The impact of non-HLA antibodies on outcomes after lung transplantation and implications for therapeutic approaches

The role of donor-specific antibodies (DSA) to mismatched human leukocyte antigens (HLA) in lung allograft rejection has been recognized over the past 20 years. During this time, there has been growing experience and recognition of an important role for non-HLA antibodies in lung allograft rejection. Multiple self-antigens have been identified that elicit autoimmune responses including collagen V, K-α 1 tubulin, angiotensin type 1 receptor, and endothelin type A receptor, but it is likely that other antigens elicit similar responses. The paradigm for the pathogenesis of these autoimmune responses consists of exposure of sequestered self-antigens followed by loss of peripheral tolerance, which then promotes allograft rejection. Studies have focused mainly on the impact of autoimmune responses on the development of Bronchiolitis Obliterans Syndrome or its mouse model surrogate. However, there are emerging data that illustrate that non-HLA antibodies can induce acute antibody-mediated rejection (AMR) after lung transplantation. Treatment has focused on antibody-depletion protocols, but experience is limited to cohort studies and appropriate controlled trials have not been conducted. It is noteworthy that depletion of non-HLA antibodies has been associated with favorable clinical outcomes. Clearly, additional studies are needed to identify the optimal therapeutic approaches to non-HLA antibodies in clinical practice.