Inhibition of mTOR pathway prevents missing self-induced NK cells-mediated rejection
HAMADA S. 1, MATHIAS V. 1,2, BARBA T. 1,3, DUBOIS V. 1,2, RABEYRIN M. 3, MORELON E. 1,3, KOENIG A. 1,3, THAUNAT O. 1,3
1 Inserm, Lyon, France; 2 Etablissement franšais du sang, Lyon, France; 3 Hospices Civils de Lyon, Lyon, France
Our team recently reported that the inability of graft endothelial cells to deliver HLA-I-dependent inhibitory signals to circulating recipient NK cells (missing self, MS) was the cause of DSA-independent microvascular inflammation (MVI) leading to chronic vascular rejection.
The purpose of this translational study was to identify the signalling pathways involved in NK cells activation and to evaluate the therapeutic potential of their pharmacological blockade.
The coculture of human purified NK cells with allogeneic microvascular endothelial cells recapitulated MS-induced NK cell rejection in vitro.
In vivo validation was made in an adapted mouse heterotopic heart transplantation model, in which donor animals were from the same genetic background as recipients [C57B6 (H2b)] but KO for MHC-I. This trick allowed stimulating recipient’s NK cells by missing self in the absence of any other allogeneic stimulation.
Finally, a monocentric pilot clinical study was conducted in 46 renal transplant patients with MS-induced NK rejection.
The coculture model revealed the crucial role of the mTOR pathway for MS-induced activation of NK cells. The addition of an mTOR inhibitor to the cocultures blocked NK cells activation and prevented the destruction of endothelial cells. These results were confirmed in the mouse heart transplantation model, in which the MVI lesions observed in the grafts of untreated controls were completely abrogated in recipients treated with mTOR inhibitor.
Finally, the replacement of MMF by an mTORinh in 16 kidney recipients diagnosed with MS-induced NK rejection resulted in the reduction of graft MVI lesions in control biopsy and an improved graft survival as compared with historical controls (n= 30) left on the same immunosuppression (MMF+CNI).
The introduction of an mTOR inhibitor in patients diagnosed with MS-induced NK rejection could reduce rejection lesions and improve graft survival.