Abstract
BackgroundChronic renal transplant dysfunction is characterized by loss of renal function and tissue remodeling, including chronic inflammation and lymph vessel formation. Proteoglycans are known for their chemokine presenting capacity. We hypothesize that interruption of the lymphatic chemokine–proteoglycan interaction interferes with the lymphatic outflow of leukocytes from the renal graft and might decrease the anti-graft allo-immune response.MethodsIn a rat renal chronic transplant dysfunction model (female Dark-Agouti to male Wistar Furth), chemokines were profiled by qRT-PCR in microdissected tubulo-interstitial tissue. Disruption of lymphatic chemokine–proteoglycan interaction was studied by (non-anticoagulant) heparin-derived polysaccharides in vitro and in renal allografts. The renal allograft function was assessed by rise in plasma creatinine and urea.ResultsWithin newly-formed lymph vessels of transplanted kidneys, numerous CD45+ leukocytes were found, mainly MHCII+, ED-1-, IDO-, HIS14-, CD103- antigen presenting cells, most likely representing a subset of dendritic cells. Treatment of transplanted rats with regular heparin and two different (non-)anticoagulant heparin derivatives revealed worsening of kidney function only in the glycol-split heparin treated group despite a two-fold reduction of tubulo-interstitial leukocytes (p<0.02). Quantitative digital image analysis however revealed increased numbers of intra-lymphatic antigen-presenting cells only in the glycol-split heparin group (p<0.01). The number of intra-lymphatic leukocytes significantly correlates with plasma creatinine and urea, and inversely with creatinine clearance.ConclusionsTreatment of transplanted rats with glycol-split heparin significantly increases the number of intra-lymphatic antigen presenting cells, by increased renal diffusion of lymphatic chemokines, thereby increasing the activation and recruitment of antigen presenting cells towards the lymph vessel. This effect is unwanted in the transplantation setting, but might be advantageous in e.g., dendritic cell vaccination.
Highlights
Chronic transplant dysfunction (CTD) is characterized by decline in kidney allograft function over time and is related to progressive tissue remodeling in the transplanted kidney
Treatment of transplanted rats with glycol-split heparin significantly increases the number of intra-lymphatic antigen presenting cells, by increased renal diffusion of lymphatic chemokines, thereby increasing the activation and recruitment of antigen presenting cells towards the lymph vessel
The results showed intra-lymphatic cells to be mainly MHCII+, ED-1, CD103- and HIS14- suggesting antigen-presenting cells are predominantly accumulating in lymph vessels in CTD (Fig 3G)
Summary
Chronic transplant dysfunction (CTD) is characterized by decline in kidney allograft function over time and is related to progressive tissue remodeling in the transplanted kidney. Lymphangiogenesis is the growth of new lymph vessel via sprouting from existing lymph vessels or by trans-differentiation of monocytes/macrophages into lymphatic endothelial cells, processes which are often initiated by tissue inflammation [4]. Inflammation promotes lymph angiogenesis by stimulating the production of lymphangiogenic factors like vascular endothelial growth factor C (VEGF-C) by activated tubular epithelial cells and macrophages [5,6], while lymph vessels can produce pro-inflammatory cytokines and form the major exit route for leukocytes. Chronic renal transplant dysfunction is characterized by loss of renal function and tissue remodeling, including chronic inflammation and lymph vessel formation. We hypothesize that interruption of the lymphatic chemokine–proteoglycan interaction interferes with the lymphatic outflow of leukocytes from the renal graft and might decrease the anti-graft allo-immune response.
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