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Kidney Week

Abstract: FR-PO1109

Inhibition of Spleen Tyrosine Kinase Decreases Donor-Specific Antibody Levels in a Rat Model of Presensitization

Session Information

  • Transplantation: Basic
    November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Transplantation

  • 1901 Transplantation: Basic

Authors

  • Tempest-Roe, Shenzhen Makahn, Imperial College London, London, United Kingdom
  • McAdoo, Stephen Paul, Imperial College London, London, United Kingdom
  • Clarke, Candice, Imperial College London, London, United Kingdom
  • Prendecki, Maria, Imperial College London, London, United Kingdom
  • Masuda, Esteban S., Rigel Pharmaceuticals, Inc, South San Francisco, California, United States
  • Roufosse, Candice A., Imperial College London, London, United Kingdom
  • Cook, H. Terence, Imperial College London, London, United Kingdom
  • Taube, David, Imperial College London, London, United Kingdom
  • Pusey, Charles D., Imperial College London, London, United Kingdom
  • Tam, Frederick W.K., Imperial College London, London, United Kingdom
Background

Antibody mediated rejection (ABMR) is the leading cause of allograft failure post transplantation and there is currently no available effective treatment. Orthotopic kidney allographs from Fischer F344 DU (F344) to Lewis RT1I (LEW) rats is a model for chronic allograft nephropathy. The aim of this study was to determine if LEW pre-sensitized with F344 whole blood produced donor specific antibodies (DSA); and whether inhibition of SYK with Fostamatinib had efficacy in reduction of circulating DSA levels.

Methods

Male LEW rats were transfused with whole blood from male F344 rats. Transfused LEW rats were treated with 40mg/kg of Fostamatinib or vehicle by oral gavage twice daily for 14 days from 7 days (early treatment), or 11 days (late treatment) post transfusion. Serum MFI levels for IgG DSA levels were determined on a BD LSRFortessa™ X- 20.

Results

This is the first time F344 to LEW whole blood transfusion has been described as a pre-sensitization model. Transfused LEW rats developed IgG DSA. Early treatment was implemented at onset of IgG antibody production (day 7), and late treatment where IgG antibody production was established and nearing peak levels (day 11) (Fig1a).
In our experiments, early treatment with Fostamatinib significantly decreased circulating IgG levels (Fig1b), late treatment, when antibody levels were established was not effective (Fig1c).

Conclusion

In conclusion, we have shown that treatment of pre-sensitized LEW rats with selective SYK inhibitor Fostamatinib at the start of IgG antibody production significantly reduced levels of circulating IgG DSA . Cytotoxic IgG antibodies have a well-established role in ABMR. This indicates a potential use of Fostamatinib as a treatment option for pre-sensitized patients requiring renal transplant or following development of a de novo DSA.