Immune Checkpoint Therapy in Multiple Sclerosis (MS)

Immune checkpoint molecules, such as programmed death (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are crucial regulators of immune responses. In the context of multiple sclerosis (MS), immune checkpoint molecules have also been investigated as potential targets for therapeutic interventions.

Introduction of Multiple Sclerosis (MS)

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) characterized by inflammation, with the majority of patients suffering from severe impairment. The frequency of this neurodegenerative disease is attributable to an autoreactive backdrop of activated lymphocytes, macrophages, and microglia, which reach the CNS and cause inflammation, leading to demyelination.

The importance of Immune System in MS

Previous research has demonstrated that the immune system plays an important role in the development of MS. An equilibrium between stimulatory and inhibitory signals controls immune cell reactivity in the periphery, attuning effector cells to their surroundings. These signals are sent via a range of regulatory molecules known as immunological checkpoints in the case of T cells. PD-1/PD-L1 and CTLA-4 may be the most important immune checkpoints for preventing autoactivation among the various checkpoint medicines.

PD-1 in MS

PD-1 and its ligands, particularly PD-L1 and PD-L2, are critical in suppressing T cell signaling and supporting immunological homeostasis and tolerance. A recent study found that immunological checkpoints such as PD-1, CTLA-4, and TIM-3 are significantly lower in MS patients than in the healthy group. Downregulation of PD-1 and PD-L1 may indicate that overstimulation of immune cells occurs in MS via signaling malfunction of these molecules.

Fig 1 The expression of PD-L1 mRNA in PBMCs of MS patients and controls.¹

CTLA-4 in MS

CTLA-4, which is mostly generated by regulatory T cells (Tregs), is involved in self-antigen tolerance and autoimmune inhibition. Because a deficiency of CTLA-4 has been demonstrated to cause autoimmune disorders in mouse models, CTLA-4 is regarded as a crucial component in regulating both central and peripheral tolerance. As a result, CTLA-4 deficiency has been linked to the emergence of autoimmune diseases like multiple sclerosis. CTLA-4 gene variants have been connected to the level of CTLA-4 expression in MS patients as well as disease risk. Furthermore, inhibiting co-stimulatory molecule interactions with CTLA4 Ig appears to protect against MS.

Fig 2 The difference in CTLA-4 expression between MS patients and controls.¹

In conclusion, immune checkpoint molecules have emerged as promising targets for therapeutic intervention in MS. The modulation of immune checkpoints holds the potential to restore immune balance, reduce inflammation, and prevent further damage in the central nervous system. Creative Biolabs provides a variety of unique services for developing immune checkpoint treatment in MS. Please contact us if you require any other information.

Reference

1. Derakhshani, Afshin et al. "Regulation of CTLA-4 and PD-L1 Expression in Relapsing-Remitting Multiple Sclerosis Patients after Treatment with Fingolimod, IFNβ-1α, Glatiramer Acetate, and Dimethyl Fumarate Drugs." Journal of personalized medicine vol. 11,8 721. 27 Jul. 2021.

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