**Acknowledgements**

possibility since ATG contains a mixture of antibodies with multiple specificities [59, 60], and thus, ATG may affect circulating thymic precursors. With this assumption in mind, we hypothesize that the capacity to regenerate hematopoiesis may impact thymic function. The *cyclo-oxygenase-2* (*COX-2*) gene promoter polymorphism at position -765 is responsible for the control of prostaglandin-E2 (PGE-2) synthesis and PGE-2 has been reported to be involved in lymphocyte reconstitution following depletion [120-122]. Indeed, COX-2 is expressed by thymic stroma [121], participates not only in thymocyte development [122], but also in accelerated hematopoiesis following myelotoxic injury [120]. We found that the *COX-2* gene promoter polymorphism at position -765 is associated with a higher risk of ATG-induced persistent CD4 T-cell lymphopenia. Pre-transplant TREC levels were higher in GG patients than in C carriers who have lower serum PGE-2 levels [123]. The possibility of selecting patients with low or high risk of immune reconstitution impairment through the *COX-2* gene promoter polymorphism could offer the opportunity to use ATG more safely. This suggests that ATG

Significant advances have been performed in the comprehension of endogenous thymus regeneration and several factors have been shown to increase thymic activity (for a recent review [108], see also Ref.[124] for IL-22). This is particularly interesting since recombinant human IL-7 has been used in clinical trials [97]. Administration of IL-7 results in an expansion

 T cell expansion [97]. Lymphopenic or normal older hosts receiving IL-7 develop an expanded circulating T cell pool with increased T cell repertoire diversity [100]. Moreover, IL-7 administration exhibits a favorable toxicity profile [97], opening the perspective of potential future use in renal transplant recipients with severe prolonged CD4+ T cell lymphopenia in case that this IL7 pathway is altered. Furthermore, IL-7 treatment of human thymus −*in vitro* or in a xenogeneic model− has been shown to increase thymic activity, as attested by elevated TREC levels [125]. Thus, IL-7 treatment may improve thymic activity after kidney

T cells with a tendency toward enhanced

T cell lymphopenia after ATG and

T cell

T cells and CD8+

We summarize in a Figure the different factors and critical steps involved in CD4+

our experience on the identification of biomarkers (CD4+

cardiovascular diseases in renal transplant recipients.

reconstitution after depletion by ATG (Figure 1). Overall, the aim of this review was to report

TREC levels at the time of transplantation) predicting transplantation-related complications (mainly atherosclerosis and cancer occurrence), and to propose to use these biomarkers in patient follow up and/or in immunosuppressive strategy design. Furthermore, we propose other "tracks" to improve the clinical relevance of these biomarkers, as well as to understand their implications in the occurrence of immunosuppression-associated complications. The efficacy of these identified biomarkers should be tested and validated in prospective clinical trials in order to select the appropriate immunosuppressive strategy. In the future, one could imagine that these biomarkers may help physicians to manage risks of cancers and

may affect T cell reconstitution before thymus.

404 Current Issues and Future Direction in Kidney Transplantation

of both naive and memory CD4+

CD8+

transplantation.

**5. Conclusion**

We thank the Région de Franche-Comté for the LipSTIC grant (to P.S.)
