This spring, hope for asthmatics

Associate Professor
Wendy Havran

“The skin, the lungs, the intestines – these are basically barriers to the outside world, where the body has immediate contact with the air you breathe, the things you touch, the food you eat, and the liquids you drink,” explains Associate Professor Wendy Havran. “They are where the body’s immune system first encounters the outside world.”

This makes the epithelial tissue, the thin layer of cells that lines these organs and makes up the outermost layer of skin, the critical point of contact. When something goes wrong at this level – when the skin is wounded or when the lungs are inflamed during an asthma attack – the epithelial tissue needs to be repaired quickly.

Havran’s studies have focused on gamma-delta (γδ) T cells, which scientists have long known reside in epithelial tissue, but whose function had been a mystery. In a study published in 2002 with Research Associate Julie Jameson, Havran showed that when skin is cut or damaged, keratinocytes, which are the major type of epithelial cell in the epidermis, are able to faster re-epithelialize tissue that has been wounded if they get help from the γδ T cells.

“We think the γδ T cells are monitoring for damage or disease. This could be anything – sunburn, a wound, polluted air, something bad you ate,” Havran explains. “Once they detect there’s a problem, they can be first responders themselves, and can also send signals to the rest of they body, bringing in other cells with their own unique functions to participate in the healing process.”

Havran and Jameson postulate that the keratinocytes, sensing disease or damage, release an antigen that is recognized by the γδ T cells, which then become activated. Once activated, the γδ T cells undergo a morphological change and become little factories. These begin mass-producing a growth factor that binds to keratinocytes and other epithelial cells, helping them proliferate and leading to the closure of the wound. The γδ T cells also proliferate, multiplying to increase the response to the wound.

Tissue can repair without the help of γδ T cells, but the process is slower. “When γδ T cells are missing, you see a delay in wound repair,” says Havran.

Havran’s recent work has focused on showing that her findings in animal models are true in humans as well. In a paper recently published in the Journal of Experimental Medicine, her team has looked at wound healing in patients. Chronic wounds are an increasing clinical problem, and are representative of a number of other types of epithelial tissue damage, including asthma, where the epithelial tissue becomes inflamed.

Havran worked with patients with major wounds like burns, and found that when healing went well, γδ T cells were indeed activated, and in chronic wounds – wounds present for more than two months – the γδ T cells were not functional.

Knowing that resident γδ T cells are not properly responding to the wound indicates that they may make a good drug target. One method could be using an agent to activate them. Another might be bringing in γδ T cells that are functioning correctly from another site in the body.

Next up, Havran is turning her attention to the process by which the keratinocytes signal the presence of damage at the epithelial tissue to γδ T cells. “We think that when there is damage or disease, certain surface molecules are expressed that aren’t normally there, and that’s a signal to the γδ T cells. No one knew what these signals were, and we think we’ve now identified two new markers that are critical for those interactions.”

The beauty of targeting γδ T cells for treatment is that the therapies could have wide application, since a variety of diseases – from skin wounds to psoriasis to asthma to ulcerative colitis – occur at the level of epithelial tissue.

Scripps Research’s focus on the basic workings of the human body, rather than on narrowly focused drug targets, enables findings with broad implications, like Havran’s. During this difficult economic time, your support for this critical angle of scientific study is more important than ever.