A study of the anti-inflammatory, anti-microbial and immunomodulatory properties of thalidomide in leprosy

During the course of their disease, leprosy patients may experience two types of inflammatory reactions- erythema nodosum leprosum (ENL) or reversal reaction (RR). Thalidomide is effective treatment for ENL, but not for RR. Using concentrations of thalidomide similar to that achieved in the treatment of ENL, we investigated thalidomide’s effect on reactions, viability of M. leprae, and integrity of plasma membranes. Cells from patients with and without RR were stimulated with M. leprae (AFB), a cytosol fraction of M. leprae (MLSA) or DHAR (DHAR) antigen, and the effect of thalidomide on lymphocyte proliferation, expression of TNF-a mRNA and synthesis of TNF-a was investigated. Thalidomide enhanced MLSA and DHAR induced proliferation of cells from RR patients. The expression of TNF-a mRNA was variable, but thalidomide generally suppressed the synthesis of TNF-a. In a sub-set of RR patients, thalidomide enhanced AFB-induced cell proliferation, and the expression of TNF-a mRNA and TNF-a. ENL has been described as a consequence of M. leprae antigens released from macrophages binding antibody and inducing inflammation. Thalidomide did not affect the viability of M. leprae residing in IFN-g/LPS activated mouse macrophages, nor did it suppress TNF-a or nitrite. Drugs may be anti-inflammatory by stabilizing cell membranes. Thalidomide failed to protect the plasma membrane of neutrophils and THP-1 cells from osmotic lysis. Thalidomide stabilized the membrane of erythrocytes from plasma free blood, but not from whole blood. In vivo, the stability of erythrocytes membranes from subjects after ingestion of thalidomide was not affected. In conclusion, thalidomide did not alter the viability of M. leprae, nor the integrity of the plasma membrane of inflammatory cells. It could enhance or suppress M. leprae antigen-induced synthesis of TNF-a. Interestingly, in 15 of 75 RR patients cells stimulated with AFB, thalidomide acted as a co-stimulant enhancing cell proliferation, synthesis of mRNA for TNF-a and TNF-a. Thalidomide’s enhancing effect on TNF-a in RR appears to be dependent on the stimulant and IL-2 signaling. As the inflammation in RR is associated with the emergence of antigen-reactive T-cells and TNF-a, we speculate that the use of thalidomide in the treatment of RR may exacerbate the reactio

SEMA4D compromises blood–brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease

AbstractMultiple sclerosis (MS) is a chronic neuroinflammatory disease characterized by immune cell infiltration of CNS, blood–brain barrier (BBB) breakdown, localized myelin destruction, and progressive neuronal degeneration. There exists a significant need to identify novel therapeutic targets and strategies that effectively and safely disrupt and even reverse disease pathophysiology. Signaling cascades initiated by semaphorin 4D (SEMA4D) induce glial activation, neuronal process collapse, inhibit migration and differentiation of oligodendrocyte precursor cells (OPCs), and disrupt endothelial tight junctions forming the BBB. To target SEMA4D, we generated a monoclonal antibody that recognizes mouse, rat, monkey and human SEMA4D with high affinity and blocks interaction between SEMA4D and its cognate receptors. In vitro, anti-SEMA4D reverses the inhibitory effects of recombinant SEMA4D on OPC survival and differentiation. In vivo, anti-SEMA4D significantly attenuates experimental autoimmune encephalomyelitis in multiple rodent models by preserving BBB integrity and axonal myelination and can be shown to promote migration of OPC to the site of lesions and improve myelin status following chemically-induced demyelination. Our study underscores SEMA4D as a key factor in CNS disease and supports the further development of antibody-based inhibition of SEMA4D as a novel therapeutic strategy for MS and other neurologic diseases with evidence of demyelination and/or compromise to the neurovascular unit

A geospatial risk assessment model for leprosy in Ethiopia based on environmental thermal-hydrological regime analysis

