Could post-transplant cyclophosphamide benefit autoimmune disease patients following autologous hematopoietic stem cell transplantation?

Autologous hematopoietic stem cell transplantation (auto-HSCT) has emerged as an effective therapeutic option for selected patients with severe autoimmune diseases, particularly relapsingremitting multiple sclerosis. However, disease relapse remains a significant challenge, suggesting the persistence of autoreactive lymphocytes and incomplete restoration of sustained immune tolerance. Post-transplant cyclophosphamide (PTCy) is widely employed following allogeneic HSCT for graftversus- host disease prophylaxis. Here, we propose that incorporation of PTCy into auto-HSCT protocols may further improve outcomes in selected autoimmune disease patients by reducing and suppressing residual autoreactive T cells that survive conditioning and subsequently undergo lymphopenia-driven and / or antigen-induced proliferation post-transplant. Drawing on mechanistic and clinical insights from allogeneic transplantation, we discuss how PTCy could augment depletion of pathogenic effector T cells while supporting hematopoietic recovery and immune reconstitution. Because complete removal of autoreactive lymphocyte populations is unlikely, long-term disease control will probably require promoting peripheral immune regulation. Multiple sclerosis is highlighted as a model disease, although the concepts discussed may extend to other autoimmune disorders. Overall, the addition of PTCy to auto-HSCT represents a novel translational strategy with the potential to enhance immune resetting, suppress residual autoreactivity, and improve long-term remission rates in autoimmune disease patients.