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Title: | Inhibition of Spleen Tyrosine Kinase Reduces Renal Allograft Injury in a Rat Model of Acute Antibody-Mediated Rejection in Sensitized Recipients. | Authors: | Nikolic-Paterson D.J. ;Han Y.;Tesch G.H.;DI Paolo J.;Mulley W.R.;Kanellis J.;Ma F.Y.;Ramessur Chandran S. | Monash Health Department(s): | Nephrology | Institution: | (Ramessur Chandran, Han, Tesch, Mulley, Kanellis, Ma, Nikolic-Paterson) Department of Nephrology, Monash Medical Centre, Clayton, VIC, Australia (Ramessur Chandran, Han, Tesch, Mulley, Kanellis, Ma, Nikolic-Paterson) Monash University Centre for Inflammatory Diseases, Monash Medical Centre, Clayton, VIC, Australia (DI Paolo) Gilead Sciences, Foster City, CA, United States | Issue Date: | 16-Aug-2017 | Copyright year: | 2017 | Publisher: | Lippincott Williams and Wilkins (E-mail: kathiest.clai@apta.org) | Place of publication: | United States | Publication information: | Transplantation. 101 (8) (pp e240-e248), 2017. Date of Publication: 01 Aug 2017. | Journal: | Transplantation | Abstract: | Background Organ transplantation into sensitized patients with preexisting donor-specific antibodies (DSA) is very challenging. Spleen tyrosine kinase (Syk) promotes leukocyte recruitment and activation via signaling through various cell surface receptors. We investigated whether a selective Syk inhibitor (GS-492429) could suppress antibody-mediated rejection (AMR) in a rat model of AMR in sensitized recipients. Methods Recipient Lewis rats (RT1l) were immunized with donor (Dark Agouti, RT1av1) spleen cells (day -5). Recipients underwent bilateral nephrectomy and orthotopic renal transplantation (day 0). Cellular rejection was minimized by tacrolimus treatment from day -1. Groups received GS-492429 (30 mg/kg, twice a day) (n = 11) or vehicle (n = 12) from 1 hour before transplantation until being killed on day 3. Results Vehicle-treated recipients developed graft dysfunction on day 1 which rapidly worsened by day 3. Histology showed severe damage (thrombosis, acute tubular injury, capillaritis) and infiltration of many Syk+ leukocytes. GS-492429 did not affect graft dysfunction on day 1, but treatment reduced allograft damage and prevented the rapid deterioration of graft function on day 3. GS-492429 reduced the prominent macrophage infiltrate and reduced the M1 proinflammatory response. Neutrophil and NK cell infiltration and capillary thrombosis were also significantly reduced by GS-492429 treatment. Serum DSA levels and the deposition of IgG and C4d in the allograft were equivalent in the 2 groups. Conclusions Treatment with a Syk inhibitor significantly reduced renal allograft injury in a model of severe antibody-mediated damage in highly sensitized recipients. Further studies are warranted to determine whether Syk inhibition is a potential adjunctive treatment in clinical AMR.Copyright © 2017 Wolters Kluwer Health, Inc. | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1097/TP.0000000000001826 | PubMed URL: | 28594748 [http://www.ncbi.nlm.nih.gov/pubmed/?term=28594748] | ISSN: | 0041-1337 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/39421 | Type: | Article |
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