A role for cytokine measurement in therapeutic monitoring of immunosuppressive drugs following lung transplantation
The strength of the allo-immune response to a transplanted organ [1,2] currently mandates combined pharmacological immunosuppression to prevent rejection. The calcineurine inhibitor Cyclosporine remains an important component of immunosuppression regimens post lung transplantation with the International Registry of Heart and Lung Transplantation recording 50% of patients receiving this drug. 
 
Cyclosporine requires therapeutic drug monitoring with the aim of maximizing efficacy whilst minimizing the risk of toxicity. Historically the trough (predose or Co) level has been used to guide the dose of cyclosporin and the dose range in lung transplantation has been determined by rather empirical review of studies in kidney transplantation [3]. A survey conducted in 1994–95 showed that most lung transplant centres however, recommended a higher range of target concentrations during the early post operative period [4]. 
 
The recommended therapeutic blood concentrations however, are broad and may vary according to the clinical situation and the choice of other immunosuppressive agents being administered. Relatively recent data has supported the use of therapeutic drug monitoring of cyclosporin by the use of whole blood drawn two hours after administration of the dose (C2) with data showing a better prediction of clinical effect [5]. Nevertheless therapeutic drug monitoring has certain general limitations with the concentration measured in blood, not necessarily the concentration of the drug at the site of action. The alternative approach, as discussed in a study by Hodge and colleagues in the January 2005 issue of Clinical and Experimental Immunology is to measure the therapeutic action of the drug either directly or indirectly [6]. 
 
In general the approaches involve in vitro assessment of T cell activation by measuring cytokine release from peripheral circulating cells either in the resting or stimulated state [7–9]. Whilst these techniques have great potential, it is not yet established whether they are predictive of clinical events. Moreover the complexity of the allo-immune response may make it difficult to model using such assays. There is also a problem regarding which compartment of the immune system should one study in order to give the best biological information. Most studies use peripheral circulating cells rather than intragraft immune cells which may be more relevant in terms of effecting graft injury. 
 
In a broad sense, the process of immune cell-mediated allograft rejection is regulated by an array of cytokines. Some of these, for example the chemokines, are produced by stressed graft cells and activated immune cells whilst others, such as IL-2 and IL-4, are produced by activated immune cells. Given the importance of this range of cytokines, it is perhaps surprising that immunosuppressive calcineurin inhibitors such as Cyclosporin A (Cs-A) are effective as they directly regulate the expression of only a very limited range of cytokines. This includes blockade of de novo expression of the T cell growth factor IL-2 following the activation of resting T cells [10] and up-regulation of the expression of TGF-β by a range of parenchymal cells [11]. Clearly the analysis of cytokine expression has the potential to provide clinically useful information about the state of allograft rejection or acceptance. However, a number of issues must first be addressed, including: