Spleen tyrosine kinase contributes to acute renal allograft rejection in the rat

Sharmila Ramessur, Gregory H Tesch, Yingjie Han, Naomi Woodman, William Mulley, John Kanellis, Kate Blease, Frank Ma, David J Nikolic-Paterson

Research output: Contribution to journalArticleResearchpeer-review

7 Citations (Scopus)

Abstract

Kidney allografts induce strong T-cell and antibody responses which mediate acute rejection. Spleen tyrosine kinase (Syk) is expressed by most leucocytes, except mature T cells, and is involved in intracellular signalling following activation of the Fcgamma-receptor, B-cell receptor and some integrins. A role for Syk signalling has been established in antibody-dependent native kidney disease, but little is known of Syk in acute renal allograft rejection. Sprague-Dawley rats underwent bilateral nephrectomy and received an orthotopic Wistar renal allograft. Recipient rats were treated with a Syk inhibitor (CC0482417, 30 mg/kg/bid), or vehicle, from 1 h before surgery until being killed 5 days later. Vehicle-treated recipients developed severe allograft failure with marked histologic damage in association with dense leucocyte infiltration (T cells, macrophages, neutrophils and NK cells) and deposition of IgM, IgG and C3. Immunostaining identified Syk expression by many infiltrating leucocytes. CC0482417 treatment significantly improved allograft function and reduced histologic damage, although allograft injury was still clearly evident. CC0482417 failed to prevent T-cell infiltration and activation within the allograft. However, CC0482417 significantly attenuated acute tubular necrosis, infiltration of macrophages and neutrophils and thrombosis of peritubular capillaries. In conclusion, this study identifies a role for Syk in acute renal allograft rejection. Syk inhibition may be a useful addition to T-cell-based immunotherapy in renal transplantation.
Original languageEnglish
Pages (from-to)54 - 62
Number of pages9
JournalInternational Journal of Experimental Pathology
Volume96
Issue number1
DOIs
Publication statusPublished - 2015

Cite this

@article{1c9c35bca83345239ac836da5a0d1f6d,
title = "Spleen tyrosine kinase contributes to acute renal allograft rejection in the rat",
abstract = "Kidney allografts induce strong T-cell and antibody responses which mediate acute rejection. Spleen tyrosine kinase (Syk) is expressed by most leucocytes, except mature T cells, and is involved in intracellular signalling following activation of the Fcgamma-receptor, B-cell receptor and some integrins. A role for Syk signalling has been established in antibody-dependent native kidney disease, but little is known of Syk in acute renal allograft rejection. Sprague-Dawley rats underwent bilateral nephrectomy and received an orthotopic Wistar renal allograft. Recipient rats were treated with a Syk inhibitor (CC0482417, 30 mg/kg/bid), or vehicle, from 1 h before surgery until being killed 5 days later. Vehicle-treated recipients developed severe allograft failure with marked histologic damage in association with dense leucocyte infiltration (T cells, macrophages, neutrophils and NK cells) and deposition of IgM, IgG and C3. Immunostaining identified Syk expression by many infiltrating leucocytes. CC0482417 treatment significantly improved allograft function and reduced histologic damage, although allograft injury was still clearly evident. CC0482417 failed to prevent T-cell infiltration and activation within the allograft. However, CC0482417 significantly attenuated acute tubular necrosis, infiltration of macrophages and neutrophils and thrombosis of peritubular capillaries. In conclusion, this study identifies a role for Syk in acute renal allograft rejection. Syk inhibition may be a useful addition to T-cell-based immunotherapy in renal transplantation.",
author = "Sharmila Ramessur and Tesch, {Gregory H} and Yingjie Han and Naomi Woodman and William Mulley and John Kanellis and Kate Blease and Frank Ma and Nikolic-Paterson, {David J}",
year = "2015",
doi = "10.1111/iep.12110",
language = "English",
volume = "96",
pages = "54 -- 62",
journal = "International Journal of Experimental Pathology",
issn = "0959-9673",
publisher = "Wiley-Blackwell",
number = "1",

}

Spleen tyrosine kinase contributes to acute renal allograft rejection in the rat. / Ramessur, Sharmila; Tesch, Gregory H; Han, Yingjie; Woodman, Naomi; Mulley, William; Kanellis, John; Blease, Kate; Ma, Frank; Nikolic-Paterson, David J.

