Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution

Background The potential benefits of haematopoietic stem-cell transplantati on are tempered by the depletion of T-cells accompanying this procedure. We used a new technique which quantifies the excisional DNA products of T-cel l-receptor (TCR) gene rearrangement to measure thymic output directly in pa tients with multiple myeloma, and thus assessed the contribution of the thy mus to immune recovery after transplantation. Methods We studied 40 patients, 34-66 years of age, who had been randomly a ssigned myeloablative chemotherapy and autologous peripheral-blood haematop oietic stem-cell transplantation with unmanipulated grafts or grafts enrich ed for CD34 stem cells. CD4 and CD8 T-cell counts were measured, thymic out put was estimated serially until 2 years after transplantation, and percent ages of naive T-cells were measured. Findings The production of substantial numbers of new naive T cells by the thymus could be detected by 100 days post-transplant; there was a significa nt inverse relation between age and recovery of new T cells. In the CD34-un selected group, numbers of TCR-rearrangement excision circles returned to b aseline after 2 years, whereas in the CD34-selected group, numbers at 2 yea rs were significantly higher than both baseline numbers (p=0.004), and 2-ye ar numbers in the unselected group (p=0.046). Increased thymic output corre lated with, and was predictive of, increased naive T-cell numbers and broad er T-cell-receptor repertoires. Interpretation Our results provide evidence that the adult thymus contribut es more substantially to immune reconstitution after haematopoietic stem-ce ll transplantation than was previously thought, and therefore could be a ta rget for therapeutic intervention.