Cytotoxic T lymphocyte monitoring in steroid‐free immunosuppression

The steadily increasing number of new drugs effective in post-transplant immunosuppression is rapidly changing long-established treatment standards in transplant medicine. Novel approaches implementing steroid-reducingor steroid-free or calcineurin inhibitor-free immunosuppression protocols are presently being tested. Although such trials are aimed at reducing drug toxicity to the graft recipient, they carry the potential risk of previously unknown drug interactions, underor over-immunosuppression, and the need to revisit diagnostic standards for rejection, toxicity, viral risks and lymphoproliferative disease (something that happened for the first time 20 yr ago when cyclosporine eradicated clinical symptoms of graft rejection). In this issue, Satterwhite et al. provide a first set of data, reporting on a higher magnitude of CTL gene expression in peripheral blood lymphocytes from renal recipients treated with a completely steroid-free immunosuppression compared with patients with an otherwise similar but steroid-based immunosuppression. Moreover, this CTL gene expression in steroid-free patients is even higher than observed in acute rejection episodes in steroid-based therapy. The approach of Satterwhite et al., incorporating molecular results into clinical trials aimed at studying the efficacy and safety of a drug combination, is an example of how to expand our knowledge on the differential effect of drugs on immune events and their histopathological manifestation within the graft. It may, however, leave us with more questions than answers. Acute rejection in most circumstances is a T-cell-mediated event and CTL effector genes are the best verified indicators of acute rejection in numerous animal transplant models and in clinical transplantation of heart, lung, liver, kidney, and islets. Partial blocking of these apoptotic pathways prolongs graft survival and complete combined blocking of pore-forming and ligand pathways in some animal models has resulted in permanent acceptance of grafts, whereas other data indicate non-CTL-associated pathways to destroy a graft. Calcineurin inhibitors such as tacrolimus used in this study block CTL gene activation very effectively (1). If a drug as an immunosuppressive agent actually induces augmentation of CTL effectors, we need to explain how the organ is effectively protected against these proapoptotic mediators. At least now there is no such data on mycophenolate mofetil. Unfortunately, Satterwhite et al. do not provide data, whether the observed enhancement of CTL gene expression in peripheral blood is matched by enhanced intragraft expression in the protocol biopsies obtained. Although peripheral blood is easy to access and would allow to take a closer look at dynamics of immune activation events, blood assays carry the risk of a low signal-to-noise range dependant on a very low frequency of effector cells outside of lymphoid organs and the graft. Data on the precision of peripheral blood monitoring compared with intragraft events and histopathology are limited to acute rejection episodes in steroidand cyclosporinetreated patients (2). No such data exist in subacute rejection and we and others have shown that blood gene expression including CTL markers does not correlate with intragraft events and does not provide any useful information in chronic allograft nephropathy (ATC 2002, abstract no. 949, Am. J. Transplant. 3(Suppl. 2): 376). Furthermore, ficoll-based harvesting is not an inert procedure to (PBMCs) and is known to activate interleukin peripheral blood mononuclear cells (IL)-15 and IL-2 for days in harvested cells (Maslinski, Strehlau, Strom, unpublished laboratory data). The induction of high-affinity IL-15a chains in PBMCs capable of inducing the transcription machinery for CTL effectors is inhibited by dexamethasone, but not calcineurin inhibitors (3). However, if Pediatr Transplantation 2003: 7: 4–6