Inhibition of Spleen Tyrosine Kinase Reduces Renal Allograft Injury in a Rat Model of Acute Antibody-Mediated Rejection in Sensitized Recipients

Chandran, Sharmila Ramessur; Han, Yingjie; Tesch, Greg H.; Paolo, Julie Di; Mulley, William R.; Kanellis, John; Frank, Y.; Nikolic-Paterson, David J.

doi:10.1097/tp.0000000000001826

Cited by 11 publications

(8 citation statements)

References 36 publications

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“…In addition to B cells, other inflammatory cells such as macrophages, T cells, and NK cells are also well known to infiltrate renal allografts during AMR and have proved to jointly contribute to AMR allograft injuries . In accordance with other studies and our previous results showing that macrophages are the most predominant inflammatory cells infiltrating the grafts of AMR, and that M1 macrophages play a dominant role in the pathogenesis of AMR, we demonstrated here that graft‐infiltrating macrophages predominantly polarized to M1 subsets in acute AMR, whereas the absolute numbers of total macrophages as well as M1 and M2 cells in grafts were dramatically reduced when treated with triptolide, and the rise of M2/Mφ ratio may be attributed to the stronger suppressive effect of triptolide on M1.…”

Section: Discussionsupporting

confidence: 91%

Triptolide inhibits donor-specific antibody production and attenuates mixed antibody-mediated renal allograft injury

Zhao

Liao

et al. 2018

American Journal of Transplantation

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Donor-specific antibodies (DSAs) are major mediators of renal allograft injury, and strategies to inhibit DSAs are important in promoting long-term graft survival. Triptolide exhibits a wide spectrum of antiinflammatory and immunosuppressive activities, and in autoimmune diseases it inhibits autoantibody levels. In this study, we investigated the suppressive role of triptolide in the generation of DSAs in transplant recipients. We found that triptolide treatment of skin allograft recipients in mice significantly suppressed the development of circulating anti-donor-specific IgG and effectively alleviated DSA-mediated renal allograft injury, which led to prolonged allograft survival. In vitro studies revealed that triptolide inhibited the differentiation of B cells into CD138 CD27 plasma cells; reduced the levels of IgA, IgG, and IgM secreted by plasma cells; and repressed somatic hypermutation and class switch recombination of B cells. Moreover, triptolide-treated recipients showed reduced numbers of B cells, plasma cells, and memory B cells in spleens and decreased numbers of T, B, natural killer (NK) cells, and macrophages infiltrating grafts. These findings highlight the importance of triptolide in suppressing DSAs and establish triptolide as a novel therapeutic agent for antibody-mediated allograft rejection.

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Section: Discussionsupporting

confidence: 91%

Triptolide inhibits donor-specific antibody production and attenuates mixed antibody-mediated renal allograft injury

Zhao

Liao

et al. 2018

American Journal of Transplantation

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“…This is consistent with a recent study in which GS-492429 suppressed renal injury in a rat model of acute antibody-mediated kidney allograft rejection without affecting T cell infiltration or T cell activation. 47 In addition, we identified substantial STAT3 activation in the rat NTN model, in both glomerular and, in particular, tubulointerstitial compartments. Finally, the renal injury still evident in GS-492429 treatment animals might be ameliorated by additional treatment with a JAK or STAT3 inhibitor.…”

Section: Discussionmentioning

confidence: 75%

An inhibitor of spleen tyrosine kinase suppresses experimental crescentic glomerulonephritis

