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Over the last four decades the strategies used to prolong graft survival in renal transplantation have been to avoid immune memory and to target T cells to prevent acute cellular rejection (TCMR). With modern crossmatch technologies and current immunosuppression we have successfully reduced acute rejection rates to 10–15% in the first year. Unfortunately this has translated into only modest improvement in long-term graft outcomes, and the evidence indicates that the immune system remains the major mediator of late graft loss [1-3]. Specifically, the importance of chronic antibody mediated rejection (AMR) from de novo donor specific antibody (DSA) has come to the forefront while TCMR has largely been relegated to a minor role in effecting graft loss [3, 4].

In the current issue, El Ters et al. [5] add to the growing body of evidence that the above construct may be too simplistic. Building on their prior work, the Mayo group highlight the findings of surveillance biopsies following acute TCMR.[6] The principal result is that early TCMR (even borderline or subclinical) is linked to ongoing inflammation (i), the subsequent development of moderate/severe graft interstitial fibrosis (GIF), transplant glomerulopathy (TG) and a higher rate of de novo Class II DSA. Indeed, those patients with early TCMR whose pathology evolves on the follow-up biopsy have an increased incidence of alloimmune mediated graft loss associated with TG and GIF.

The authors' report of TG as the major association with late graft loss is of particular interest. While they propose early TCMR leads to the development of de novo DSA, which in turn could result in AMR and the evolution of TG, there is insufficient detail to fully corroborate this conclusion. Nevertheless, it is consistent with the work of others in France [7], Spain [8] and Canada [9], who have linked early TCMR (clinical or subclinical) to the subsequent risk of developing de novo DSA and chronic AMR (including TG) resulting in graft loss. An alternative, and not mutually exclusive, possibility is that TG evolves from ongoing TCMR targeting the glomeruli. Interestingly, Akalin et al. [10] reported a cohort of patients with C4d−/DSA− TG and postulated a role for chronic TCMR in mediating TG for which he has now provided supporting microarray evidence at the 2013 ATC (abstract #28).

Taking a broader perspective, how discrete is rejection when it occurs? As de novo DSA arise by indirect allorecognition and require both B cell and CD4+ T cell activation, it is likely that this coordinate interaction leads to both T and B cell memory and effector responses. Indeed, Wiebe et al. [9] described three clinical phenotypes associated with de novo DSA (acute dysfunction, indolent dysfunction and stable function) in which patients frequently had pathologic features of TCMR (Banff Grade IA/B, or borderline) concomitant with AMR. It is possible that there is active cross-talk between T and B cells that may be self-reinforcing (e.g. B cells acting as APC for T cells, and T cells enhancing helper function in the lymph node to improve high-affinity antibody production).

As scientists and clinicians we attempt to simplify biological processes, whether these are physiological or are the manifestations of disease. In the latter case, increasing diagnostic precision and refined disease classifications may lead to more tailored therapies, one of the goals of “personalized medicine.” Indeed, in an effort to gain understanding of the rejection response, we have imposed on the process such attributes as acute and chronic; early and late; clinical and subclinical; and classify rejection as TCMR and AMR. While this has led to major advances, the risk is that we “can't see the forest for the trees.” From the immune system's perspective, its role is to protect the host at all costs and by whatever mechanisms are available. We suggest that the immune system provides an integrated response to achieve allograft rejection with TCMR and AMR being either linked through time or coexisting. If such is the case, then it behooves us to keep T cells in the forefront, alongside B cells/plasma cells and DSA, in order to improve long-term outcomes.

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

References

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