Reparixin, a CXCR1/2 inhibitor in islet allotransplantation

Abstract

Quality of life in Type 1 diabetic patients may be improved with islet transplantation, but lifelong immunosuppression is required to prevent rejection. Allo-immune response is a key player in graft dysfunction and although the adaptive immune response is well characterized, the effect of the innate immune reaction after transplantation is only recently becoming appreciated. In this study, we address how the innate response affects long-term outcomes in a murine islet allotransplant model. CTLA-4 Ig treatment is known to significantly prolong kidney subcapsular islet allograft survival and enhance glucose tolerance. The combination of CTLA-4 Ig with reparixin, which blocks against inflammatory neutrophil infiltration, yielded no long-term graft survival in an intrahepatic allotransplant model but had similar long-term graft survival in the kidney subcapsular model. Seven days after transplant, serum blood IFN-g levels were significantly lower in the CTLA-4 Ig with reparixin treatment group compared to controls. IL-12p70 cytokine levels were increased with combination treatment, a positive modulation of the inflammatory response to the allograft. Furthermore, KC GRO, also known as CXCL1, was decreased in serum 7 d after transplant. Histologically, we found that immune cell infiltrate, CD4C and CD8C T cell populations along with both CXCR1C and CXCR2C cell populations were decreased within the CTLA-4 Ig and reparixin islet transplant graft. Overall these data provide insight into the down regulation of T-cell recruitment by CTLA-4 Ig and decreased neutrophil activation and recruitment with reparixin after long-term islet graft survival.

Long-term inhibition of dipeptidyl-peptidase 4 reduces islet infiltration and downregulates IL-1β and IL-12 in NOD mice

“…Serum levels of pro-inflammatory and inflammatory cytokines were determined with Mesco Scale Discovery multiplexed-assay kit (Meso Scale Discovery, Gaithersburg, MD, USA). Serum levels of IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, TNF-α and IFN-γ were measured according to the references [16] , [17] .…”

Engineering immunomodulatory biomaterials for type 1 diabetes

“…Although not yet applied for islet transplantation, examples of controlled release platforms incorporating these agents include anti-TNFα released from chitosan, hyaluronic acid or PEG-PCL composites [144][145][146] , and IL-1Ra released from pluronic-based gels, elastin-like polypeptides or co-polymer particles 147,148 . Other candidates that have exhibited anti-coagulation effects on islet in vitro include and thus could be explored for biomaterial-based delivery in vivo include , the thrombin inhibitor Melagatran 149 , anti-coagulant enzyme activated protein C 150 , low molecular weight dextran sulfate 151 , C5a-inhibitory peptide 152 , Withaferin A and other nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibitors 153,154 , as well as reparixin (an CXCL1/2 inhibitor) 155 .an,. Finally, anticoagulant materials, such as heparin-conjugated silk fibroin 156 , and anti-complement surfaces, such as factor H, a serum protein, modified surfaces 157 , can provide anti-inflammatory materials within the islet microenvironment.…”

Synergic Crosstalk between Inflammation, Oxidative Stress, and Genomic Alterations in BCR–ABL-Negative Myeloproliferative Neoplasm

“…This increase contributes to the formation of an endothelial cell niche favoring the growth of MF hematopoietic stem cells [25,26] (Figure 1). This endothelial cell niche can be altered in vitro by reparixin, an antagonist of the receptors for IL-8 CXCR1/2 [27,28], which are present in high abundance on MF spleen CD34+ cells. A clinical trial to evaluate the actions of reparixin in MF has been proposed by the Myeloproliferative Neoplasm Research Consortium.…”