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 Fcγ-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.
authors.affiliation: Department of Nephrology, Monash Medical Centre, Clayton, Vic., Australia; Centre for Inflammatory Diseases, Monash Medical Centre, Monash University, Clayton, Vic., Australia.
authors.forename: Sharmila
authors.initials: S
authors.lastname: Ramessur Chandran
authors.forename: Greg H
authors.initials: GH
authors.lastname: Tesch
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Han
authors.forename: Naomi
authors.initials: N
authors.lastname: Woodman
authors.forename: William R
authors.initials: WR
authors.lastname: Mulley
authors.forename: John
authors.initials: J
authors.lastname: Kanellis
authors.forename: Kate
authors.initials: K
authors.lastname: Blease
authors.forename: Frank Y
authors.initials: FY
authors.lastname: Ma
authors.forename: David J
authors.initials: DJ
authors.lastname: Nikolic-Paterson
mesh_terms: D000208:Acute Disease; D064591:Allografts; D000818:Animals; D002633:Chemotaxis; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000201:enzymology* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology / Q000601:surgery*; D016030:Kidney Transplantation / Q000009:adverse effects*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D015398:Signal Transduction; D000072377:Syk Kinase; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D013997:Time Factors
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606898:Syk protein, rat
keywords: Syk; T-cell activation; humoral rejection; macrophage; neutrophil