To the Editor:
Dr. Randhawa's thoughtful letter (1) raises many issues about our papers (2, 3) and highlights important areas of uncertainty, especially in late kidney transplants with dysfunction. The new effort to attribute causality to each individual transplant failure requires a lively dialogue and Dr. Randhawa’ insights are a welcome contribution.
T cell-mediated rejection (TCMR) is identified by the current Banff histologic criteria, mediated by effector T cells in the graft. Experience from clinical trials is that this condition if properly managed does not lead to progressive graft deterioration.
The second situation in which T cells are found in kidney transplants is in injured and scarred tissue—the response to wounding. Effector memory T cells enter damaged tissue and accumulate in scarred transplants over time, regardless of whether scarring is because of rejection or recurrence of primary disease. In our previous studies of protocol biopsies at 6 weeks, the main correlate of T cell transcript expression was previous delayed graft function that is, peritransplant injury (4). The accumulation of T cell infiltrates in injured tissue probably accounts for most borderline biopsies and for the presence of T cells in late cases with ABMR.
We have suggested that there is a third explanation for the presence of T cells: a local, a local-grade and self-limited form of TCMR, that we designated as “forme fruste” TCMR (4). This would explain why treatment of subclinical TCMR fails to improve outcomes—the treatment of self-limited disease would not be expected to alter outcomes. This may reflect the generation of small numbers of effector T cells specific for donor antigen that create focal TCMR that is self-limited.
However, we cannot find evidence that T cells in the graft play any essential role in ABMR. ABMR is dependent on T cells' help for donor-specific antibody production, but this help probably occurs in the secondary lymphoid organs, not in the graft. Some evidence used to argue for the role of TH1 cells may be based on misinterpreting NK features such as granzyme B and interferon-γ expression.
Dr. Randhawa is correct that there is often a component of TCMR in late rejection, particularly in nonadherent patients. This may present as isolated TCMR or as mixed TCMR and ABMR. Often the overlay of atrophy-scarring and of ABMR changes can cause this TCMR component to be missed. But our experience to date has been that the cases that progress to failure have alloantibody and probably have ABMR as they fail, although they may not be biopsied as they near end stage. This is the difference between attribution and diagnosis.
The current Banff criteria for TCMR, developed in an earlier era in unscarred biopsies of kidneys from younger donors, cannot exclude TCMR is scarring is extensive, as in the late troubled transplant with advanced atrophy-scarring. This is one of the arguments for the use of molecular testing of biopsies. But even using such assays, we have not observed smoldering slowly progressive pure TCMR, resistant to treatment, as a cause of late graft failure.