Abstract
Introduction: In spite of recent advances in early renal transplant survival, chronic allograft damage remains a serious obstacle to the long term success of kidney transplantation. Dendritic cells (DCs) and macrophages play a crucial role in both innate and adaptive immune responses provoked by Toll-like receptors (TLRs) that lead to sterile inflammation in ischemia-reperfusion injury. Based on our novel findings of the anti-inflammatory action of CORMs, we studied TLR mediated immune activation in allograft damage to unveil possible TLR/CORMs based therapeutic intervention in renal transplantation. Method: TLR expression in DCs, Macrophage, and human monocytes by RT-PCR, Western Blot and immunostaining. TLR manipulation by over-expressing dominant negative form of specific TLR; blocking by inhibitory peptides; knocking down by siRNA, shRNA; Inhibition with TLR antagonist or inhibitors; Stimulation of TLR with natural ligands or DAMPs; Treatment of cells with CORM401 & inactive CORM401. Detection of IL6, TNFα, IL10, IL12 etc by ELISA. Characterization of the DCs by TLR4, 9, MHCclassII, CD83, CD80, CD86, IL12, IL10 by flow cytometry. Result: When CORM-3 was infused directly into the donor kidney, an improvement in survival, function and histology vs. controls (p<0.05) was observed. In addition, Brown Norway rats were pre-treated with CORM-2 6hr prior to procurement and transplantation into allogeneic Lewis rats. Histologic examination (day10) showed lymphocytic infiltrate, glomerular congestion, and acute tubular necrosis in control animals whereas CORM-2 treated animals had completely normal histology. TLRs were differentially expressed by bone marrow DCs, macrophages and human monocyte-derived cells. Gene expression analysis of 43,000 mRNAs demonstrated that CORM-401 modulated many genes which include markers of DC maturation (CD80, CD83, CD86), diverse immune responses (TLR9, NFkB, TNFa, IL6, IL1b, IL10) and pro-to-anti-inflammatory conversion (Regnase1, TRIB1). Random Forest algorithm analysis on immune functions also concluded wide spectrum of intervention of CORM-401 from immune activation to leukocyte activation.Conclusion: TLRs on DCs and macrophages promote inflammation subsequent to kidney IRI, the leading cause of rejection. CORMs have potential to protect kidney allograft function and survival.
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