Recurrence of Primary Sclerosing Cholangitis after Living Donor Liver Transplantation and Roles of B-Cell Depletion

Abstract

Primary sclerosing cholangitis (PSC) recurs at a high rate after living donor liver transplantation. This high recurrence rate is thought to involve: (1) HLA homology (genetic predisposition of the liver graft) and (2) the mechanism of autoimmune disorder. Seven patients have undergone living donor liver transplantation for PSC at our institution. There has been no PSC recurrence in 2 patients 5 years after they had undergone ABO-incompatible living donor liver transplantation and after 2 years of follow-up. These patients differed from other patients in that they received pre-transplant rituximab (RTX) to avoid humoral rejection after ABO-incompatible transplantation. Subjects: The subjects were 7 patients who had undergone living donor liver transplantation. They were 3 men and 4 women aged 3-42 years at the time of transplantation. In 6 subjects, donors were their parents who matched the recipients at three or more of six HLA loci. The remaining one subject was a woman, matching only 1 HLA locus with the donor who was of fifth degree of kinship to the patient. PSC recurrence was determined by blood biochemical tests, MRCP imaging, and liver biopsy. Immunodeficient mice were engrafted with peripheral blood mononuclear cells from patients who used RTX, and anti-donor antibodies against blood group antigens were measured by ELISA. Results: Five patients had a PSC recurrence 1-3 years after transplantation. RTX was not used in these 5 patients because of blood group compatibility with the donors, who were their parents. In 2 patients who received pre-transplant RTX, there was no PSC recurrence 5 years after transplantation and after 2 years of follow-up. When humanized NOG mice were sensitized to donor blood group antigens, the recipient B cells did not produce antibodies to donor blood group antigens. Discussion: The results of humanized NOG mice indicated that B1 cells responsive to donor blood group antigens (present in donor liver) are deleted before reconstitution of B cells that were depleted with RTX, and immune tolerance is induced. B1 cells are thought to be involved in autoimmune disorders. The results of this study suggest the potential involvement of B1 cell immune tolerance against donor antigens in the prevention of PSC recurrence.