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Cooper A.M.,Trudeau Institute Inc.
Cold Spring Harbor Perspectives in Medicine | Year: 2015

The mouse provides a tool with which to probe the complex interaction between the mam-malian immune system and the slow-growing, inflammatory, and persistent bacterium, Mycobacterium tuberculosis (Mtb). Simple mouse models using genetic deletion or antibody inhibition have identified causal connections between specific components of the immune response and survival upon challenge with Mtb, and these studies have corresponded with observations made in humans. To improve on current intervention strategies, it is essential that the complex interactions between the components of the immune response that mediate and regulate the protective response to Mtb infection be dissected; furthermore, the pathways by which specific molecules and cells act must be delineated. The mouse model provides a tool with which to achieve this goal; however, experimental design and data interpretation must be made in the context of data sets generated from the entire tuberculosis field. © 2015 Cold Spring Harbor Laboratory Press; all rights reserved. Source

Teng M.W.L.,QIMR Berghofer Medical Research Institute | Teng M.W.L.,University of Queensland | Bowman E.P.,Merck And Co. | McElwee J.J.,Merck And Co. | And 9 more authors.
Nature Medicine | Year: 2015

The cytokine interleukin-12 (IL-12) was thought to have a central role in T cell-mediated responses in inflammation for more than a decade after it was first identified. Discovery of the cytokine IL-23, which shares a common p40 subunit with IL-12, prompted efforts to clarify the relative contribution of these two cytokines in immune regulation. Ustekinumab, a therapeutic agent targeting both cytokines, was recently approved to treat psoriasis and psoriatic arthritis, and related agents are in clinical testing for a variety of inflammatory disorders. Here we discuss the therapeutic rationale for targeting these cytokines, the unintended consequences for host defense and tumor surveillance and potential ways in which these therapies can be applied to treat additional immune disorders. © 2015, Nature America, Inc. All rights reserved. Source

Torrado E.,Trudeau Institute Inc. | Cooper A.M.,Trudeau Institute Inc.
Cytokine and Growth Factor Reviews | Year: 2010

Tuberculosis is primarily a disease of the lung. Constant expression of cellular immunity in this organ is required to control Mycobacterium tuberculosis growth, but this can also result in chronic inflammation and pathologic consequences. During primary tuberculosis both IFN-γ and IL-17 are induced: both are potent inflammatory cytokines capable of inducing expression of chemokines that promote cell recruitment and granuloma organization throughout infection. During the chronic phase, a balance between Th1 and Th17 responses needs to be achieved to control bacterial growth and limit immunopathology, as a shift of the response towards excessive IL-17 production may sustain extensive neutrophil recruitment and tissue damage. Thus, regulation of Th1 and Th17 responses during tuberculosis is essential to promote anti-mycobacterial immunity and prevent extensive immunopathological consequences. © 2010 Elsevier Ltd. Source

Orme I.M.,Colorado State University | Robinson R.T.,Medical College of Wisconsin | Cooper A.M.,Trudeau Institute Inc.
Nature Immunology | Year: 2015

Tuberculosis is a disease of the lung, and efficient transmission is dependent on the generation of a lesion in the lung, which results in a bacterium-laden cough. Mycobacterium tuberculosis (Mtb) is able to manipulate both the innate and acquired immune response of the host. This manipulation results in an effective CD4+ T cell response that limits disease throughout the body but can also promote the development of progressively destructive lesions in the lung. In this way Mtb infection can result in an ambulatory individual who has a lesion in the lung capable of transmitting Mtb. The inflammatory environment within the lung lesion is manipulated by Mtb throughout infection and can limit the expression of acquired immunity by a variety of pathways. © 2015 Nature America, Inc. Source

Torrado E.,Trudeau Institute Inc. | Cooper A.M.,Trudeau Institute Inc.
Advances in Experimental Medicine and Biology | Year: 2013

The outcome of natural infections with pathogenic mycobacteria can range from early asymptomatic clearance through latent infection to clinical disease. Different host and pathogen-specific factors have been implicated in determining the outcome of these infections; however, it is clear that the interaction of mycobacteria with the innate and acquired components of the immune system plays a central role. Specifically, the recognition of mycobacterial components by innate immune cells through different pathogen recognition receptors (PPRs) induces a cytokine response that can promote early control of the infection. In fact, in the majority of individuals that come into contact with mycobacteria, this response is enough to control the infection. Among PRRs, Toll-like receptors (TLRs), Nucleotide Oligomerization Domain (NOD)-like receptors, and C-type lectins have all been implicated in recognition of mycobacteria and in the initiation of the cytokine response. Defining the mechanisms by which distinct mycobacterial components and their receptors stimulate the immune response is an area of intense research. © Springer Science+Business Media New York 2013. Source

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