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It is clear that preformed or de novo donor specific HLA antibodies effect acute and chronic antibody mediated rejection (AMR), but it is less certain what the role and scope of non-HLA antibodies are in mediating graft injury and loss (reviewed in [[1] ]). Nonetheless, the fact that HLA matched sibling transplants still require immunosuppression, have diminished 10-year graft survival proportional to their degree of sensitization, and experience biopsy-proven early AMR in the absence of donor specific HLA antibody support the existence of non-HLA antigens that can serve as targets for naïve or memory cellular immunity and/or non-HLA antibodies.

One hypothesis is that alloantigen sensitization occurs from non-HLA polymorphic differences between the donor and recipient (e.g. MICA, MICB, etc.). Unfortunately, progress in this area has been limited by the lack of validated clinical assays for non-HLA alloantibodies, the confounding presence of donor specific HLA antibodies, or the use of old technology to document absence of concomitant HLA sensitization, and, in the case of MICA antibodies, lack of proof of donor specificity. There is also a lack of correlation with histopathology. In studies of anti-endothelial cell antibodies (AECA) where donor-reactivity is suggested using a novel donor endothelial cell crossmatch, the identity of the non-HLA alloantigen is lacking [2]. Therefore, we have evidence of association of non-HLA alloantibodies with acute rejection or graft failure without definitive proof of causality and limited antigen characterization.

A second hypothesis is that autoantigen sensitization occurs from the exposure of cryptic epitopes after tissue injury or inflammation (e.g. vimentin, K-α 1 tubulin, collagen V, agrin, etc.)[3-5]. In the current issue, Cardinal et al. present convincing evidence in human and animal studies that an autoantibody directed at the LG3 fragment of the heparan sulphate proteoglycan perlecan is an accelerator of immune-mediated vascular injury [6]. Specifically, pre-formed anti-LG3 and donor specific anti-HLA correlated independently with early acute vascular rejection in renal allografts and when present together was associated with early graft loss. To test for causality an untreated aortic allograft model was subjected to an ischemic insult, after which injection of anti-LG3 significantly increased vascular inflammation and obliterative remodeling. This degree of inflammation was absent in allografts without an ischemic injury or in isografts despite the ischemic injury. The authors conclude that the effect of anti-LG3 requires both the exposure of LG3 epitopes after ischemic injury and ongoing alloimmune-mediated inflammation.

What remains unclear is the scope of impact of preformed anti-LG3 in transplantation, or any of the autoantibodies for that matter, that would justify their routine assessment; acute vascular rejection occurred in only 5.7% of 861 consecutive transplants in this report [6]. Similarly, Amico et al. reported that early AMR related to donor specific HLA antibody had diminished (6.5% to 0%) with the advent of solid phase HLA technology leaving only 2.3% of transplants experiencing early AMR related solely to non-HLA antibodies [7]. Conversely, whether de novo anti-LG3 is common (as in the case of anti-K-α 1 tubulin after lung transplant [4]) or rare, associated with chronic AMR, or dependent on concomitant donor specific HLA antibodies to mediate injury is yet to be determined.

Finally, this is not the first time that anti-perlecan antibodies have been associated with microvascular injury in the allograft; Joosten et al. demonstrated in an F344 to LEW rat model of chronic AMR that anti-perlecan antibodies can be isolated from transplant glomerulopathy lesions [8]. Nor is it the first demonstration that the full impact of preformed autoantibodies might require concomitant alloimmunity; Mahesh et al. found that anti-vimentin antibodies resulted in accelerated rejection in allo- but not isografts [9]. Rather this work adds to the growing body of evidence that both allo- and autoimmunity can act in concert to mediate allograft injury and loss. Therefore, it should direct us to look for antibodies beyond HLA, and determine their epidemiology and linkage to biopsy proven early and late AMR. Such knowledge may in turn allow us to optimally assign pretransplant risk, and to properly design studies and therapies into the future addressing acute and chronic AMR.

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The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

References

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