Multiple Sclerosis and the LIF/IL-6 Axis: Use of Nanotechnology to Harness the Tolerogenic and Reparative Properties of LIF.

Abstract

Leukaemia inhibitory factor (LIF) plays a critical role in "stemness" versus "differentiation", a property that underpins the core value of LIF as a therapeutic for both the treatment of autoimmune disease and for promoting tissue repair. This value can be realized using nano-engineering technology, where a new generation of tools can, with unprecedented ability, manipulate biological functions. One striking example is the treatment of multiple sclerosis (MS). The underpinning biology is the newly identified LIF/IL-6 axis in T lymphocytes, which can tilt the behaviour between immune tolerance versus immune attack. This LIF/IL-6 axis is ideally suited to nanotherapeutic manipulation, given its inherent mechanistic simplicity of two mutually opposing feed-forward loops that determine either tolerogenic (LIF) or inflammatory (IL-6) immunity. Using LIF that is formulated in biodegradable nanoparticles (LIF-NP) and targeted to CD4+ T cells, the axis is harnessed towards immune tolerance. This has implications for the treatment of autoimmune diseases, where the clinical burden is immense. It encompasses more than 100 diseases and, in the USA alone, costs more than $100 billion in direct health care costs annually. Other properties of LIF include the promotion of healthy neuro-glial interactions within the central nervous system (CNS), where, in addition to MS, LIF-NP therapy is relevant to inflammatory neurodegenerative diseases that represent a large and increasing need within aging populations. Thirdly, LIF is a reparative growth factor that can maintain genomic plasticity. LIF-NP supports the use of stem cell-based therapies in regenerative medicine plus augment therapeutic benefits within the patient. These core properties of LIF are greatly amplified in value by the advantage of being formulated as nanoparticles, namely (i) targeted delivery, (ii) exploitation of endogenous regulatory pathways and (iii) creation of surrogate micro-stromal niches. We discuss LIF-NP as a means to harness endogenous pathways for the treatment of MS, both to reset immune self-tolerance and to promote repair of myelin that is required to support health within the nervous system.