Research sets foundation for new generation of vaccines for HIV, influenza

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Scientists have taken a major step toward the goal of altering viruses, bacteria and tumor cells so that they demand attention from immune cells designed to destroy them.

According to research published today in the journal Immunity, researchers at the University of Rochester Medical Center have determined for the first time a single biochemical feature of disease-causing molecules (pathogens) that, if changed, would force them to provoke an attack by the human immune system.

Recognizing molecules as "self," versus foreign invaders to be destroyed, is a central responsibility of the immune system. Tumors closely resemble self or "host" tissues and can confuse the system. Viruses and bacteria are immediately recognizable as foreign, but have learned to change shape so often that the system loses track of them. Pathogens use the same tricks to escape the immunity provided by vaccines.

In an effort to deny diseases the ability to hide, researchers have for years been asking a key question: Why do our bodies select certain, small pieces (epitopes) of each disease-causing molecule to trigger an immune response, while ignoring the rest? Those few, triggering protein fragments are termed "immunodominant." Unfortunately, the immune system sometimes makes poor choices about which epitopes to pay attention to, and which to ignore. Understanding of how immunodominance is conferred would enable vaccine designers to shift the immune system spotlight to parts of pathogens that they cannot change in efforts to escape detection. For example, a vaccine could be designed to target a protein fragment central to a virus's ability to reproduce, or to invade its prey.

"Our study identified for the first time the chemical mechanism that determines immunodominance, and proved that it can be fine-tuned," said Andrea Sant, Ph.D., a professor within the David H. Smith Center for Vaccine Biology and Immunology at the University of Rochester Medical Center, and the study's lead author. "If confirmed, the findings could launch a new wing of research seeking to re-engineer viruses, bacteria and tumor cells to make them hundreds of times more likely to be noticed and destroyed by our immune system."

As part of the immune response, T cells, one type of white blood cell, partner with dendritic cells to make careful decisions about which pieces of pathogens will trigger a full-scale immune attack. Dendritic cells roam the body, checking each particle they come across for a self or invader "label." Upon encountering an invader, a dendritic cell will "swallow it," cut it up, and carry the pieces to the nearest lymph node.

Once in the lymph node, major histocompatibility complex (Mhc) proteins inside the dendritic cell present immunodominant epitopes on the cell's surface for consideration by T cells gathered there. Once activated by high enough levels of target epitope for long enough periods of time, T cells become armed and capable of destroying the pathogen in question.

Sant's study provides the first proof that it is something about the invader epitope itself that drives and focuses T cell response, and not some action of enzymes inside the dendritic cell as once thought. The quality determining immunodominance is the strength and lifespan (kinetic stability) of the bond between the Mhc protein and a given epitope. Kinetic stability determines whether, in the face of competing reactions within the immune system, an epitope:Mhc complex can remain intact on the dendritic cell surface long enough to demand T cell attention. Sant's team found that immunodominant peptides were likely to stay bound to Mhc molecules for an average of 150 hours, where nondominant epitopes held on for less than 10 hours.

"What's exciting is that kinetic stability is determined by how tightly an epitope fits into the Mhc protein, and we can control that fit with standard techniques," Sant said. "By switching out single amino acid building blocks, we were able to drastically increase the potency of the T cell response to target epitopes. If confirmed, this discovery will bring immundominance and a major portion of the immune system under our control for the first time."

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