Geospatial methods were used to study the associations of the environmental thermal-hydrological regime with leprosy prevalence in the Oromia and Amhara regions of Ethiopia. Prediction models were developed that indicated leprosy prevalence was related to: (i) long-term normal climate grid data on temperature and moisture balance (rain/potential evapo-transpiration); (ii) satellite surveillance data on the Normalized Difference Vegetation Index (NDVI) and daytime earth surface temperature (Tmax) from the Advanced Very High Resolution Radiometer (AVHRR); and (iii) a Genetic Algorithm Rule-Set Prediction (GARP) model based on NDVI and Tmax data in relation to leprosy prevalence data. Our results suggest that vertical transmission is not the only means of acquiring leprosy and support earlier reports that a major factor that governs transmission of leprosy is the viability of Mycobacterium leprae outside the human body which is related to the thermal-hydrologic regime of the environment

Astrocytic tight junctions control inflammatory CNS lesion pathogenesis

Lesions and neurologic disability in inflammatory CNS diseases such as multiple sclerosis (MS) result from the translocationof leukocytes and humoral factors from the vasculature, first across the endothelial blood-brain barrier (BBB) and thenacross the astrocytic glia limitans (GL). Factors secreted by reactive astrocytes open the BBB by disrupting endothelial tightjunctions (TJs), but the mechanisms that control access across the GL are unknown. Here, we report that in inflammatorylesions, a second barrier composed of reactive astrocyte TJs of claudin 1 (CLDN1), CLDN4, and junctional adhesion moleculeA (JAM-A) subunits is induced at the GL. In a human coculture model, CLDN4-deficient astrocytes were unable to controllymphocyte segregation. In models of CNS inflammation and MS, mice with astrocyte-specific Cldn4 deletion displayedexacerbated leukocyte and humoral infiltration, neuropathology, motor disability, and mortality. These findings identify asecond inducible barrier to CNS entry at the GL. This barrier may be therapeutically targetable in inflammatory CNS disease

Astrocytic TYMP and VEGFA drive blood-brain barrier opening in inflammatory central nervous system lesions

In inflammatory central nervous system conditions such as multiple sclerosis, breakdown of the blood-brain barrier is a key event in lesion pathogenesis, predisposing to oedema, excitotoxicity, and ingress of plasma proteins and inflammatory cells. Recently, we showed that reactive astrocytes drive blood-brain barrier opening, via production of vascular endothelial growth factor A (VEGFA). Here, we now identify thymidine phosphorylase (TYMP; previously known as endothelial cell growth factor 1, ECGF1) as a second key astrocyte-derived permeability factor, which interacts with VEGFA to induce blood-brain barrier disruption. The two are co-induced NFκB1-dependently in human astrocytes by the cytokine interleukin 1 beta (IL1B), and inactivation of Vegfa in vivo potentiates TYMP induction. In human central nervous system microvascular endothelial cells, VEGFA and the TYMP product 2-deoxy-d-ribose cooperatively repress tight junction proteins, driving permeability. Notably, this response represents part of a wider pattern of endothelial plasticity: 2-deoxy-d-ribose and VEGFA produce transcriptional programs encompassing angiogenic and permeability genes, and together regulate a third unique cohort. Functionally, each promotes proliferation and viability, and they cooperatively drive motility and angiogenesis. Importantly, introduction of either into mouse cortex promotes blood-brain barrier breakdown, and together they induce severe barrier disruption. In the multiple sclerosis model experimental autoimmune encephalitis, TYMP and VEGFA co-localize to reactive astrocytes, and correlate with blood-brain barrier permeability. Critically, blockade of either reduces neurologic deficit, blood-brain barrier disruption and pathology, and inhibiting both in combination enhances tissue preservation. Suggesting importance in human disease, TYMP and VEGFA both localize to reactive astrocytes in multiple sclerosis lesion samples. Collectively, these data identify TYMP as an astrocyte-derived permeability factor, and suggest TYMP and VEGFA together promote blood-brain barrier breakdown