MHC class II, antigen presentation and tumor necrosis factor in renal tubular epithelial cells

MHC class II, antigen presentation and tumor necrosis factor in renal tubular epithelial cells. Proximal tubular (PT) epithelial cells express MHC class II (la) antigens in immunologically-mediated renal injury. To study the role of PT as accessory cells, we generated several murine PT-like epithelial cell lines by transformation with origin-defective SV40 DNA. These transformed cell lines display typical alkaline phosphatase and γglutamyl-transpeptidase enzyme activity, proliferation to epidermal growth factor (EGF) and sodium-dependent glucose uptake. Clonal lines of transformed tubular cells from both normal C3H/FeJ and autoimmune MRL-lpr mice do not constitutively express la antigens or mRNA for class II. However, stimulation with recombinant interferon-γ (rIFN-γ) induces la mRNA and surface product in the cell lines. These la-positive cells can process and present hen egg-white lysozyme (HEL) to antigen-specific Iak-restricted T cell hybrids. Unstimulated tubular cells do not express detectable IL-1α, IL-1β, TNF-α, or IL-6 mRNA. However, stimulation with IL-1α or LPS induces TNF-α transcripts. We conclude that these cell lines have characteristics most consistent with a proximal tubular origin. They also bear characteristics of accessory cells such as processing and presentation of antigen and TNF-α gene expression. We speculate that PT have the capacity to participate in the pathogenesis of immune renal injury

Acute interstitial nephritis of HIV-positive patients under atazanavir and tenofovir therapy in a retrospective analysis of kidney biopsies

We performed a retrospective analysis on kidney biopsies of 30 human immunodeficiency virus (HIV)-positive patients. Twenty-two of them received highly active antiretroviral therapy (HAART). Tenofovir containing HAART together with atazanavir, a new protease inhibitor, was administered to three patients. All of them developed acute renal failure. The kidney biopsies of these patients showed an acute interstitial nephritis or a chronic interstitial nephritis with an acute component. Withdrawal of atazanavir and tenofovir resulted in recovery of renal function in all three patients. Acute interstitial nephritis was observed only in 1 of 19 patients without atazanavir or tenofovir treatment. We conclude that acute interstitial nephritis and consecutive acute renal failure is a relevant side effect of atazanavir and tenofovir therapy in HIV-positive patients

The Role of T Cell Costimulation via DNAM-1 in Kidney Transplantation

DNAX accessory protein-1 (DNAM-1, CD226) is a co-stimulatory and adhesion molecule expressed mainly by natural killer cells and T cells. DNAM-1 and its two ligands CD112 and CD155 are important in graft-versus-host disease, but their role in solid organ transplantation is largely unknown. We investigated the relevance of this pathway in a mouse kidney transplantation model. CD112 and CD155 are constitutively expressed on renal tubular cells and strongly upregulated in acutely rejected renal allografts. In vitro DNAM-1 blockade during allogeneic priming reduced the allospecific T cell response but not the allospecific cytotoxicity against renal tubular epithelial cells. Accordingly, absence of DNAM-1 in recipient mice or absence of CD112 or CD155 in the kidney allograft did not significantly influence renal function and severity of rejection after transplantation, but led to a higher incidence of infarcts in CD112 and CD155 deficient kidney allografts. Thus, DNAM-1 blockade is not effective in preventing transplant rejection. Despite of being highly expressed, CD112 and CD155 do not appear to play a major immunogenic role in kidney transplantation. Considering the high incidence of renal infarcts in CD112 and CD155 deficient grafts, blocking these molecules might be detrimental

Similar rejection but higher rate of infarcts in renal allografts from CD155 or CD112 KO donors.

<p>Renal allografts were performed in a non-life supporting manner. All allografts were harvested on day 21. Strain combinations were fully MHC-mismatched: (A) BALB/c WT (n = 5) or CD155 KO (n = 5) into B6 and (B) B6 WT (n = 5) or CD112 KO (n = 3) into CBA. Representative H & E stainings are shown. All allografts displayed severe interstitial infiltrates as well as tubulitis in more than 50% of the graft. Furthermore, arteritis was detected in all grafts classifying them to Banff grade II or III. The chosen pictures are taken from allografts with the following Banff grades: (A) BALB/c to B6: IIA; CD155 KO to B6: IIB; (B) B6 to CBA: IIB; CD112 to CBA: III (scale bar 200 μm). (C) Apoptotic cells in renal allografts were detected by immunohistochemical staining for ssDNA. (D) Representative picture of a necrotic area in an H & E slide of a CD155 KO renal allograft (scale bar 1200 μm). (E) The area of necrotic tissue in H & E stained slides from renal allografts was detected by scanning them at a resolution of 0.23 μm. Quantification was performed using NDPView software. Groups were compared using the Mann-Whitney-test.</p

Renal allograft function in DNAM-1 deficient recipients.

<p>Renal transplantation was performed in two steps. First, fully MHC-mismatched CBA kidney allografts were transplanted into WT BALB/c or DNAM-1 deficient mice. The second kidney was removed 7 days after surgery and 3 days later renal graft function was estimated by measurement of serum creatinine und urea. Mean BUN WT 167.2 ± 48.4 mg/dl vs. DNAM1-KO 97.5 ± 42.1 mg/dl, P = 0.36. One mouse in the DNAM1-KO group and 2 mice in the WT group had to be excluded because of surgical complications. Thus, in the final analysis 6 mice were included in the WT group and 4 in the DNAM1-KO group.</p

DNAM-1 and its two ligands.

<p>Schematic illustration of the DNAM-1 pathway in the interaction between a T cell and an antigen presenting cell (APC). The T cell recognizes its cognate antigen in the context of MHC with its T cell receptor (TCR). For further activation it needs costimulatory signals, which can be delivered via DNAM-1 (CD226) binding to its two ligands CD155 and CD112 expressed on the APC. CD155 and CD112 also bind TIGIT, a co-inhibitory receptor of the Ig-family. CD155 has an additional receptor called CD96.</p