Abstract
The kidney is the most frequently transplanted solid organ. Recruitment of inflammatory cells, ranging from diffuse to nodular accumulations with defined microarchitecture, is a hallmark of acute and chronic renal allograft injury. Lymphotoxins (LTs) mediate the communication of lymphocytes and stromal cells and play a pivotal role in chronic inflammation and formation of lymphoid tissue. The aim of this study was to assess the expression of members of the LT system in acute rejection (AR) and chronic renal allograft injury such as transplant glomerulopathy (TG) and interstitial fibrosis/tubular atrophy (IFTA). We investigated differentially regulated components in transcriptomes of human renal allograft biopsies. By microarray analysis, we found the upregulation of LTβ, LIGHT, HVEM and TNF receptors 1 and 2 in AR and IFTA in human renal allograft biopsies. In addition, there was clear evidence for the activation of the NFκB pathway, most likely a consequence of LTβ receptor stimulation. In human renal allograft biopsies with transplant glomerulopathy (TG) two distinct transcriptional patterns of LT activation were revealed. By quantitative RT-PCR robust upregulation of LTα, LTβ and LIGHT was shown in biopsies with borderline lesions and AR. Immunohistochemistry revealed expression of LTβ in tubular epithelial cells and inflammatory infiltrates in transplant biopsies with AR and IFTA. Finally, activation of LT signaling was reproduced in a murine model of renal transplantation with AR. In summary, our results indicate a potential role of the LT system in acute renal allograft rejection and chronic transplant injury. Activation of the LT system in allograft rejection in rodents indicates a species independent mechanism. The functional role of the LT system in acute renal allograft rejection and chronic injury remains to be determined.
Highlights
Incidence and severity of acute allograft rejection (AR) has been improved with better oneyear graft survival, but long-term allograft outcome has lacked behind expectations [1,2,3,4,5]
Since LTs have an important function in various inflammatory processes we investigated the expression of members of the LT family and LT target genes in acute and chronic allograft injury
The upregulation of transcripts controlled by the NF-κB signalling pathway, such as CXCL12 (SDF-1), CXCL13 (BLC), CCL19 (ELC) and BAFF in acute rejection (AR) and interstitial fibrosis/tubular atrophy (IFTA) (Fig 1C and 1D) strongly suggests activation of the LTα1β2-lymphotoxin β receptor (LTβR) or LIGHT-LTβR axis since aside from CD40L-CD40 interaction and BAFF [37,38,39,40] LTβR activation is one of three major inducers of the alternate NF-κB pathway [41]
Summary
Incidence and severity of acute allograft rejection (AR) has been improved with better oneyear graft survival, but long-term allograft outcome has lacked behind expectations [1,2,3,4,5]. Cytokines play a significant role in acute and chronic allograft rejection. Cytokines stimulate immune cell proliferation, (lymph-) angiogenesis and tissue fibrosis. They can exert immune regulatory functions and limit graft inflammation [4, 6,7,8,9]. Lymphotoxins (LTs) are important players in acute and chronic inflammation, yet their contribution to kidney allograft injury has not been thoroughly investigated. Even though early studies have provided evidence for the expression of LTβ in rejected rat and human renal allografts [25, 26], a comprehensive investigation regarding the expression of LTs in kidney allografts has not been undertaken. The aim of this study was to examine the differential regulation of components of the LT system in human renal allograft biopsies and a murine model of renal transplantation
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