The genealogy, methodology, similarities and differences of immune reconstitution therapies for multiple sclerosis and neuromyelitis optica.

Immune reconstitution therapies (IRTs) are a type of short course procedure or pharmaceutical agent within the MS pharmacopeia. They emanate from oncology and induce transient incomplete lympho-ablation with or without myelo-ablation, resulting in potential prolonged immunomodulation. Thus, they provide significant prophylaxis from disease activity without retreatment. Modern IRT for autoimmunity encompasses a heterogeneous group of pulsed lympho- and non-myelo-ablative treatments designed to re-boot the adaptive immune system in a quasi-permanent manner - a re-induction of ontogeny. IRT is the extensive debulking of an auto-aggressive immune system to attempt to reach the Holy Grail of immune tolerance. This incomplete yet significant lympho-ablation induces lymphoproliferation, reduces pathogenic clonal cells, causes thymopoiesis and results in the induction of immune tolerance. Lympho-ablation with immune reconstitution can result in minimal residual autoimmunity. There is a resetting of the immune thermostat - i.e., the immunostat. IRTs have the potential to provide prolonged periods of disease inactivity without retreatment in part through the immunological results of their pulsatile lymphocyte depletion. It is vital to increase our understanding of how IRTs alter a patient's immune response to the antigenic target of the disease so that we can devise newer, more durable and safer forms of such agents. What common features do extant IRTs (i.e., stem cell transplant, alemtuzumab and oral cladribine) have to produce the durable therapeutic response without long term treatment in neuroimmunological diseases such as MS (multiple sclerosis) and NMOSD (neuromyelitis optica spectrum disorders)? Can we learn from these critical features to predict what other maneuvers or agents might effect similar clinical results with equal or greater efficacy and safety?