Regenerating Immunotolerance in Multiple Sclerosis with Autologous Hematopoietic Stem Cell Transplant

Abstract

Multiple sclerosis (MS) is an inflammatory disorder of the central nervous system where evidence implicates an aberrant adaptive immune response in the accrual of neurological disability. The inflammatory phase of the disease responds to immunomodulation to varying degrees of efficacy; however, no therapy has been proven to arrest progression of disability. Recently, more intensive therapies, including immunoablation with autologous hematopoietic stem cell transplantation (AHSCT), have been offered as a treatment option to retard inflammatory disease, prior to patients becoming irreversibly disabled. Empirical clinical observations support the notion that the immune reconstitution (IR) that occurs following AHSCT is associated with a sustained therapeutic benefit; however, neither the pathogenesis of MS nor the mechanism by which AHSCT results in a therapeutic benefit has been clearly delineated. Although the antigenic target of the aberrant immune response in MS is not defined, accumulated data suggest that IR following AHSCT results in an immunotolerant state through deletion of pathogenic clones by a combination of direct ablation and induction of a lymphopenic state driving replicative senescence and clonal attrition. Restoration of immunoregulation is evidenced by changes in regulatory T cell populations following AHSCT and normalization of genetic signatures of immune homeostasis. Furthermore, some evidence exists that AHSCT may induce a rebooting of thymic function and regeneration of a diversified naïve T cell repertoire equipped to appropriately modulate the immune system in response to future antigenic challenge. In this review, we discuss the immunological mechanisms of IR therapies, focusing on AHSCT, as a means of recalibrating the dysfunctional immune response observed in MS.

Keywords: T cell receptor repertoire; alemtuzumab; autologous hematopoietic stem cell transplantation; cladribine; immune tolerance; lymphopenia-induced proliferation; multiple sclerosis.

Figure 1

(A) An unknown factor triggers oligodendrocyte apoptosis. Microglia are activated and phagocytose the apoptotic oligodendrocytes. (B) Phagocytic cells containing oligodendrocyte myelin breakdown products traffic to the deep cervical lymph nodes via the central nervous system (CNS) lymphatics (glymphatics) where they activate an inflammatory immune response directed toward the undefined antigenic target of disease. (C) The inflammatory response in multiple sclerosis is defined by a dominance of Th1 and Th17 lymphocytes, pro-inflammatory cytokines, and impaired suppressor activity of Tregs. (D) Activated lymphocytes re-enter the CNS where they become re-activated and recruit local and systemic immune populations resulting in demyelination and subsequent axonal loss.

Figure 2

Inflammatory activity in multiple sclerosis (MS) may be detected clinically and/or radiologically. (A) The pre-symptomatic phase of the disease is defined by radiologically apparent relapses in the absence of clinical symptoms. (B) Following the first symptomatic demyelinating event, clinical and radiological relapses continue to occur. (C) Secondary progressive (SP) MS is defined by irreversible accumulation of disability due to chronic axonal loss which associates with ongoing brain atrophy and minimal inflammatory change on magnetic resonance imaging.

Figure 3

Model of the immune reconstitution occurring following autologous hematopoietic stem cell transplantation. (A) The pre-transplant environment is defined by clonally expanded populations of lymphocytes driving central nervous system inflammation with dysfunctional immunosuppressive lymphocytes. (B) Early reconstitution is driven by lymphopenia-induced proliferation of predominately CD8⁺ memory populations. Pie chart depicts T cell receptor (TCR) repertoire which is dominated by lymphopenia-induced proliferation induced expansions of clonal populations. (C) Late reconstitution involves a recovery of thymic output of naïve T cells. Pie chart depicts an increase in TCR diversity. Replicative senescence results in exhaustion of the previous expanded populations.