Metallothionein: A Novel Therapeutic Target for Treatment of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a group of disorders characterized by chronic inflammation within the gastrointestinal tract. It is a multifactorial disease associated with immune-cell mediated oxidative damage to the intestinal mucosa. There is no cure for IBD, but anti-cytokine therapy can limit target inflammation and disease progression. Unfortunately, many patients are nonresponsive or develop resistance to anti-cytokine therapy over time creating a need for new therapeutic agents. Metallothionein (MT) is a small, highly conserved stress response protein that has been shown to modulate the immune response as a pro-inflammatory agent, regulates divalent heavy metal homeostasis, and acts as a reactive metabolite scavenger. Our research, as well as other groups studying MT, has described MT induction and release during IBD inflammatory stress response. The release of MT results in activation of inflammatory responses leading to progressive inflammation and subsequent expansion of MT synthesis. A monoclonal antibody specific for MT has been used in murine models of IBD and should only target the extracellular pool of MT, thus representing a novel therapeutic approach to this disease.

Detection and Manipulation of the Stress Response Protein Metallothionein.

Metallothioneins (MTs) are small molecular weight stress response proteins that play a central role as reservoir of essential divalent heavy metal cations such as zinc and copper, and also can diminish the effects of toxic heavy metals such as mercury and cadmium. Historically, MT has been considered to be an intracellular protein with roles to play in the management of heavy metals, as a regulator of cellular redox potential, and as a buffer of free radicals. Our recent studies have highlighted immunomodulatory role of MT in inflammatory diseases and also in the progression of metastatic cell movement. Hence, manipulation and detection of MT is essential for its possible use as a diagnostic and in therapeutic interventions of chronic inflammation. This review describes procedures used to detect MT using techniques such as western immunoblot, competition ELISA, flow cytometry and immunohistochemistry. Additionally, it also describes the use of a colorimetric cell proliferation assay (CellTiter 96 AQueous One Solution/MTS) to study the proliferative effect of MT. © 2017 by John Wiley & Sons, Inc.

B cell responses in older adults with latent tuberculosis: Considerations for vaccine development.

Reactivation of latent tuberculosis (LTBI) is more common among the aging population and may contribute to increased transmission in long-term health care facilities. Difficulties in detecting LTBI due to potential blunting of the tuberculin skin test (TST), and the lowered ability of the elderly to tolerate the course of antibiotics, underscore the need for an effective vaccine. Immuno-senescence reduces the capacity of vaccines to induce sufficient levels of protective immunity against many pathogens, further increasing the susceptibility of the elderly to infectious diseases. We sought to evaluate the response of B cells to Mycobacterium tuberculosis (Mtb) in residents of long-term care facilities to determine the feasibility of using a vaccine to control infection and transmission from reactivated LTBI. Our results demonstrate that although B cell responses were higher in subjects with LTBI, Mtb antigens could stimulate B cell activation and differentiation in vitro in TST negative subjects. B cells from elderly subjects expressed high basal levels of Toll-like receptor (TLR)2 and TLR4 and responded strongly to Mtb ligands with some activation pathways dependent on TLR2. B cells derived from blood, tonsil and spleen from younger subjects responded similarly and to the same magnitude. These results suggest that B cell responses are robust in the elderly and modifications to a TB vaccine, such as TLR2 ligand-based adjuvants, may help increase immune responses to a protective level.