Immune surveillance of the central nervous system in multiple sclerosis — Relevance for therapy and experimental models

Abstract

Treatment of central nervous system (CNS) autoimmune disorders frequently involves the reduction, or depletion of immune-competent cells. Alternatively, immune cells are being sequestered away from the target organ by interfering with their movement from secondary lymphoid organs, or their migration into tissues. These therapeutic strategies have been successful in multiple sclerosis (MS), the most prevalent autoimmune inflammatory disorder of the CNS. However, many of the agents that are currently approved or in clinical development also have severe potential adverse effects that stem from the very mechanisms that mediate their beneficial effects by interfering with CNS immune surveillance. This review will outline the main cellular components of the innate and adaptive immune system that participate in host defense and maintain immune surveillance of the CNS. Their pathogenic role in MS and its animal model experimental autoimmune encephalomyelitis (EAE) is also discussed. Furthermore, an experimental model is introduced that may assist in evaluating the effect of therapeutic interventions on leukocyte homeostasis and function within the CNS. This model or similar models may become a useful tool in the repertoire of pre-clinical tests of pharmacological agents to better explore their potential for adverse events.

An optimized method to process mouse CNS to simultaneously analyze neural cells and leukocytes by flow cytometry

“…1-4). Even in naïve mice, a small but detectable number of myeloid (CD11b + ) and non-myeloid (CD45 + CD11b − ) leukocytes were reliably detected by flow cytometry in accordance with the continuous monitoring of the CNS by blood-borne immune cells such as T lymphocytes (Hussain et al, 2014;Ousman and Kubes, 2012). Although T lymphocytes do not have extensive cell processes as do neural cells (e.g.…”

Cutting Edge: CD99 Is a Novel Therapeutic Target for Control of T Cell–Mediated Central Nervous System Autoimmune Disease

“…Preventing WBC infiltration into the CNS reduces the extent of CNS inflammation and thereby ameliorates MS symptoms; however this does not come without risk (49, 52). Both anti-VLA-4 and Fingolimod therapies have been reported to impede the ability to protect against latent and chronic CNS viral infections by impairing immune surveillance (53–56).…”

IL-12/IL-23p40 Is Highly Expressed in Secondary Lymphoid Organs and the CNS during All Stages of EAE, but Its Deletion Does Not Affect Disease Perpetuation

“…The role of CD4 + T cell subsets in the etiology of MS is substantiated by observations made in the murine model experimental autoimmune encephalomyelitis (EAE) [3]. An early event in the activation and subsequent differentiation of naïve antigen-specific T cells into effector cells in EAE, and possibly MS is directed by their interaction with antigen-presenting cells (APCs) in lymphoid tissues [4]. APCs, including dendritic cells and macrophages, produce interleukin (IL)-12, which induces interferon gamma (IFNγ) secretion and CD4 + T helper (Th)1 differentiation.…”