Tofacitinib halts progression of graft dysfunction in a rat model of mixed cellular and humoral rejection

Background The progression from acute to chronic antibody-mediated rejection in kidney transplant recipients is usually not prevented by current therapeutic options. Here, we investigated whether the use of tofacinitib, a Janus kinase 3 inhibitor, was capable of preventing the progression of allograft dysfunction in a Fisher-to-Lewis rat model of kidney transplantation. Methods Rats were treated from the third week after transplantation in order to allow the development of rejection. Treatment was based on cyclosporin A, rapamycin or tofacitinib. Renal function was assessed at 1, 4, 8 and 12 weeks after transplantation while rat survival, histological lesions and infiltrating lymphocytes were analyzed at 12 weeks. Results Tofacitinib prolonged graft survival, preserved tubular and glomerular structures and reduced humoral damage characterized by C4d deposition. Tofacitinib was able to reduce donor-specific antibodies. In addition, T and NK cell graft infiltration was reduced in tofacitinib treated rats. Although rapamycin treated rats also showed prolonged graft survival, glomerular structures were more affected. Moreover, only tofacitinib treatment reduced the presence of T, B and NK cells in splenic parenchyma. Conclusions Tofacitinib is able to reduce the immune response generated in a rat model of kidney graft rejection, providing prolonged graft and recipient survival, better graft function and less histological lesions. CORRESPONDING AUTHOR Fritz Diekmann, MD, Hospital Clínic de Barcelona, Department of Nephrology and Renal Transplantation, Villarroel 170 (Escala 12 – Planta 5). E-08036 Barcelona, Spain. Tel.: +34-932275444. Fax: +34-934546033. fdiekman@clinic.ub.es Authorship Jordi Rovira: participated in research design, performance of research, data analysis and writing of the paper. María J Ramírez-Bajo: participated in data analysis, performance of research. Elisenda Banon-Maneus: participated in data analysis, performance of research. Marta Lazo-Rodríguez: participated in data analysis, performance of research. Daniel Moya-Rull: participated in data analysis, performance of research. Natalia Hierro-Garcia: participated in data analysis, performance of research. Valeria Tubita: participated in data analysis, performance of research. Gastón J Piñeiro: participated in data analysis, performance of research. Ignacio Revuelta: participated in data analysis, performance of research. Pedro Ventura-Aguiar: participated in data analysis, performance of research. David Cucchiari: participated in data analysis, critical revision of the manuscript for important intellectual content. Federico Oppenheimer: critical revision of the manuscript for important intellectual content. Mercè Brunet: participated in data analysis, critical revision of the manuscript for important intellectual content. Josep M Campistol: critical revision of the manuscript for important intellectual content. Fritz Diekmann: participated in research design, data analysis and writing of the paper. Disclosure The authors declare no conflicts of interest. Funding This study has been funded by the project PI11/01112 and Redes Tematicas De Investigacion Cooperativa En Salud, REDINREN (RD12/0021/0028 and RD16/0009/0023) both co-funded by ISCIII-Subdirección General de Evaluación and Fondo Europeo de Desarrollo Regional (FEDER) "Una manera de hacer Europa". CERCA Programme/Generalitat de Catalunya. This work was developed at the Centre de Recerca Biomèdica Cellex, Barcelona, Spain. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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