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.

Keywords: disease-modifying therapies (DMT); hematopoietic stem cell (HSC) transplantation; immune reconstitution; immunological memory; vaccination.

Figure 1

Immune reconstitution in MS after HSCT. Thymus-dependent T cell regeneration and immune regulation mediated by T and natural killer (NK) cells constitute the major identified pathways influencing immune reconstitution in patients with MS after HSCT. Thymus-derived CD4 T cells show a new, diverse repertoire and deletion of preexisting CD4 clones. CD8 T cells show an incomplete renewal of TCR repertoire suggesting expansion of residual or regenerated virus-specific clones. Increase of regulatory CD4⁺FOXP3⁺, CD8⁺CD57⁺T cells, and NK cells and eradication of pro-inflammatory Th17 and Th17-1 cells (MAIT) are observed after HSCT. NK cells induce necrotic cell death in Th17 and Th17-1 cells by the NKG2D pathway, while CD8⁺CD57⁺ cells suppress CD4⁺ T cell proliferation. Anergy is reported on CD8⁺ T cells that express high levels of CD57, a marker of senescence, and inhibitory effects are exerted by the immune checkpoint inhibitor PD-1. HSC, hematopoietic stem cells; CLP, common lymphocyte progenitor; NK regs, regulatory natural killer CD3-CD56^hi. Figure created with BioRender.com.

Figure 2

Stem memory cells in healthy and autoimmune disease. Stem memory cells constitute a subset of T cells with self-renewal and multipotent capacity. Generated from naïve cells, stem memory cells develop into memory subsets including central memory and effector memory. Stem memory cells express a naïve-like phenotype (CD45RA⁺, CCR7⁺, CD62L⁺, CD27⁺, CD28⁺, and IL7Ra⁺) and memory markers (CD95⁺, CXCR3⁺, IL-2Rb⁺, CD58⁺, and CD11a⁺), which vary during further differentiation. While essential to immunological memory in healthy immune system, memory stem cells also represent a reservoir of autoreactive clones in autoimmune disease. For example, in type I diabetes (TDI) self-reactive β-cell-specific CD8 T cells maintain a memory stem cell phenotype that favors a persistent production of pathogenic clones. In systemic lupus erythematosus, memory stem cells differentiate easily into T follicular helper cells (Tfh) that contribute to B cell differentiation and antibody production. In multiple sclerosis, stem memory cells recognizing, hypothetically, myelin antigens could represent a supply of pro-inflammatory and cytotoxic cells targeting myelin and damaging neurons. Figure created with BioRender.com.