Blood group incompatible transplantation is one of the measures to alleviate the donor shortage in organ transplantation.However, when an antibody binds to a blood group sugar chain of a transplanted organ, blood flow is impaired and organ function is abolished, resulting in rejection.In addition, as an essential solution to the shortage of donors, research is underway toward the practical application of xenotransplantation using animal organs, but as with blood group incompatible transplantation, intractable rejection is a barrier. It was.

　In this study, he said that he elucidated the mechanism by which existing immunosuppressive drugs do not work for refractory rejection and xenograft rejection in blood group incompatible transplants.In blood group-incompatible transplantation, although calcineurin inhibitors efficiently suppress the production of antibodies that cause rejection, unexpected and severe rejection may occur.Regarding this mechanism, the researchers found that stimulation of Toll-like receptors (TLRs) expressed on B cells that respond to sugar chain antigens eliminates the effects of calcineurin inhibitors. I found it.In other words, if an infection develops after an incompatible transplant, the pathogen stimulates the TLR and the immunosuppressive drug loses its effectiveness, leading to rejection.

　It was also found that in xenotransplantation, the effect of calcineurin inhibitor cannot be obtained by the same mechanism because the heterologous antigen stimulates TLR together with the B cell receptor.On the other hand, it was discovered that BTK inhibitors and HDAC inhibitors, which are anticancer agents, can simultaneously suppress cell stimulation from B cell receptors and TLRs, and can avoid xenograft rejection extremely effectively.Since the safety and pharmacokinetics of these drugs have already been confirmed in humans, there are high expectations for clinical application.

　It can be said that this result will lead to overcoming long-standing problems in blood group incompatible transplantation and xenotransplantation.

Paper information:[American Journal of Transplantation] TLR-MyD88-signaling blockades inhibit refractory B-1b cell immune responses to transplant-related glycan antigens