Han

Frank

Paolo

et al. 2018

Int J Immunopathol Pharmacol

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Non-selective inhibitors of spleen tyrosine kinase (SYK) efficiently suppress disease in T cell-dependent models of crescentic glomerulonephritis. However, the therapeutic potential of selective SYK inhibitors in this disease has not been established. In addition, we lack knowledge regarding SYK expression in non-myeloid cells in glomerulonephritis. We addressed these two issues in a rat model of nephrotoxic serum nephritis (NTN) using a SYK inhibitor, GS-492429. Disease was induced in Sprague-Dawley rats (Study 1) or Wistar-Kyoto (WKY) rats (Study 2) by immunization with sheep IgG and administration of sheep anti-rat nephrotoxic serum. Animals were untreated or received GS-492429 (30 mg/kg/bid) or vehicle treatment from 2 h before nephrotoxic serum injection until being killed 3 or 24 h later (Study 1) or 14 days later (Study 2). Two-colour confocal microscopy found that SYK expression in NTN kidney was restricted to myeloid cells and platelets, with no evidence of SYK expression by T cells, mesangial cells, podocytes or tubular epithelial cells. In Study 1, GS-492429 treatment significantly reduced glomerular neutrophil and macrophage infiltration, with protection from glomerular thrombosis and proteinuria. In Study 2, GS-492429 treatment reduced glomerular crescent formation by 70% on day 14 NTN in conjunction with reduced glomerular thrombosis, glomerulosclerosis and tubular damage. This was accompanied by a marked reduction in markers of inflammation (CCL2, TNF-α, NOS2, MMP-12). Importantly, the protective effects of GS-492429 were independent of T cell infiltration and activation and independent of JAK/STAT3 signalling. In conclusion, this study demonstrates that a SYK inhibitor can suppress the development of crescentic glomerulonephritis through effects upon myeloid cells and platelets.

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“…It will be crucial to investigate the protective potential of fostamatinib in sensitized transplanted rats from developing chronic AMR. In a rat model of acute rejection, involving the Dark Agouti (DA/Arc, RT1 av1 ) kidney transplanted into the LEW, SYK inhibition demonstrated the ability to reduce acute injury in transplanted renal allografts in sensitized recipients 46 . This study explored the efficacy of SYK inhibitor GS-492429 in acute rejection, with a splenocyte transfusion for the sensitization method.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of spleen tyrosine kinase decreases donor specific antibody levels in a rat model of sensitization

Tempest-Roe

Prendecki

McAdoo

et al. 2022

Sci Rep

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Antibody mediated rejection is a major cause of renal allograft loss. Circulating preformed donor specific antibodies (DSA) can result as a consequence of blood transfusion, pregnancy or prior transplantation. Current treatment strategies are limited due to partial or transient efficacy, adverse side-effects or patient unsuitability. Previous in vivo studies exploring autoimmune diseases have shown that spleen tyrosine kinase (SYK) signalling is involved in the development of pathogenic autoantibody. The role of SYK in allogenic antibody production is unknown, and we investigated this in a rodent model of sensitization, established by the transfusion of F344 whole blood into LEW rats. Two-week treatment of sensitized rats with selective SYK inhibitor fostamatinib strongly blocked circulating DSA production without affecting overall total immunoglobulin levels, and inhibition was sustained up to 5 weeks post-completion of the treatment regimen. Fostamatinib treatment did not affect mature B cell subset or plasma cell levels, which remained similar between non-treated controls, vehicle treated and fostamatinib treated animals. Our data indicate fostamatinib may provide an alternative therapeutic option for patients who are at risk of sensitization following blood transfusion while awaiting renal transplant.

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Inhibition of Spleen Tyrosine Kinase Reduces Renal Allograft Injury in a Rat Model of Acute Antibody-Mediated Rejection in Sensitized Recipients

Abstract: 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.

Cited by 11 publications

References 36 publications

Triptolide inhibits donor-specific antibody production and attenuates mixed antibody-mediated renal allograft injury

Triptolide inhibits donor-specific antibody production and attenuates mixed antibody-mediated renal allograft injury

An inhibitor of spleen tyrosine kinase suppresses experimental crescentic glomerulonephritis

Inhibition of spleen tyrosine kinase decreases donor specific antibody levels in a rat model of sensitization

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