Alemtuzumab mediates the CD39+ T-regulatory cell response via CD23+ macrophages.

Alemtuzumab (ALM) effectively prevents relapses of multiple sclerosis (MS). It causes lymphocyte depletion with subsequent enhancement of the T-regulatory cell population. Direct administration of ALM to T cells causes cytolysis. However, the T cells may be indirectly affected by monocyte-derived cells, which are resistant to ALM cytotoxicity. We aimed to examine whether ALM modulates monocytes and whether the crosstalk between monocytes and lymphocytes previously exposed to ALM would result in anti-inflammatory effects. The CD14+ monocytes of 10 healthy controls and 10 MS (treatment naive) patients were isolated from peripheral blood mononuclear cells (PBMCs), exposed to ALM and reintroduced to PBMCs depleted of CD14+ cells. The macrophage profile was assessed and T-cell markers were measured. ALM promoted M2 anti-inflammatory phenotype as noted by an increased percentage in the populations of CD23+ , CD83+ and CD163+ cells. The CD23+ cells were the most upregulated (7-fold, P = 0.0002), and the observed effect was higher in patients with MS than in healthy subjects. ALM-exposed macrophages increased the proportion of T-regulatory cells, without affecting the proportion of T-effector cells. Neutralizing the CD23+ monocytes with antibodies reversed the effect specifically on the CD4+ CD39+ T-regulatory cell subpopulation but not on the CD4+ CD25hi CD127lo FOXP3+ subpopulation. ALM induces the conversion of monocytes into anti-inflammatory macrophages, which in turn promotes T-regulatory cell enhancement, in a CD23-dependent manner. These findings suggest that the mechanism of action of ALM is relevant to aspects of MS pathogenesis.

Inhibition of effector function but not T cell activation and increase in FoxP3 expression in T cells differentiated in the presence of PP14.

BACKGROUND: T-helper polarization of naïve T cells is determined by a complex mechanism that involves many factors, eventually leading to activation of Th1, Th2, or Th17 responses or alternatively the generation of regulatory T cells. Placental Protein 14 (PP14) is a 28 kDa glycoprotein highly secreted in early pregnancy that is able to desensitize T cell receptor (TCR) signaling and modulate T cell activation. METHODOLOGY/PRINCIPAL FINDINGS: Prolonged antigen-specific stimulation of T cells in the presence of PP14 resulted in an impaired secretion of IFN-γ, IL-5 and IL-17 upon restimulation, although the cells proliferated and expressed activation markers. Furthermore, the generation of regulatory CD4(+)CD25(high)Foxp3(+) T cells was induced in the presence of PP14, in both antigen-specific as well as polyclonal stimulation. In accordance with previous reports, we found that the induction of FoxP3 expression by PP14 is accompanied by down regulation of the PI3K-mTOR signaling pathway. CONCLUSIONS/SIGNIFICANCE: These data suggest that PP14 arrests T cells in a unique activated state that is not accompanied with the acquisition of effector function, together with promoting the generation of regulatory T cells. Taken together, our results may elucidate the role of PP14 in supporting immune tolerance in pregnancy by reducing T cell effector functions along with augmenting Treg differentiation.

Nasal vaccination with troponin reduces troponin specific T-cell responses and improves heart function in myocardial ischemia-reperfusion injury.

Myocardial ischemia with subsequent reperfusion (MI/R) can lead to significant myocardial damage. Ischemia initiates inflammation at the blood-microvascular endothelial cell interface and contributes significantly to both acute injury and repair of the damaged tissue. We have found that MI/R injury in mice is associated with a cellular immune response to troponin. Myocardial cells exclusively synthesize troponin and release the troponin into the bloodstream following injury. Mucosally administered proteins induce T cells that secrete anti-inflammatory cytokines such as IL-10 and transforming growth factor beta at the anatomical site where the protein localizes. We found that nasal administration of the three subunits of troponin (C, I and T isoforms), given prior to or 1 h following MI/R, decreased infarct size by 40% measured 24 h later. At 1.5 months following MI/R, there was a 50% reduction in infarct size and improvement in cardiac function as measured by echocardiography. Protection was associated with a reduction of cellular immunity to troponin. Immunohistochemistry demonstrated increased IL-10 and reduced IFN-gamma in the area surrounding the ischemic infarct following nasal troponin. Adoptive transfer of CD4+ T cells to mice from nasally troponin-treated mice 1 h after the MI/R decreased infarct size by 72%, whereas CD4+ T cells from IL-10-/- mice or nasally BSA-treated mice had no effect. Our results demonstrate that IL-10-secreting CD4+ T cells induced by nasal troponin reduce injury following MI/R. Modulation of cardiac inflammation by nasal troponin provides a novel treatment to decrease myocardial damage and enhance recovery after myocardial ischemia.

A nasal proteosome adjuvant activates microglia and prevents amyloid deposition.

OBJECTIVE: We assessed whether peripheral activation of microglia by a nasal proteosome-based adjuvant (Protollin) that has been given safely to humans can prevent amyloid deposition in young mice and affect amyloid deposition and memory function in old mice with a large amyloid load. METHODS: Amyloid precursor protein (APP) transgenic (Tg) J20 mice received nasal treatment with Protollin weekly for 8 months beginning at age 5 months. Twenty-four-month-old J20 mice were treated weekly for 6 weeks. RESULTS: We found reduction in the level of fibrillar amyloid (93%), insoluble beta-amyloid (Abeta; 68%), and soluble Abeta (45%) fragments in 14-month-old mice treated with Protollin beginning at age 5 months. Twenty-four-month-old mice treated with nasal Protollin for 6 weeks had decreased soluble and insoluble Abeta (1-40) and (1-42) and improved memory function. Activated microglia (CD11b+ cells) colocalized with Abeta fibrils in the 24-month-old animals, and microglial activation correlated with the decrease in Abeta. No microglial activation was observed in 14-month-old mice, suggesting that once Abeta is cleared, there is downregulation of microglial activation. Both groups had reduction in astrocytosis. Protollin was observed in the nasal cavity and cervical lymph node but not in the brain. Activated CD11b+SRA+ (scavenger receptor A) cells were found in blood and cervical lymph node and increased interleukin-10 in cervical lymph node. No toxicity was associated with treatment. INTERPRETATION: Our results demonstrate a novel antibody-independent immunotherapy for both prevention and treatment of Alzheimer's disease that is mediated by peripheral activation of microglia with no apparent toxicity.

Neurological abnormalities associated with celiac disease.

BACKGROUND: Celiac disease (CD) is a gluten-sensitive enteropathy in genetically susceptible individuals. Anecdotal reports suggest that the nervous system might be affected in the disorder, but the severity and prevalence of such an involvement have not been systematically evaluated. MATERIALS AND METHODS: Analysis of files of CD patients diagnosed between 1980 and 1999 for neurological abnormalities. Diagnosis of CD was based on the modified criteria of the European Society for Pediatric Gastroenterology and Nutrition. RESULTS: Of 148 CD patients, 18 (12%) had 21 neurological disorders that could not be attributed to any other condition including muscle abnormality (3), epilepsy (3), psychiatric disease (4), peripheral neuropathy (3), cerebrovascular disease (1), myelopathy (1) and Down syndrome (2). Other disorders probably unrelated to CD were present in 8 patients. CONCLUSION: If this association is not coincidental, both the central and the peripheral nervous systems may be affected in CD by a spectrum of neurological disorders that are either the outcome of CD or share the same pathogenesis with the enteropathy.