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Tofacitinib Halts Progression of Graft Dysfunction in a Rat Model of Mixed Cellular and Humoral Rejection

Rovira, Jordi, PhD1,2; Ramírez-Bajo, María José., PhD2,3; Banon-Maneus, Elisenda, PhD2,3; Lazo-Rodríguez, Marta2,3; Moya-Rull, Daniel2,3; Hierro-Garcia, Natalia1; Tubita, Valeria1; Piñeiro, Gastón J., MD4; Revuelta, Ignacio, MD, PhD1,2,4; Ventura-Aguiar, Pedro, MD4; Cucchiari, David, MD4; Oppenheimer, Federico, MD, PhD4; Brunet, Mercè, PhD5; Campistol, Josep M., MD, PhD1,2,4; Diekmann, Fritz, MD, PhD1,2,4

doi: 10.1097/TP.0000000000002204
Original Basic Science—General

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 tofacitinib (TOFA), 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 to allow the development of rejection. Treatment was based on cyclosporin A, rapamycin or TOFA. Renal function was assessed at 1, 4, 8, and 12 weeks after transplantation, whereas 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 natural killer cell graft infiltration was reduced in TOFA-treated rats. Although rapamycin-treated rats also showed prolonged graft survival, glomerular structures were more affected. Moreover, only TOFA treatment reduced the presence of T, B and natural killer 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.

Rovira et al report tofacitinib, a Janus kinase 3 inhibitor, reduces T and NK cell infiltration, preserves tubular and glomerular structures, and prevents the progression of allograft dysfunction in a Fisher-to-Lewis rat model of kidney transplantation.

1 Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

2 Red de Investigación Renal (REDINREN), Madrid, Spain.

3 Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Fundació Clínic per la Recerca Biomèdica (FCRB), Barcelona, Spain.

4 Departament de Nefrologia i Trasplantament Renal, Institut Clínic de Nefrologia i Urologia (ICNU), Hospital Clínic de Barcelona, Barcelona, Spain.

5 Laboratori de Farmacologia i Toxicologia, Servei de Bioquímica i Genètica Molecular, Centre Diagnòstic Biomèdic, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain.

Received 11 October 2017. Revision received 23 March 2018.

Accepted 24 March 2018.

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.

The authors declare no conflicts of interest.

J.R. participated in research design, performance of research, data analysis and writing of the article. M.J.R.-B. participated in data analysis, performance of research. E.B.-M. participated in data analysis, performance of research. M.L.-R. participated in data analysis, performance of research. D.M.-R. participated in data analysis, performance of research. N.H.-G. participated in data analysis, performance of research. V.T. participated in data analysis, performance of research. G.J.P. participated in data analysis, performance of research. I.R. participated in data analysis, performance of research. P.V.-A. participated in data analysis, performance of research. D.C. participated in data analysis, critical revision of the manuscript for important intellectual content. F.O. participated in critical revision of the article for important intellectual content. M.B. participated in data analysis, critical revision of the manuscript for important intellectual content. J.M.C. participated in the critical revision of the manuscript for important intellectual content. F.D. participated in research design, data analysis and writing of the article.

Correspondence: Fritz Diekmann, MD, PhD, Hospital Clínic de Barcelona, Department of Nephrology and Renal Transplantation, Villarroel 170 (Escala 12-Planta 5), E-08036 Barcelona, Spain. (fdiekman@clinic.ub.es).

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