Prevention and treatment of liver allograft antibody-mediated rejection and the role of the ‘two-hit hypothesis’

Abstract

Severe acute AMR is rare but diagnosable, and there is need to determine the incidence of and optimal therapy for less severe combined AMR and TCMR. Chronic AMR is likely more common and of significant relevance to long-term allograft survival improvement. The two-hit hypothesis may help to explain the rarity of both findings and shed insight onto future prevention and treatment strategies.

Liver transplantation: Rejection and tolerance

“…On the contrary, the role of DSA in chronic liver injury (eg, chronic liver AMR) remains to be clarified. As the expression of HLA class II is limited at steady state, the “2‐hit” hypothesis has been postulated to be the mechanism of chronic AMR in the liver . According to this hypothesis, circulating DSA becomes harmful only after an independent injury to the liver that causes up‐regulation of HLA expression on the endothelial cell surface.…”

Donor‐Specific Antibodies in Liver Transplantation

“…However, several cases of acute AMR associated with DSAs in LT emerged and prompted further research. Clinically, acute AMR presents with graft dysfunction or failure, elevated aminotransferase levels, and consumptive thrombocytopenia in the first several weeks after transplant . This occurs mainly in sensitized patients with preformed DSAs.…”

“…Interestingly, DSAs may have more impact on graft survival in deceased donor than living donor LT, particularly with preformed DSAs . Finally, DSA has been implicated in preservation injury, plasma cell hepatitis, biliary anastomotic strictures, and graft fibrosis …”

The Role of Humoral Alloreactivity in Liver Transplantation: Lessons Learned and New Perspectives

“…This is best illustrated by normal biopsies without histologic signs of tissue injury which can be obtained from clinically stable LT recipients with circulating DSA, even among patients who have undergone complete withdrawal of immunosuppression therapy [11, 47]. Based on this evidence, Kim et al have proposed the “two-hit hypothesis,” in which a concurrent insult causing allograft inflammation is needed for alloantibodies to incur observable dysfunction [48]. …”