PUBLIC RELEASE DATE:

30-Jan-2014

Contact: Karen Kreeger karen.kreeger@uphs.upenn.edu 215-349-5658 University of Pennsylvania School of Medicine

PHILADELPHIA Substances called adjuvants that enhance the body's immune response are critical to getting the most out of vaccines. These boosters stimulate the regular production of antibodies -- caused by foreign substances in the body -- toxins, bacteria, foreign blood cells, and the cells of transplanted organs.

But, biologists think that vaccine adjuvants could be much better: The currently available licensed adjuvants are poor inducers of T helper cells and even worse at inciting killer T cells that clear viruses, as well as eradicate cancer cells.

The lab of David Weiner, PhD, professor of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, identifies new adjuvants that can produce the desired T-cell response. "Different molecular adjuvants, such as cytokines, are being studied as a way to increase the efficacy of vaccines," explains Weiner. "The development of DNA-based vaccines with cytokine adjuvants has emerged as particularly promising for inducing antiviral and anti-tumor, cell-mediated immune responses."

Daniel Villarreal, a graduate student in the Weiner lab, and colleagues report in Cancer Research this week that the protein IL-33 boosts the immune system of a human papilloma virus animal model of cancer. IL-33 is a cytokine, a small protein that signals immune cells such as T cells to travel to a site of infection or injury.

Although still experimental, DNA vaccines are a conceptual leap forward over standard vaccines, as they are not live and never expose the person being vaccinated to a true pathogen or infectious agent. They are transient and do their job by fooling the host's immune system into believing there is an infectious agent invading their cells so that the host responds by producing protective levels of T cells, in particular CD8 killer T cells. DNA vaccines have been studied in animal models of viral, bacterial, and parasitic disease, as well as animal models of tumors. Due to major advances in their immune potency DNA vaccines are being studied in human clinical trials for treating cancer and infectious diseases.

The team showed that IL-33 can further enhance the response of memory T cells, the long-lived cells that can patrol and protect the body from infections and cancers, when given with a DNA vaccine compared to a vaccine without IL-33. What's more, IL-33 and the DNA vaccine augmented immunological responses in both CD4 helper T cells and CD8 killer T cells, with a large proportion of CD8 killer T cells demonstrating a further improvement in the ability of DNA vaccines to drive the immune system to kill tumor cells in animals.

"Our results support the further study and possible development of IL-33 as adjuvants in vaccinations against pathogens, including in the context of antitumor immunotherapy," says Weiner. Additional cancer and infectious diseases studies in diverse animal models are in progress.

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Protein serves as a natural boost for immune system fight against tumors

The biochemist Professor Volker A. Erdmann at Freie Universitt Berlin succeeded for the first time in creating mirror-image enzymes -- so-called Spiegelzymes -- out of nucleic acids. The Spiegelzymes can be used in living cells for the targeted cutting of natural nucleic acids.

In an article published in PLOS ONE, Erdmann and his co-authors delineate how engineered Spiegelzymes have great potential for cutting up individual nucleic acids responsible for human diseases, and thus "deactivating" them. According to Erdmann Spiegelzymes, also called molecular scissors, have the advantage that they do not trigger side reactions of the immune system and they are extremely stable.

In the experiments Erdmann and his team were able to show that with specially constructed Spiegelzymes the production of a green glowing protein could be inhibited in the cells. The Spiegelzymes cut the messenger RNA, the molecule responsible for the production of the protein. Following similar procedures, it should be possible to prevent the synthesis of any one of the approximately 21,000 proteins anchored in the human genome, says Erdmann.

Volker A. Erdmann thinks it is plausible that in the future it will be possible to intervene in the processes of a cell to selectively cut RNA molecules that regulate the synthesis of proteins and other nucleic acids. Since RNA molecules are responsible for ensuring that a stem cell develops into a skin cell or muscle cell, or even a tumor cell, the targeted use of Spiegelzymes shows promise for completely new applications in basic research, biotechnology, and molecular medicine.

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The above story is based on materials provided by Freie Universitaet Berlin. Note: Materials may be edited for content and length.

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Mirror-image nucleic acids as molecular scissors in biotechnology and molecular medicine