional lymph nodes by regressing corneal lymphatic vessels to enhance allograft survival in high-risk eyes. In this article, we will give an overview of current strategies to modulate lymphatic trafficking with a special focus on recently reported strategies, which may be easy to translate into clinical practice. This novel concept of temporary, pretransplant regression of lymphatic vessels at the site of transplantation to promote subsequent corneal transplant survival (“lymphangioregressive preconditioning”) may also be applicable to other transplantation sites later.

Neutrophil Interactions with the Lymphatic System

“…For instance, inhibiting the lymphatic vasculature led to increased inflammation in mouse models of skin inflammation [100,101], inflammatory bowel disease [102,103] and rheumatoid arthritis [104]. However, inhibiting this process improves graft survival in corneal transplantation [105,106].…”

Lymphatic Vessel Regression and Its Therapeutic Applications: Learning From Principles of Blood Vessel Regression

“…We have arrived at this nuanced understanding of apoptosis in BV regression as a result of much research, and to our knowledge, there have been few investigations of the role of apoptosis in LV regression. In a study, Hou et al (2021) utilized ultraviolet A light crosslinking to induce regression of corneal LVs and BVs in an apoptosis-dependent manner. Perhaps in an example of migration-dependent temporary LV regression, Gur-Cohen et al (2019) demonstrated a transient dissociation of LVs from the hair follicle stem cell niche after the onset of the hair cycle and noted the absence of apoptosis in this context.…”

“…Despite the advent of human leukocyte antigen matching and the administration of immunosuppressants, allograft rejection remains the leading cause of graft failure beyond 1 year post-transplantation ( Yamakawa et al, 2018 ; Wong, 2020 ). Lymphangiogenesis has been observed following transplantation of solid organs such as the heart, kidney, and lungs as well as the normally avascular cornea ( Wong, 2020 ; Hou et al, 2021 ). This proliferation of novel LVs connects the transplanted organ to the systemic lymphatic circulation, thereby facilitating the arrival of antigen-presenting cells (APCs) to draining lymph nodes ( Donnan et al, 2021 ).…”

“…Due to its immune privileged and avascular nature, the murine cornea also has been utilized as a research model of transplant rejection. Studies have repeatedly demonstrated that corneal neovascularization is correlated with corneal transplantation rejection risk ( Bachmann et al, 2010 ; Le et al, 2018 ; Hou et al, 2021 ). Moreover, multiple studies from the Cursiefen group showed that promoting LV regression prior to corneal transplantation in high-risk eyes improves the likelihood of graft survival ( Hou et al, 2017 , 2018 ; Le et al, 2018 ).…”

Lymphatic Clearance of Immune Cells in Cardiovascular Disease

“…In addition to regulating interstitial fluid homeostasis, the lymphatics are an integral component of the immune system, facilitating the transport of immune cells, pathogens, and antigens [101] from the sites of injured and infected tissues to draining lymph nodes (dLNs) for generation of protective T and B cell responses [101,102]. Allied to this, they also provide a key route for exit of immune cells during the resolution of tissue inflammation, not only following myocardial infarction, but also lung injury and allograft rejection [97,[103][104][105]. In normal resting tissue the numbers of immune cells migrating in afferent lymphatics are small, comprising mainly T-cells (approximately 90%) and immature antigen presenting dendritic cells (DCs) engaged in background immune surveillance.…”