Kinetics of Homeostatic Proliferation and Thymopoiesis after rATG Induction Therapy in Kidney Transplant Patients

BACKGROUND: Lymphocyte-depleting therapy is associated with long-lasting effects on repopulated T cells and subsequent increased rates of infections and malignancies. The mechanisms of T-cell repopulation and their posttransplantation kinetics are not fully understood. METHODS: We studied thymopoiesis by CD31(+) naïve T cells (recent thymic emigrants) and homeostatic proliferation by Ki-67(+) T cells in rabbit antithymocyte globulin (rATG)-treated patients the first 6 months after transplantation. Patients receiving basiliximab or no induction therapy served as controls. RESULTS: At 6 months after transplantation, T-cell numbers were lower than before transplantation in rATG-treated patients, whereas T-cell numbers remained stable in both control groups. In this time period, thymopoiesis was similar between the three treatment groups; CD8(+) T cells showed the highest percentage of recent thymic emigrants. At month 1, percentages of Ki-67(+) naïve and memory CD4(+) and CD8(+) T cells were the highest in rATG-treated patients, but these percentages declined in the months thereafter. When CD31 was used to distinguish between cytokine- and antigen-driven proliferation in naïve T cells, we found evidence for cytokine-dependent proliferation. Cytokine-dependent proliferation was also shown by in vivo increased percentages of phosphorylated STAT5 and high expression levels of the interleukin-7 receptor-α and interleukin-15 receptor-α by T cells. CONCLUSION: These findings demonstrate that, in the first month after rATG therapy, cytokine-induced homeostatic proliferation is involved in T-cell repopulation of both naïve and memory T cells. At later time points, the contribution of homeostatic proliferation diminished, which explains the observed incomplete T-cell recovery.