In: International Journal of Experimental Pathology, Vol. 96, No. 1, 2015, p. 54 - 62.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Spleen tyrosine kinase contributes to acute renal allograft rejection in the rat

AU - Ramessur, Sharmila

AU - Tesch, Gregory H

AU - Han, Yingjie

AU - Woodman, Naomi

AU - Mulley, William

AU - Kanellis, John

AU - Blease, Kate

AU - Ma, Frank

AU - Nikolic-Paterson, David J

PY - 2015

Y1 - 2015

N2 - Kidney allografts induce strong T-cell and antibody responses which mediate acute rejection. Spleen tyrosine kinase (Syk) is expressed by most leucocytes, except mature T cells, and is involved in intracellular signalling following activation of the Fcgamma-receptor, B-cell receptor and some integrins. A role for Syk signalling has been established in antibody-dependent native kidney disease, but little is known of Syk in acute renal allograft rejection. Sprague-Dawley rats underwent bilateral nephrectomy and received an orthotopic Wistar renal allograft. Recipient rats were treated with a Syk inhibitor (CC0482417, 30 mg/kg/bid), or vehicle, from 1 h before surgery until being killed 5 days later. Vehicle-treated recipients developed severe allograft failure with marked histologic damage in association with dense leucocyte infiltration (T cells, macrophages, neutrophils and NK cells) and deposition of IgM, IgG and C3. Immunostaining identified Syk expression by many infiltrating leucocytes. CC0482417 treatment significantly improved allograft function and reduced histologic damage, although allograft injury was still clearly evident. CC0482417 failed to prevent T-cell infiltration and activation within the allograft. However, CC0482417 significantly attenuated acute tubular necrosis, infiltration of macrophages and neutrophils and thrombosis of peritubular capillaries. In conclusion, this study identifies a role for Syk in acute renal allograft rejection. Syk inhibition may be a useful addition to T-cell-based immunotherapy in renal transplantation.

AB - Kidney allografts induce strong T-cell and antibody responses which mediate acute rejection. Spleen tyrosine kinase (Syk) is expressed by most leucocytes, except mature T cells, and is involved in intracellular signalling following activation of the Fcgamma-receptor, B-cell receptor and some integrins. A role for Syk signalling has been established in antibody-dependent native kidney disease, but little is known of Syk in acute renal allograft rejection. Sprague-Dawley rats underwent bilateral nephrectomy and received an orthotopic Wistar renal allograft. Recipient rats were treated with a Syk inhibitor (CC0482417, 30 mg/kg/bid), or vehicle, from 1 h before surgery until being killed 5 days later. Vehicle-treated recipients developed severe allograft failure with marked histologic damage in association with dense leucocyte infiltration (T cells, macrophages, neutrophils and NK cells) and deposition of IgM, IgG and C3. Immunostaining identified Syk expression by many infiltrating leucocytes. CC0482417 treatment significantly improved allograft function and reduced histologic damage, although allograft injury was still clearly evident. CC0482417 failed to prevent T-cell infiltration and activation within the allograft. However, CC0482417 significantly attenuated acute tubular necrosis, infiltration of macrophages and neutrophils and thrombosis of peritubular capillaries. In conclusion, this study identifies a role for Syk in acute renal allograft rejection. Syk inhibition may be a useful addition to T-cell-based immunotherapy in renal transplantation.

UR - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352352/pdf/iep0096-0054.pdf

U2 - 10.1111/iep.12110

DO - 10.1111/iep.12110

M3 - Article

VL - 96

SP - 54

EP - 62

JO - International Journal of Experimental Pathology

JF - International Journal of Experimental Pathology

SN - 0959-9673

IS - 1

ER -