Lymphocyte production and loss rates remain elevated post-autologous hematopoietic stem cell transplantation

Regulation of lymphocyte numbers is critical and under normal circumstances lymphocyte numbers remain relatively stable. It is generally assumed that when lymphocyte numbers decrease, the immune system responds homeostatically by increasing lymphocyte production and survival rates, thereby facilitating lymphocyte reconstitution. The widely-accepted concept of lymphopenia-induced proliferation is largely based on experiments in mice. In humans, it is well known that T-cell reconstitution tends to be very slow. This challenges the idea that increased lymphocyte production and survival aid recovery from lymphopenia in humans. Here, we investigated whether lymphocyte production and survival rates are increased in patients who underwent an autologous hematopoietic stem cell transplantation (autoHSCT), using in vivo deuterium labelling and mathematical modelling. We found that the production rate of most T- and B-cell subsets in these patients were 2 to 8-times higher than in healthy controls. Against our expectations, lymphocyte loss rates were also significantly increased, and increased lymphocyte production and loss rates were also observed for lymphocyte subsets of which cell numbers had already normalized. Thus, despite the slow reconstitution of lymphocytes in autoHSCT patients, T- and B-cell production rates are increased. This increased production, however, does not simply reflect a homeostatic mechanism, as it goes hand in hand with increased cell loss, and does not normalize when cell numbers do.