Inhibition of in vitro and in vivo T cell responses by recombinant human Tim-1 extracellular domain proteins
INTERNATIONAL IMMUNOLOGY
Authors: Mesri, M; Smithson, G; Ghatpande, A; Chapoval, A; Shenoy, S; Boldog, F; Hackett, C; Pena, CE; Burgess, C; Bendele, A; Shimkets, RA; Starling, GC
Abstract
Members of the T cell, Ig domain and mucin domain (Tim) family of proteins have recently been implicated in the control of T cell-mediated immune responses. Tim-1 (HUGO designation HAVCR1) polymorphisms have been linked to the regulation of atopy in mice and humans, suggestive of a role in immune regulation. Tim-1 is expressed upon activation of T cells. In concert with the increased expression of Tim-1, a binding partner for the extracellular domain of Tim-1 (eTim-1) was induced on activated T cells, and mRNA expression data was consistent with the binding partner being Tim-4. We found that co-immobilized recombinant eTim-1 was able to inhibit T cell activation mediated by CD3 + CD28 mAb. eTim-1 mediated its inhibitory effects on proliferation by arresting cell cycle at G(0)/G(1) phase through regulation of cell cycle proteins. In vivo, administration of eTim-1 proteins led to a decrease in both ear (contact hypersensitivity to oxazolone) and joint (methylated BSA antigen-induced arthritis) swelling. The inhibitory activity of eTim-1 in the T(h)1-dependent models was evidence that eTim-1 is able to modulate T cell responses. Manipulation of the Tim-1 interaction with its binding partner on T cells may therefore provide a novel target for therapeutic intervention in T cell-mediated diseases.
Molecular biomarker candidates of acute kidney injury in zero-hour renal transplant needle biopsies
TRANSPLANT INTERNATIONAL
Authors: Korbely, Reka; Wilflingseder, Julia; Perco, Paul; Kainz, Alexander; Langer, Robert M.; Mayer, Bernd; Oberbauer, Rainer
Abstract
P>The aim of this study was to assess gene expression levels of four biomarker candidates [lipocalin 2 (LCN2), the kidney injury molecule 1 (HAVCR1), netrin 1, and the cysteine-rich, angiogenic inducer, 61] in the tubulointerstitial and the glomerular compartment of zero-hour kidney biopsies in order to predict developing delayed graft function (DGF). Thirty-four needle kidney biopsy samples of deceased donors were manually microdissected. Relative gene expression levels were determined by real-time RT-PCR. For the validation of the biomarker candidates, we calculated a mixed model comparing kidneys with DGF, primary function and control samples from the healthy parts of tumor nephrectomies. Significant biomarker candidates were analyzed together with donor age in multivariable regression models to determine the prognostic value. Expression levels of LCN2 and HAVCR1 in the tubulointerstitium were significantly upregulated in the DGF group (LCN2: fold change = 3.78, P = 0.031 and HAVCR1: fold change = 3.44, P = 0.010). Odds ratios of both genes could not reach significance in the multivariable model together with donor age. The area under the curve of the receiver operating characteristic ranges between 0.75 and 0.83. LCN2 and HAVCR1 gene expression levels in zero-hour biopsies show potential to act as early biomarkers for DGF.