Homeostatic expansion as a barrier to lymphocyte depletion strategies

Following lymphodepletion, lymphocytes repopulate the immune space both through enhanced thymopoiesis and proliferation of residual nondepleted peripheral lymphocytes. The term homeostatic proliferation (alternatively homeostatic expansion or lymphopenia-induced proliferation) refers to the latter process. Homeostatic proliferation is especially relevant to reconstitution of the lymphocyte compartment following immunodepletion therapy in transplantation. Repopulating lymphocytes can skew toward an effector memory type capable of inducing graft rejection, autoimmunity, or, in the case of allogeneic bone marrow transplantation, graft versus host disease. Here we review recent studies exploring the biologic mechanisms underlying homeostatic proliferation and explore implications for therapy in transplantation.

Two immune-depleting agents, alemtuzumab and rabbit antithymocyte globulin, have been well characterized in their abilities to induce an effector-memory phenotype in repopulating lymphocytes. Additionally, we have gained new understandings of the mechanisms by which the cytokines interleukin-7 and interleukin-15 regulate this process. Recent studies have also explored the functions of noncytokine and signaling molecules in lymphopenia-induced proliferation. Finally, we have seen the promise and limitations of several therapeutic approaches, including recombinant interleukin-7 therapy, CD8-targeted antibodies, and peri-transplant cyclophosphamide, to treat posttransplant lymphopenia and reduce the risks of immune dysregulation following homeostatic proliferation.

Immune dysfunction following homeostatic proliferation is a special challenge in transplantation. A deeper understanding of the underlying biology has led to a number of promising new therapies to overcome this problem.