In this study, we assessed the involvement of IL-1β in early angiogenic responses induced by malignant cells using Matrigel plugs supplemented with B16 melanoma cells. We found that during the angiogenic response, IL-1β and vascular endothelial growth factor (VEGF) interact in a newly described autoinduction circuit, in which each of these cytokines induces the other. The IL-1β and VEGF circuit acts through interactions between bone marrow–derived VEGF receptor 1+/IL-1R1+ immature myeloid cells and tissue endothelial cells. Myeloid cells produce IL-1β and additional proinflammatory cytokines, which subsequently activate endothelial cells to produce VEGF and other proangiogenic factors and provide the inflammatory microenvironment for angiogenesis and tumor progression. These mechanisms were also observed in a nontumor early angiogenic response elicited in Matrigel plugs by either rIL-1β or recombinant VEGF. We have shown that IL-1β inhibition stably reduces tumor growth by limiting inflammation and inducing the maturation of immature myeloid cells into M1 macrophages. In sharp contrast, only transient inhibition of tumor growth was observed after VEGF neutralization, followed by tumor recurrence mediated by rebound angiogenesis. This occurs via the reprogramming of VEGF receptor 1+/IL-1R1+ cells to express hypoxia inducible factor-1α, VEGF, and other angiogenic factors, thereby directly supporting proliferation of endothelial cells and blood vessel formation in a paracrine manner. We suggest using IL-1β inhibition as an effective antitumor therapy and are currently optimizing the conditions for its application in the clinic.

Microglia integrate within the neural tissue with a distinct ramified morphology through which they scan the surrounding neuronal network. Here, we used a digital tool for the quantitative morphometric characterization of fine cortical microglial structures in mice, and the changes they undergo with aging and in Alzheimer’s-like disease. We show that, compared with microglia in young mice, microglia in old mice are less ramified and possess fewer branches and fine processes along with a slightly increased proinflammatory cytokine expression. A similar microglial pathology appeared 6–12 months earlier in mouse models of Alzheimer’s disease (AD), along with a significant increase in brain parenchyma lacking coverage by microglial processes. We further demonstrate that microglia near amyloid plaques acquire unique activated phenotypes with impaired process complexity. We thus show that along with a chronic proinflammatory reaction in the brain, aging causes a significant reduction in the capacity of microglia to scan their environment. This type of pathology is markedly accelerated in mouse models of AD, resulting in a severe microglial process deficiency, and possibly contributing to enhanced cognitive decline.

Vaccination against amyloid ␤-peptide (A␤) has been shown to be successful in reducing A␤ burden and neurotoxicity in mouse models of Alzheimer's disease (AD). However, although A␤ immunization did not show T cell infiltrates in the brain of these mice, an A␤ vaccination trial resulted in meningoencephalitis in 6% of patients with AD. Here, we explore the characteristics and specificity of A␤-induced, T cell-mediated encephalitis in a mouse model of the disease. We demonstrate that a strong A␤-specific T cell response is critically dependent on the immunizing T cell epitope and that epitopes differ depending on MHC genetic background. The amounts and the ratio between the two forms and their deposition in the brain are affected by mutations in the APP and presenilin genes or the presence of the ApoE4 allele (3, 4). Immunolabeling of extracellular A␤ in the brain reveals neuritic and diffuse plaques. The former are colocalized with activated microglia and astrocytes as well as degenerating neurons, whereas the latter do not clearly associate with glial activation or neurotoxicity (5). Recent findings also demonstrate a role for A␤ synaptotoxicity independent of plaques, possibly mediated by soluble A␤ oligomers at intra-and extracellular compartments (6-9).Parenteral immunization of APP transgenic (Tg) mice with synthetic A␤ in adjuvant can markedly decrease the number and density of A␤ deposits in the brain, with concomitant improvement in neuritic dystrophy and gliosis (10, 11). Positive effects have also been found after repetitive mucosal (intranasal) administration of the A␤ peptide to Tg mice (12, 13). Passive transfer of A␤ antibodies has shown similar beneficial neuropathological effects (14-16); however, brain hemorrhage appears as a possible side effect of this approach if tested in mice with cerebral amyloid angiopathy (7).The finding that active vaccination with A␤ had profound A␤-lowering effects in an animal model of AD led to a clinical trial in which an A␤1-42 synthetic peptide was administered parenterally with adjuvant to patients with mild to moderate AD. Although a phase I safety study in a small number of patients did not reveal significant side effects, a subsequent phase II trial was discontinued shortly after its initiation, when Ϸ6% of the treated patients developed meningoencephalitis (17). Nonetheless, a cohort of patients with AD vaccinated with A␤ have shown promising results, demonstrating slower decline of cognitive functions over a 1-year period, which was evident also in patients who experienced transient encephalitis (18). Postmortem analysis of brain sections revealed decreased A␤ plaques in neocortex regions associated with activated microglia and T cell infiltrates in the CNS, as compared with unimmunized patients with AD (19).The meningoencephalitis observed after A␤ vaccination of patients with AD is postulated to be the result of activation of A␤-reactive T cells in the periphery and their migration to A␤ plaques in the brain. Understanding the factors that are required to ...

The generation of new neurons and glia from a precursor stem cell appears to take place in the adult brain. However, new neurons generated in the dentate gyrus decline sharply with age and to an even greater extent in neurodegenerative diseases. Here we raise the question whether peripheral immune mechanisms can generate immunity to such deficits in neuronal repair. We demonstrate that in contrast to primarily innate immunity cytokines, such as interleukin-6 and tumor necrosis factor-alpha, the adaptive immunity cytokine IFN-gamma enhances neurogenesis in the dentate gyrus of adult mice and improves the spatial learning and memory performance of the animals. In older mice, the effect of IFN-gamma is more pronounced in both wild-type mice and mice with Alzheimer's-like disease and is associated with neuroprotection. In addition, IFN-gamma reverses the increase in oligodendrogenesis observed in a mouse model of Alzheimer's disease. We demonstrate that limited amounts of IFN-gamma in the brain shape the neuropoietic milieu to enhance neurogenesis, possibly representing the normal function of the immune system in controlling brain inflammation and repair.