The potential for targeting CD4+CD25+ regulatory T cells in the treatment of multiple sclerosis in humans

Abstract

Comparative analyses of surface-marker expression and in vitro assays of function indicate that significant differences exist in the state of activation of the lymphoid cells in both the blood and cerebrospinal fluid (CSF) between patients with multiple sclerosis (MS) and healthy controls. Of specific interest is the finding that T cells recognizing central-nervous-system (CNS)-derived antigens are found at slightly higher frequencies and in a higher activation state in the circulation of patients with MS as compared to healthy controls [1–3]. This implicates that the autoreactive T cell and the loss of immune regulatory mechanisms are critical in the etiology of MS. Various therapeutic interventions have focused on reducing either the general state of activation of the entire immune system (such as high-dose steroids during acute episodes) or the specific activation of CNS-responsive T cells. The goals of T-celldirected therapies have been to induce T-cell anergy, to alter the T-cell response in the patient from Th1 (inflammatory) to Th2 (anti-inflammatory), or induce the peripheral deletion of autoreactive T cells. The recently identified population of T cells known as CD4+CD25+ regulatory T cells (TR cells) that appears to have an increased propensity for recognition of self-antigens and act to down-modulate the immune response was found to be functionally deficient in patients with MS as compared to those isolated from healthy subjects [4]. Thus the CD4+CD25+ TR population may be an ideal target for the design of future therapies focused on augmenting their inhibitory activity in patients with MS. In this chapter we will discuss what is known about the state of the immune system in patients with MS, and how the various current and future therapies may affect the interaction between inflammatory and regulatory T-cell subsets and thus regulate the disease.