Treatment of multiple sclerosis (MS) patients with glatiramer acetate (GA, Copolymer-1, Copaxone(r)) has been associated with induction of GA-reactive Th2 and CD4+CD25+ regulatory T cells (Treg). Research indicates that GA also exerts immunomodulatory activity on antigen (Ag) presenting cells (APC), causing them to secrete an anti-inflammatory "type II" cytokines. We investigated how GA treatment alters monocyte activity and how these APC influence T cell activation. GA treatment of mice promoted development of "type II" monocytes, which were characterized by increased secretion of IL-10 and TGF-?, reduced secretion of TNF and IL-12, and reduced STAT1 signaling. Type II monocytes promoted differentiation of na?ve T (Th0) cells into Th2 and FoxP3+ Treg independent of Ag specificity. Adoptive transfer of type II monocyte-induced regulatory T cells specific for a non-self Ag ameliorated EAE, indicating that cross-reactivity with myelin Ag, considered a prerequisite for T cell-mediated immune modulation by GA, is not required. Adoptive transfer of type II monocytes into mice with EAE reversed paralysis, suppressed Th17 cell development and promoted both Th2 differentiation and expansion of Treg. These findings indicate that APC are a primary target for GA- mediated immune modulation. We have also established how this novel paradigm, adoptive transfer of regulatory monocytes, can be used to study APC-T cell interaction in vivo. We propose to investigate the pathway(s) involved in type II differentiation of monocytes by GA treatment and to characterize how type II monocytes lead to induction of Th2 cells and Treg in vivo. We hypothesize that, in addition to STAT1, other signaling pathways, in particular STAT3 and NF-?B, may be altered in type II monocytes. We hypothesize that expression of TGF-2 by type II monocytes is necessary for these cells to induce regulatory T cells in vivo. Specifically, we propose, (1) to evaluate properties of type II monocytes in vivo and characterize their requirements for induction of Treg and Th2 cells. We will determine type II monocytes survival and how long they retain their capability to induce immune modulation in recipient mice. By adoptive transfer of IL-10-deficient or TGF-?-deficient "type II monocytes" we will establish the relative contribution of these cytokines for induction of regulatory T cells by monocytes. We will evaluate whether type II monocytes induce adaptive or natural Treg cells. (2) Molecular pathways (e.g. NF-?B and MAPK) that may be involved in type II monocyte differentiation will be examined. (3) In parallel with our murine studies, we will evaluate type II monocyte development in MS patients that initiate GA treatment and address whether type II monocytes 5hat may develop in these patients participate in the induction of regulatory T cells. Our proposed studies are highly relevant to MS therapy as they may provide insight leading to the development of reagents that may promote type II APC differentiation and T cell immune modulation more effectively than GA.

Public Health Relevance

Recent research has demonstrated that glatiramer acetate (GA, Copolymer-1, Copaxone(r)), an approved therapy for multiple sclerosis (MS), induces anti-inflammatory "type II" antigen presenting cells (APC) that are responsible for T cell immune modulation, providing a new understanding how GA functions in MS treatment. In this research program, we will elucidate the mechanisms responsible for induction of type II anti-inflammatory monocytes in mice and in GA-treated patients and determine how these regulatory APC influence T cell regulation. These studies should provide insight leading to the development of reagents that may promote type II APC differentiation and T cell immune modulation more effectively than GA.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Utz, Ursula
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University of California San Francisco
Schools of Medicine
San Francisco
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