Function And Mechanism Of Systematic Tolerance Induced By Spontaneous Kidney Allograft In Mice

Organ transplant is one of the best methods to treat end-stage diseases.However,immune responses to allografts represent the major barrier in organ transplantation.Immune tolerance to avoid life-long immune-suppression is a critical goal in the field.Bone marrow transplantation following non-myeloablative conditioning based chimerism protocol induce tolerance to the kidney allograft from the same donar in large animals,recently being applied to clinic use.But same conditioning fails to induce tolerance to heart graft.Our group demonstrated that through donor kidney cotransplantation,stable tolerance of heart allografts has been achieved in nonhuman primates.But the underlined mechanisms remain to be elucidated.Immune cells exhaustion refers to the differential state of the cells with reduced effector function after being exposed to the over loaded antigens.The immune check-point blockage based immune therapy,which reinvigorate the exhausted cells,has become one of the most promising method to treat tumor.Whether immune cell exhaustion influences the outcome of alloimmune responses remains to be firmly established.To investigate the mechanisms of the heart transplant tolerance induced by the donar strain kidney graft,we used the mice spontaneous acceptance renal transplantation model(DBA/2J donar kidney to C57BL/C recipient),followed by the cervical heart transplantation from the same donar strain.Co-transplanted heart grafts are accepted by the recipients 1 weeks after kidney transplant,whereas kidney grafts fail to induce skin graft tolerance.2 weeks after the kidney being implanted,heart graft still can be accepted following allograft nephrectomy.Depletion of Treg trigger the rejection of heart graft both in the induction phase and the maintaining phase of tolerance.ELISPOT assay shows abrogated alloresponse of the recipients splenocytes towards donar antigens.DBA kidney still can be accepted by thymectomized B6 recipients,the survival of secondarty transplanted heart is prolonged by the kidney graft,but can not achieve long-term tolerance.Kidney allograft infiltrating CD8+ T cells express higher level of inhibitory receptors including PD-1,TIGIT,TIM-3,CD39,with the impired ability of secreting inflammatory cytokines.Blockage of the PD-1 pathway on CD8+ T cells will abrogate the well-established tolerance.Finally,we provide insights into the exhausted CD8+ T cells infiltrated in the kidney graft.Moreover,the spontaneous tolerance to the renal graft depends on the exhausted phenotype of the CD8+ T cells.Blocking the PD-1 pathway trigger the rejection to tolerized kidney graft.Both kidney graft tolerance and rely on Treg function.But kidney induced heart graft tolerance partially depends on the central deletional tolerance mechanism.