Please use this identifier to cite or link to this item:
https://repository.monashhealth.org/monashhealthjspui/handle/1/39421
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 | Link to associated publication: | Click here for full text options | 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 | Subjects: | *antibody mediated rejection article bilateral nephrectomy cell infiltration controlled study *enzyme inhibition graft recipient kidney transplantation kidney tubule damage leukocyte limit of quantitation macrophage natural killer cell nonhuman rat *renal graft dysfunction/et [Etiology] spleen cell thrombosis complement component C4d/ec [Endogenous Compound] immunoglobulin G/ec [Endogenous Compound] *protein kinase Syk/ec [Endogenous Compound] protein kinase Syk inhibitor tacrolimus unclassified drug gs 492429 animal cell priority journal animal experiment animal model animal tissue leukocyte limit of quantitation macrophage natural killer cell nonhuman priority journal rat *renal graft dysfunction / *etiology spleen cell thrombosis cell infiltration graft recipient bilateral nephrectomy Article *antibody mediated rejection controlled study kidney tubule damage animal experiment animal cell *enzyme inhibition kidney transplantation animal tissue animal model |
Appears in Collections: | Articles |
Show full item record
Items in Monash Health Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.