Azizul Haque

Downregulation of IL-17 and IL-6 in the central nervous system by glatiramer acetate in experimental autoimmune encephalomyelitis

T helper 17 (Th17) cells are pivotal in the immune pathogenesis of EAE. Glatiramer acetate (GA) can enhance Treg FOXp3 expression. We demonstrate that GA downregulates the expression of both IL-17 and IL-6 in two different EAE models. Increased mRNA expression in CNS for ROR gamma t, IL-17, IL-12/IL-23, IL-6, TNF-alpha, STAT4 and Th1 cytokines were significantly reduced by GA with a concomitant rise in SMAD3. The increased expression of TNF-alpha, IL-6, and IL-17 in CNS of CD25+ depleted animals was suppressed by GA treatment. This study demonstrates that both Th1 polarization and Th17 expression are modulated by GA.

Augmentation of regulatory B cell activity in experimental allergic encephalomyelitis by glatiramer acetate

We recently showed that B cells reduce CNS inflammation in mice with experimental allergic encephalomyelitis (EAE). Here, we demonstrate that adoptively transferred CD5/CD19+ B cells protect against EAE severity. Furthermore, we show that glatiramer acetate (GA), a therapeutic for relapsing multiple sclerosis treatment, amplifies this effect. Transfer of GA-conditioned B cells leads to increased production of immunoregulatory cytokines and reduced CNS inflammation, as well as decreased expression of the chemokine receptor, CXCR5, and elevated BDNF expression in the CNS. Thus B cells can protect against EAE, and GA augments this effect in maintaining immune homeostasis and controlling EAE disease progression.

Increased expression of B cell-associated regulatory cytokines by glatiramer acetate in mice with experimental autoimmune encephalomyelitis

B cells are of increasing importance as a target for multiple sclerosis treatment. Here we show that GA treatment of mice with experimental autoimmune encephalomyelitis (EAE) biases cytokine production by B cells towards cytokines associated with regulation in MS including interleukin (IL)-4, -10 and -13 and reduces pro-inflammatory IL-6, IL-12, and TNF alpha levels. GA also down-regulates expression of B cell-activating factor (BAFF) of the TNF family and a proliferation-inducing ligand (APRIL), as well as the BAFF receptor in mice with EAE. Thus, GA impacts both B cell survival and B cell cytokine production during CNS inflammatory disease in an EAE model.

TNF-α production by U937 promonocytes is enhanced by factors released from HIV-infected T4 lymphocytes : TNF-α is one of the mediators causing lysis of HIV-infected T4 cells

In the present study, we have shown that the addition of culture supernatants from HIV-infected SupT1 cells (T4) but not from noninfected cells markedly increased the production of TNF-alpha by U937 promonocytic cells after stimulation with phorbol 12-myristate 13-acetate (PMA). Pretreatment of supernatants with the antibodies to granulocyte/macrophage colony-stimulating factor (GM-CSF) or TNF-alpha, but not interferon-gamma, significantly diminished this enhancing effect. These results suggest that HIV may play an indirect role by producing cytokines from infected T4 cells that can lead to an increased production of TNF-alpha by monocytic cells. Further, TNF-alpha produced by U937 cells following stimulation with PMA plus lipopolysaccharide or with phytohemagglutinin induced lysis of HIV-infected T cells. TNF-alpha-induced cytotoxicity was markedly higher toward HIV-infected than toward noninfected T4 cells. Addition of antibody to TNF-alpha during the cytotoxic phase of response resulted in a reduction of about 50% in the percentage of cytotoxicity, indicating TNF-alpha as one of the lytic mediators.

Confronting potential influenza A (H5N1) pandemic with better vaccines.

Better understanding of host-virus interaction is essential to produce effective vaccines against influenza (H5N1) viruses.

Glatiramer acetate biases dendritic cells towards an anti-inflammatory phenotype by modulating OPN, IL-17, and RORγt responses and by increasing IL-10 production in experimental allergic encephalomyelitis

Paralleling our previous mechanistic studies of glatiramer acetate (GA; Copaxone) activity, we show that GA curbs the expression of Toll-like receptor (TLR) 9 and the universal adapter protein Myd88 in mice with EAE, the animal model for multiple sclerosis. Concurrent with enhanced dendritic cell (DC) production of IL-10, GA interferes with OPN, IL-17, and ROR gamma expression in DCs of mice with EAE, and suppresses brain expression of the EAE-induced chemokines, MIP1α and β, IP-10 and RANTES. Thus GA not only biases dendritic cells towards an anti-inflammatory phenotype, but also suppresses the expression of factors that affect the blood-brain barrier penetration during neuroinflammation.

