NIV Congres
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Alemtuzumab as anti-rejection therapy in kidney transplant patients induces homeostatic T cell proliferation and impairs IL7 but not IL2 responses
Bouvy, A.P., Hesselink, D.A., Klepper, M., Weimar, W. W., Baan, C.C.
Categorie(ën):
Introduction Induction therapy with alemtuzumab is known to result in T cell depletion followed by a slow immune recovery leading to hypo-responsiveness to the graft. Whether the same effects occur when alemtuzumab is given during immune activation, i.e. anti-rejection therapy is unknown. In this study we investigated the repopulation, phenotype and cytokine responsiveness of T cells after alemtuzumab anti-rejection therapy.
Methods Patients (n=11) were treated with alemtuzumab (2 days 30mg sc) for steroid-resistant rejection. Flow cytometric analysis was performed on whole blood to measure the expression of the proliferation marker Ki67 and to study interleukin 2 (IL2) and IL7 mediated phosphorylation of STAT5, a nuclear transcription factor for T cell activation and proliferation, in CD4 and CD8 naïve (CD45RO-CCR7+), central memory (CM; CD45RO+CCR7+), effector memory (EM; CD45RO+CCR7-) and EMRA (CD45RO-CCR7-) T cells, before and 3 months after treatment.
Results Threemonths after alemtuzumab therapy the T cell population recovered to 5% of baseline level (570 vs. 47 cells/µL, p<0.01), with no differences between CD4 and CD8 T cell recovery. The CD4 T cell pool showed a phenotypic shift towards memory T cells (median 70%, range 42-88% vs. 98% range 75-100%, p=0.01). In the CD8 T cells only the percentage of effector memory T cells increased (20% range 3-42% vs. 32 range 21-44%, p=0.04). Ki67 expression was significantly higher in both CD4 and CD8 T cells at 3 months when compared to baseline levels (p<0.01). For CD4 T cells higher percentages of Ki67+ T cells were both present in CM and EM T cells (p<0.01). Where for CD8 T cells only an increased percentage in the EM subset (p=0.02) was measured. At the functional level repopulated CD4 and CD8 T cells were not affected in their capacity to phosphorylate STAT5 when stimulated by IL2. However, in response to IL7 the STAT5 phosphorylation capacity was decreased in the total CD4 population (p=0.02) as well as in the CD4 memory subsets (all p<0.03).
Conclusion After alemtuzumab anti-rejection therapy, repopulation takes place via homeostatic proliferation with a subsequent phenotypic shift towards memory T cells. In addition, CD4 T cells showed impaired STAT5 phosphorylation capacity in response to IL7 but not to IL2. This can be explained by tachyphylaxis, exhaustion or down-regulation of the IL7 receptor.