Immune Reconstitution Following Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis: A Review on Behalf of the EBMT Autoimmune Diseases Working Party

Abstract

Multiple sclerosis (MS) is a central nervous system (CNS) disorder, which is mediated by an abnormal immune response coordinated by T and B cells resulting in areas of inflammation, demyelination, and axonal loss. Disease-modifying treatments (DMTs) are available to dampen the inflammatory aggression but are ineffective in many patients. Autologous hematopoietic stem cell transplantation (HSCT) has been used as treatment in patients with a highly active disease, achieving a long-term clinical remission in most. The rationale of the intervention is to eradicate inflammatory autoreactive cells with lympho-ablative regimens and restore immune tolerance. Immunological studies have demonstrated that autologous HSCT induces a renewal of TCR repertoires, resurgence of immune regulatory cells, and depletion of proinflammatory T cell subsets, suggesting a “resetting” of immunological memory. Although our understanding of the clinical and immunological effects of autologous HSCT has progressed, further work is required to characterize the mechanisms that underlie treatment efficacy. Considering that memory B cells are disease-promoting and stem-like T cells are multipotent progenitors involved in self-regeneration of central and effector memory cells, investigating the reconstitution of B cell compartment and stem and effector subsets of immunological memory following autologous HSCT could elucidate those mechanisms. Since all subjects need to be optimally protected from vaccine-preventable diseases (including COVID-19), there is a need to ensure that vaccination in subjects undergoing HSCT is effective and safe. Additionally, the study of vaccination in HSCT-treated subjects as a means of evaluating immune responses could further distinguish broad immunosuppression from immune resetting.

The current standing of autologous haematopoietic stem cell transplantation for the treatment of multiple sclerosis

“…Regarding guidance for vaccination following aHSCT, a comprehensive report covering numerous aspects of immune reconstitution following aHSCT for MS was recently published on behalf of the EBMT [ 93 ]. The authors describe the loss of immunity following transplantation, as well as persistently poor immune defence against pathogens that persists for several years post-aHSCT.…”

“…The authors describe the loss of immunity following transplantation, as well as persistently poor immune defence against pathogens that persists for several years post-aHSCT. The EBMT guidance is, therefore, to implement a routine vaccination program 3–6 months following aHSCT, with the knowledge that, in the early post-transplantation period, vaccination response may be suboptimal [ 93 ].…”

Hematopoietic stem cell transplantation and cellular therapies for autoimmune diseases: overview and future considerations from the Autoimmune Diseases Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT)

“…HSCT exerts its therapeutic effect in ADs through various mechanisms, including the immunosuppressive conditioning regimen able to eradicate the autoreactive immunologic memory, and the regeneration and renewal of the immune system, leading to the re-induction of immune tolerance to rewire aberrant immune response toward self-antigens [ 26 , 34 ]. Moreover, changes in the microbiome profile [ 35 ], which have been linked to various ADs, merit further investigations in the context of immune recovery.…”

“…Remission of disease activity in patients with severe active MS undergoing autologous HSCT relies not only on the effect of high-dose chemotherapy and intense lymphodepletion, but also on the renewal [ 34 ] of the immune compartment. Initially conceived as an extreme “rescue” therapy in MS patients with a poor prognosis who have failed all other therapies, delivery of HSCT subsequently changed [ 41 – 47 ], including more patients in earlier inflammatory phases of the disease, with a gradual shift to a major predominance of relapsing remitting over progressive forms [ 8 , 48 ].…”

Hematopoietic Stem Cell Transplantation for Neurological Disorders: A Focus on Inborn Errors of Metabolism

“…Collected HSC are then reinfused to rescue bone marrow hematopoietic recovery in the ablated patient ( Carreras et al, 2019 ). Immune reconstitution is ideally re-conditioned toward self-tolerance, which is further beneficial if autoimmunity is present ( Cencioni et al, 2022 ). Importantly, HSC only differentiate into hematopoietic cells in this context and do not seem to participate in tissue repair outside of the bone marrow compartment.…”