Does lymphopenia preclude restoration of immune homeostasis? The particular case of type 1 diabetes

Induction of hematopoietic chimerism initiates tolerizing processes that often restore control over autoimmune reactions: graft versus autoimmunity reaction. In view of the limited capacity of autologous bone marrow transplants and some cases of persistent autoimmune diabetes after allogeneic transplants, we hypothesize that the preparative conditioning regimens adopted from the oncological setting are suboptimal approaches to rebooting the immune system. In general, homeostatic expansion under lymphopenic conditions favors the recovery and development of cytotoxic T cells. Autoimmune diabetes is a particular case in which debulking is ineffective due to resistance of the effector cells to depletion by conventional immunosuppressive therapies. Furthermore, resetting of immune activity is impaired by lymphopenia-induced proliferation of residual diabetogenic clones and delayed recovery of suppressor cells. For control of the autoimmune reaction it is essential to design immunomodulatory approaches that overcome rejection while avoiding homeostatic expansion of residual diabetogenic clones.