Lymphotoxin expression in human and murine renal allografts

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.

NFκB and Kidney Injury

“…In humans, all the components of the NFκB pathway were shown to be expressed in renal allografts with acute rejection and chronic renal allograft injury through qPCR, but there is no clear functional relationship between the expression of NFκB components and allograft rejection or long-term outcome (124). Spontaneous, clinical operational tolerance, characterized as well-functioning allograft without rejection after recession of immunosuppression, has been associated with lower c-Rel expression and a higher proportion of Tregs in allograft biopsies (125).…”

Influence of polymorphisms in the vascular endothelial growth factor gene on allograft rejection after kidney transplantation: a meta-analysis

“…Allograft rejection can be categorized largely into acute rejection (AR) which occurs days/weeks up until three months post-KT, or chronic rejection (CR) which is seen as progressive loss of graft function after three months post-KT 5 . Key factors that contribute to allograft rejection may involve cytokines that are secreted by immune cells and antibodies against graft antigens 6 . Cytokines have been recognized as potent immunomodulatory biomolecules that mediate physiological and pathological immune responses.…”

Influence of interleukin-18 polymorphisms on kidney transplantation outcomes: A meta-analysis

“…This variation may help individualize immunosuppressive regimens by identifying alleles that could increase risk or confer protection for immune-mediated complications [5]. Cytokines are potent immunomodulatory molecules that mediate the immune response [6]. Their production has been shown to be genetically controlled and polymorphisms of many cytokine genes affect their transcriptional activities, resulting in individual variations in cytokine production [7].…”