In this video collection, authors of findings published in The Journal of Clinical Investigation present personally guided tours of their results. The journal accepts video submissions from authors of recently accepted manuscripts. Instructions can be found on the Author's Take Guidelines page.
Results from early-phase clinical trials have indicated that recombinant adeno-associated viruses (rAAV) could potentially be used for gene therapy. In each trial, however, patients have developed T cell-mediated immune responses that may interfere with therapeutic gene expression. In this episode, Terence Flotte and Christian Mueller discuss their recent study investigating T cell responses to intramuscular injection of a rAAV encoding M-type a1-antitrypsin (AAT) in patients with AAT-deficiency. Their results demonstrate that AAT expression persists for up to 12 months and suggest that immunomodulation of T cell populations may not be necessary for long-term, rAAV-mediated transgene expression.
In order to mount an effective immune response, T cells must be primed with the appropriate antigens to help them recognize malignant or pathogen-infected cells. Tim Greten and colleagues examined how necrotic cell death influences T cell cross-priming. Here they report on a molecular mechanism that blocks antigen cross-presentation by necrotic cells. Moreover, they found that this mechanism could be circumvented to promote immunogenicity of tumor cells.
H5N1 avian influenza is a highly pathogenic virus that has been responsible for several outbreaks of bird flu in humans over the past decade. In previous outbreaks, the virus spread through direct contact between humans and infected birds, but was not able to spread from human to human. Recent studies in ferrets have demonstrated that mutations in the viral HA gene allow the virus to be transmitted via respiratory droplets indicate that such mutations may also make the virus transmissible between humans. In this episode, James Crowe of Vanderbilt University describes his group’s recent investigation of the ability to human H5N1 vaccines to neutralize respiratory droplet transmissible forms of the virus. Using peripheral blood mononuclear cells from vaccinated humans, Crowe and colleagues identified antibodies that recognized both wild type and respiratory droplet transmissible forms of viral HA. Structural studies were used to further characterize the motifs required for antibody recognition. These findings indicate that the polyclonal sera currently used for vaccination can neutralize respiratory droplet transmissible forms of the virus.
Mechanosensory hair cells in the inner ear transduce mechanical stimuli into neural signals to mediate hearing and balance. Hair cell death is caused by a variety of stresses, including exposure to ototoxic drugs, which causes hearing loss for an estimated 500,000 Americans each year. Heat shock proteins (HSPs) are induced in response to cellular stress and induction of HSP70 was previously shown to protect against the ototoxic effects of aminoglycoside antibiotics. To determine the molecular mechanisms that underlie HSP70's protective effects, Lindsey May and colleagues utilized cultured utricles from adult mouse ears to examine stress responses in hair cells. They found that HSP70 was expressed by glia-like supporting cells that surround hair cells in response to heat shock stress. Moreover, expression of HSP70 in supporting cells or application of exogenous HSP70 inhibited aminoglycoside antibiotic-induced hair cell death. The data indicate that supporting cells protect sensory hair cells by secreting HSP70.
Brown adipose tissue (BAT), which mediates non-shivering thermogenesis, contributes to whole body energy expenditure and weight regulation in rodents. Given the tissue's high energy consumption, understanding the mechanisms that drive BAT recruitment and activation could be useful in the development of novel anti-obesity therapies. In this episode of Author's Take, Takeshi Yoneshiro and Masayuki Saito discuss their recent study in which subjects exposed subjects to a daily cold stimulus for 6 weeks had increased BAT activation and reduced overall fat mass. Yoneshiro and colleagues also observed that treatment with capsinoids, the spicy compounds found in chili peppers, resulted in BAT accumulation and increased energy expenditure in individuals who previously had low or undetectable BAT. These results suggest that methods to increase BAT levels could be used to fight obesity.