Publications

Martinez FO, Sica A, Mantovani A, Locati M.
Istituto Clinico Humanitas, I-20089 Rozzano, Italy.
Macrophages are widely distributed immune system cells that play an indispensable role in homeostasis and defense. They can be phenotypically polarized by the microenvironment to mount specific functional programs. Polarized macrophages can be broadly classified in two main groups: classically activated macrophages (or M1), whose prototypical activating stimuli are IFNgamma and LPS, and alternatively activated macrophages (or M2), further subdivided in M2a (after exposure to IL-4 or IL-13), M2b (immune complexes in combination with IL-1beta or LPS) and M2c (IL-10, TGFbeta or glucocorticoids). M1 exhibit potent microbicidal properties and promote strong IL-12-mediated Th1 responses, whilst M2 support Th2-associated effector functions. Beyond infection M2 polarized macrophages play a role in resolution of inflammation through high endocytic clearance capacities and trophic factor synthesis, accompanied by reduced pro-inflammatory cytokine secretion. Similar functions are also exerted by tumor-associated macrophages (TAM), which also display an alternative-like activation phenotype and play a detrimental pro-tumoral role. Here we review the main functions of polarized macrophages and discuss the perspectives of this field.

Liu J, Johnson TV, Lin J, Ramirez SH, Bronich TK, Caplan S, Persidsky Y, Gendelman HE, Kipnis J.
Laboratory of Neuro-Immune Regulation, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Despite active investigation of copolymer-1 (Cop-1) for nearly 40 years the mechanisms underlying its neuroprotective properties remain contentious. Nonetheless, current dogma for Cop-1 neuroprotective activities in autoimmune and neurodegenerative diseases include bystander suppression of autoimmune T cells and attenuation of microglial responses. In this report, we demonstrate that Cop-1 interacts directly with primary human neurons and decreases neuronal cell death induced by staurosporine or oxidative stress. This neuroprotection is mediated through protein kinase Calpha and brain-derived neurotrophic factor. Dendritic cells (DC) uptake Cop-1, deliver it to the injury site, and release it in an active form. Interactions between Cop-1 and DC enhance DC blood brain barrier migration. In a rat model with optic nerve crush injury, Cop-1-primed DC induce T cell independent neuroprotection. These findings may facilitate the development of neuroprotective approaches using DC-mediated Cop-1 delivery to diseased nervous tissue.

Aharoni R, Sonego H, Brenner O, Eilam R, Arnon R.
Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Inflammatory bowel diseases (IBDs) are complex multifactorial immunological disorders characterized by dysregulated immune reactivity in the gut and imbalance between pro-inflammatory and anti-inflammatory reactivity. The therapeutic effect of the immunomodulatory drug glatiramer acetate (GA, Copaxone, copolymer 1) has been established in several IBD models, including trinitrobenzene sulfonic acid (TNBS) and dextran sulfate sodium (DSS)-induced colitis, as well as in a spontaneous colitis model. In the present study we investigated the mechanism of action of GA and cells specifically induced by it. Immunization of naive mice by GA, generated a lymphocyte population of the Th2/3 subtype, that drastically reduced disease manifestations upon their adoptive transfer to mice with DSS colitis. This was demonstrated by the substantial decrease in weight loss, intestinal bleeding and diarrhea, as well as by the prevention of macroscopic and microscopic colonic damage. In contrast, adoptive transfer of control lysozyme-specific cells did not induce any beneficial effect on the disease. Moreover, GA-specific short-term T-cell lines, either exogenously labeled or genetically marked, adoptively transferred by the intraperitoneal route to colitis-induced mice, localized in the inner layers of the colon and secreted in situ the regulatory cytokine TGF-beta. These results demonstrate the accumulation of GA-specific Th2/3 cells secreting regulatory cytokines in the injured colon, and thus draw a direct linkage between the therapeutic effect of GA in IBD and an immunomodulatory effect at the site in which the pathological process occurs.

Jee Y, Piao WH, Liu R, Bai XF, Rhodes S, Rodebaugh R, Campagnolo DI, Shi FD, Vollmer TL.
Barrow Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
CD4(+)CD25(+) regulatory T cells (Tregs) are potent immunosuppressors that are pivotal in the maintenance of self-tolerance. The involvement of Tregs in therapies for immune-mediated diseases has been proposed, but direct supporting evidence is still lacking. While investigating mechanisms underlying the clinical benefits of glatiramer acetate (GA) in an animal model of multiple sclerosis (MS), i.e., experimental autoimmune encephalomyelitis (EAE), we recently demonstrated that GA can protect mice deficient in the Th(2) cytokines IL-4, IL-10 and IL-4/IL-10 from acquiring EAE, suggesting that mechanisms other than Th(2) cells may be responsible for the therapeutic effects of GA. Here we demonstrate that GA treatment boosts the expression of Foxp3 on Tregs during EAE. Furthermore, adoptive transfer of purified Tregs from GA-treated EAE mice is more effective in preventing EAE development than Tregs from untreated EAE controls. Thus, our current data provide evidence that Tregs may be the major contributor to GA's therapeutic action in EAE and, possibly, MS. Further mechanistic studies to reveal the molecular events linking GA with Tregs may optimize GA treatment and lead to the development of new, even more effective therapies that utilize this mechanism of action.

Weber MS, Hohlfeld R, Zamvil SS.
Department of Neurology and Program in Immunology, University of California, San Francisco, CA 94143, USA.
Glatiramer acetate (GA) (Copolymer-1, Copaxone, Teva, Israel, YEAK) is a polypeptide-based therapy approved for the treatment of relapsing-remitting multiple sclerosis. Most investigations have attributed the immunomodulatory effect of GAs to its capability to alter T-cell differentiation. Specifically, GA treatment is believed to promote development of Th2-polarized GA-reactive CD4(+) T-cells, which may dampen neighboring inflammation within the central nervous system. Recent reports indicate that the deficiency in CD4(+)CD25(+)FoxP3(+) regulatory T-cells in multiple sclerosis is restored by GA treatment. GA also exerts immunomodulatory activity on antigen presenting cells, which participate in innate immune responses. These new findings represent a plausible explanation for GA-mediated T-cell immune modulation and may provide useful insight for the development of new and more effective treatment options for multiple sclerosis.