Detecting Adaptive Immunity Applications in Transplantation Monitoring

In recent decades, continuous improvements in immunosuppressive therapy have led to a significant increase in kidney allograft survival. Despite innovative developments and improvements in immunosuppression, chronic allograft injury and late graft loss still remainmajor causes of morbidity andmortality. In clinical practice, long-term immunosuppression is adapted and fine-tuned according to drug levels, kidney function, and biopsy results. As an invasive procedure, indication biopsy still represents an indispensible diagnostic gold standard. However, in an effort to further improve outcomes on the basis of individualized treatment, there is an urgent need for noninvasive assays, as well as biomarkers, to more accurately monitor allogeneic responses and predict the risk of acute and chronic allograft rejection. This article discusses strategies for immune monitoring of T-cell responsiveness and humoral alloreactivity. Furthermore, new microarray and gene profiling data are highlighted, which may identify hyporesponsive transplant recipients who could benefit from a reduction or even withdrawal of immunosuppression. Finally, supplementary transplant risk assessment markers, such as soluble CD30 and urinary effector molecule analysis, are discussed as promising new tools. Recent developments and improvements in test principles to monitor and predict allograft immunity are encouraging and may herald the transition of present empiric immunosuppression to individualized immunosuppressive treatment. Nonetheless, before implementation of immune monitoring in routine clinical practice, there is still a need for prospective trials designed to clarify the actual diagnostic potential of individual test systems in a therapeutic context. In addition to serial monitoring of immunosuppressive drug levels and kidney function, allograft biopsy still represents an indispensible and powerful diagnostic gold standard. Morphologic and immunohistochemical results, which are commonly interpreted, classified, and scored according to the Banff scheme and its amendments, provide a valuable basis for guided treatment, including rejection therapy and adaptation of the quantity and quality of maintenance immunosuppression. A thorough work-up of indication biopsies, which are performed because of graft dysfunction, allows for a subtle differentiation of distinct acute or chronic rejection forms, as well as distinct types of non-alloimmune injury, such as acute tubular injury, medication toxicity, recurrence of disease,de novo glomerulonephritis, or viral infection. The diagnostic and predictive value of serial protocol biopsies in recipients without graft dysfunction, however, is still under discussion. Although subclinical acute and/ or chronic rejection has been shown to be associated with inferior long-term allograft function, it still remains unprovenwhether therapeutic interventions on the basis of such early lesions without graft dysfunction are really justified. Moreover, major hurdles to the routine implementation of serial surveillance biopsies are the invasiveness of needle biopsy, the associated expense, and a significant (although low) complication rate. There has been continuous interest from the transplant community in establishing minimally invasive (peripheral blood) or noninvasive (urine) diagnostic assays to identify patients with pending or ongoing immunologic injury. The objective of such efforts may not necessarily be to circumvent renal biopsy but, rather, to complement a multifaceted diagnostic algorithm providing more detailed and continuous information about the actual net immunosuppressive burden and/or the activation state of alloantigen-specific immunity. As a diagnostic adjunct, ex vivo immunologic monitoring could rationally guide (i) targeted rejection therapy, preferably before rejection becomes clinically relevant; (ii) individualization of immunosuppressive therapy; and (iii) reduction or even withdrawal of treatment in stable allograft recipients to spare them from excessive immunosuppression. In the light of these apparent CURRENT OPINION Mol Diagn Ther 2010; 14 (1): 1-11 1177-1062/10/0001-0001/$49.95/0 a 2010 Adis Data Information BV. All rights reserved.