Non-HLA antibody associated rejection in solid organ transplantation

Abstract

HLA-antibodies have since long been recognized as primary targets of the recipient’s immune response after solid organ transplantation (Tx). HLA-antibodies are therefore directly associated with rejection and a decreased clinical outcome after Tx. Increasing evidence also shows an association between the presence of non-HLA antibodies and the clinical outcome in these patients. In this literature review, the current evidence for an association between the presence of non-HLA antibodies and graft rejection is summarized. Non-HLA antibodies, a heterogeneous collection of (non)-polymorphic antigens, include among others MICA, the Angiotensin II Type I receptor and vimentin. While polymorphic antigens could be regarded as allo antibodies, there is also a lot of evidence for the generation of auto antibodies. This might be explained by the generation of cryptic and sequestered epitopes on non-HLA antigens after injury induced by Tx surgery. However, the line of demarcation between the auto- and alloresponse is yet unclear and alloreactivity resulting from Tx may as well induce autoreactivity. While many papers have thus tried to elucidate the role of non-HLA antibodies after Tx in humans, much evidence is circumstantial. Detection of non-HLA antibodies in patients is moreover hampered by the fact that there are no universally established tests to determine their presence. Interpretation of past results is hereby further complicated. Definite evidence for a causal contribution of non-HLA Abs in rejection of Tx patients has therefore yet to be provided. The distinction whether non-HLA antibodies are secondary players or causally involved in the pathological process leading to rejection could lead to new insights regarding Tx management. While most non-HLA antibodies are probably unimportant for Tx pathology or present at clinically irrelevant levels, proven non-HLA antibody contribution could lead to the implementation of treatment in clinical practice. Relevant antibodies could appear both pre Tx, as the result of ischemic events or injury and could help identify patients with increased risks for transplant related complications, or post Tx, suggesting an altering immune status. Although animal studies seem to point towards relevant roles of at least auto antibodies against vimentin and cardiac myosin after heart Tx, K-α1-Tubulin and Collagen V after lung Tx and the Angiotensin II type I receptor after kidney Tx, in humans the situation is probably more complicated. Underlying pathology and disease history may pave the way for the generation of an unique and dynamic antibody pattern. A check-list for patients suspected of non-HLA AMR should help clinicians identify those at risk for this classification. Thus, despite the lack of causal evidence, it may be advised to include pre and post Tx monitoring of non-HLA antibodies in standard clinical practice.