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

2018; Wolters Kluwer; Volume: 102; Issue: 7 Linguagem: Inglês

10.1097/tp.0000000000002204

1534-6080

Jordi Rovira, María José Ramírez-Bajo, Elisenda Bañón-Maneus, Marta Lazo-Rodríguez, Daniel Moya-Rull, Natalia Hierro-Garcia, Valeria Tubita, Gastón Piñeiro, Ignacio Revuelta, Pedro Ventura‐Aguiar, David Cucchiari, Federico Oppenheimer, Merçè Brunet, Josep M. Campistol, Fritz Diekmann,

T-cell and B-cell Immunology

In Brief 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.