Inhibition of spleen tyrosine kinase reduces renal allograft injury in a rat model of acute antibody-mediated rejection in sensitized recipients

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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 signalling 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 (RT1) were immunized with donor (Dark Agouti, RT1) 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 (30mg/kg/bid) (n=11) or vehicle (n=12) from 1hr 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. CONCLUSION: 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.

Original languageEnglish
Pages (from-to)e240-e248
Number of pages9
JournalTransplantation
Volume101
Issue number8
DOIs
Publication statusPublished - 1 Aug 2017

Cite this

@article{bcda98bef2e044ec8ed0ddb8c6625106,
title = "Inhibition of spleen tyrosine kinase reduces renal allograft injury in a rat model of acute antibody-mediated rejection in sensitized recipients",
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 signalling 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 (RT1) were immunized with donor (Dark Agouti, RT1) 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 (30mg/kg/bid) (n=11) or vehicle (n=12) from 1hr 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. CONCLUSION: 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.",
author = "{Ramessur Chandran}, Sharmila and Yingjie Han and Tesch, {Greg H.} and {Di Paolo}, Julie and Mulley, {William R.} and John Kanellis and Ma, {Frank Y.} and Nikolic-Paterson, {David J.}",
year = "2017",
month = "8",
day = "1",
doi = "10.1097/TP.0000000000001826",
language = "English",
volume = "101",
pages = "e240--e248",
journal = "Transplantation",
issn = "0041-1337",
publisher = "LWW",
number = "8",

}

TY - JOUR

T1 - Inhibition of spleen tyrosine kinase reduces renal allograft injury in a rat model of acute antibody-mediated rejection in sensitized recipients

AU - Ramessur Chandran, Sharmila

AU - Han, Yingjie

AU - Tesch, Greg H.

AU - Di Paolo, Julie

AU - Mulley, William R.

AU - Kanellis, John

AU - Ma, Frank Y.

AU - Nikolic-Paterson, David J.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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 signalling 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 (RT1) were immunized with donor (Dark Agouti, RT1) 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 (30mg/kg/bid) (n=11) or vehicle (n=12) from 1hr 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. CONCLUSION: 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.

AB - 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 signalling 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 (RT1) were immunized with donor (Dark Agouti, RT1) 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 (30mg/kg/bid) (n=11) or vehicle (n=12) from 1hr 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. CONCLUSION: 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.

UR - http://www.scopus.com/inward/record.url?scp=85020480369&partnerID=8YFLogxK

U2 - 10.1097/TP.0000000000001826

DO - 10.1097/TP.0000000000001826

M3 - Article

VL - 101

SP - e240-e248

JO - Transplantation

JF - Transplantation

SN - 0041-1337

IS - 8

ER -