Addressing Therapeutic Options for Ebola Virus Infection in Current and Future Outbreaks

ABSTRACT Ebola virus can cause severe hemorrhagic disease with high fatality rates. Currently, no specific therapeutic agent or vaccine has been approved for treatment and prevention of Ebola virus infection of humans. Although the number of Ebola cases has fallen in the last few weeks, multiple outbreaks of Ebola virus infection and the likelihood of future exposure highlight the need for development and rapid evaluation of pre- and postexposure treatments. Here, we briefly review the existing and future options for anti-Ebola therapy, based on the data coming from rare clinical reports, studies on animals, and results from in vitro models. We also project the mechanistic hypotheses of several potential drugs against Ebola virus, including small-molecule-based drugs, which are under development and being tested in animal models or in vitro using various cell types. Our paper discusses strategies toward identifying and testing anti-Ebola virus properties of known and medically approved drugs, especially those that can limit the pathological inflammatory response in Ebola patients and thereby provide protection from mortality. We underline the importance of developing combinational therapy for better treatment outcomes for Ebola patients.

Apoptosis in Toxoplasma gondii activated T cells: the role of IFNγ in enhanced alteration of bcl-2 expression and mitochondrial membrane potential.

In the present study we addressed the question whether Toxoplasma gondii could promote apoptosis in T lymphocytes in the acute stage of infection. Using in vivo activated T cells and then culturing them for a short time, we observed activation-induced cell death in T. gondii infected mice. A higher level of activation-induced cell death (AICD) was seen in susceptible C57BL/6 mice than in resistant CBA/J mice following infection with the same P strain of parasite. Apoptosis in T cells of susceptible mice was associated with altered induction of Bcl-2/Bax, loss of Mitochondrial Transmembrane Potential. Both CD4+ and CD8+ T cells were found to be susceptible to apoptosis; CD4+ T cells were sensitive to Fas-mediated death whereas CD8+ T cells were insensitive to this signal. Caspase inhibitors had less effect on DNA fragmentation in CD4+ compared to CD8+ T cells. Exposure of CD4+ T cells to anti-IFNgamma mAb resulted in an increase in the number of T cells that were positive for anti-apoptotic molecule Bcl-2 and DiOC6, a cationic dye that accumulates in intact mitochondria. These changes were less noticeable in CD8+ T cells following treatment with anti-IFNgamma mAb. These findings provide further insight into the mechanisms of T cell apoptosis in T. gondii infection.

Alteration of CD39 + Foxp3 + CD4 T cell and cytokine levels in EAE/MS following anti-CD52 treatment

While examining the therapeutic value of anti-CD52 antibody against EAE/MS, we identified a unique subset of CD39+ Tregs in repopulating GALT tissues, a major lymphoid reservoir, which was accompanied by amelioration of disease. Furthermore, anti-CD52 treatment leads to increased expression of BDNF, IL-10, and SMAD3 in the brains of EAE mice. This condition is associated with suppression of IL-17, a critical inflammatory factor in EAE/MS progression. Additionally, we found elevated levels of CD4+CD39+ Tregs in PBMCs of RRMS patients treated with humanized anti-CD52 mAb. Thus, anti-CD52 can affect multiple immune mediated pathways involved in the pathogenesis of EAE/MS.

Tuberculosis and survival in past populations: A paleo-epidemiological appraisal

Historical assessments of the last two centuries consistently placed tuberculosis as the leading cause of mortality. However, for earlier periods, we can only calculate the frequencies of archaeological bone lesions, which tell us little about the real impact of the disease on mortality. These lesions are usually observed in individuals who have developed immune resistance, which is visible as healed osteo-articular lesions. This study aimed to test the differential impacts of tuberculosis, cribra orbitalia and cribra femoris on adult survival and sex-based survival. We analyzed 28 French adult samples from the Antiquity and the Early Middle Ages. The age-at-death of 1480 individuals was estimated using cementochronology. Survival curves and median age-at-death were calculated to test new hypotheses that challenge the parasitic and deficiency theories of bone stress markers. Comparisons between carriers and non-carriers provided new information concerning the plausible causes of bone stress markers related to infections and TB. The most likely hypothesis is skeletal demineralization and osteoclastic resorption, which are usually observed close to tubercular granuloma or distant from active lesions. The bone marrow niche of Mycobacterium tuberculosis within CD271(+) BM-MSCs stem cells is the proposed explanation for the localized cortical resorption that is observed in bone stress markers.