Tag Archive for: immunoglobulin E

Schistosoma haematobium egg

For hemorrhagic cystitis, harnessing the power of a parasite

Schistosoma haematobium egg

“Urogenital Schistosoma infestation, which is caused by S. haematobium, also causes hemorrhagic cystitis, likely by triggering inflammation when the parasite’s eggs are deposited in the bladder wall or as eggs pass from the bladder into the urinary stream. S. haematobium eggs secrete proteins, including IPSE, that ensure human hosts are not so sickened that they succumb to hemorrhagic cystitis,” says Michael H. Hsieh, M.D., Ph.D.

Every year, hundreds of thousands of U.S. patients – and even more throughout the world – are prescribed cyclophosphamide or ifosfamide. These two chemotherapy drugs can be life-saving for a wide range of pediatric cancers, including leukemias and cancers of the eyes and nerves. However, these therapies come with a serious side effect: Both cause hemorrhagic cystitis in up to 40 percent of patients. This debilitating condition is characterized by severe inflammation in the bladder that can cause tremendous pain, life-threatening bleeding, and frequent and urgent urination.

Infection with a parasitic worm called Schistosoma haematobium also causes hemorrhagic cystitis, but this organism has a fail-safe: To keep its host alive, the parasite secretes a protein that suppresses inflammation and the associated pain and bleeding.

In a new study, a Children’s-led research team harnessed this protein to serve as a new therapy for chemotherapy-induced hemorrhagic cystitis.

“Urogenital Schistosoma infestation, which is caused by S. haematobium, also causes hemorrhagic cystitis, likely by triggering inflammation when the parasite’s eggs are deposited in the bladder wall or as eggs pass from the bladder into the urinary stream. S. haematobium eggs secrete proteins, including IPSE, that ensure human hosts are not so sickened that they succumb to hemorrhagic cystitis,” says Michael H. Hsieh, M.D., Ph.D., senior author of the study published April 3, 2018, by The FASEB Journal. “This work in an experimental model is the first published report of exploiting an uropathogen-derived host modulatory molecule in a clinically relevant model of bladder disease, and it points to the potential utility of this as an alternate treatment approach.”

S. mansoni IPSE binds to Immunoglobulin E (IgE), an antibody produced by the immune system that is expressed on the surface of basophils, a type of immune cell; and mast cells, another immune cell that mediates inflammation; and sequesters chemokines, signaling proteins that alert white cells to infection sites. The team produced an ortholog of the uropathogen-derived protein. A single IV dose proved superior to multiple doses of 2-Mercaptoethane sulfonate sodium (MESNA), the current standard of care, in suppressing chemotherapy-induced bladder hemorrhaging in an experimental model. It was equally potent as MESNA in dampening chemotherapy-induced pain, the research team finds.

“The current array of medicines we use to treat hemorrhagic cystitis all have shortcomings, so there is a definite need for novel therapeutic options,” says Dr. Hsieh, a Children’s National Health System urologist. “And other ongoing research projects have the potential to further expand patients’ treatment options by leveraging other urogenital parasite-derived, immune-modulating molecules to treat inflammatory bowel diseases and autoimmune disorders.”

Future research will aim to describe the precise molecular mechanisms of action, as well as to generate other orthologs that boost efficacy while reducing side effects.

In addition to Dr. Hsieh, Children’s study co-authors include Lead Author, Evaristus C. Mbanefo; Loc Le and Luke F. Pennington; Justin I. Odegaard and Theodore S. Jardetzky, Stanford University; Abdulaziz Alouffi, King Abdulaziz City for Science and Technology; and Franco H. Falcone, University of Nottingham.

Financial support for this research was provided by National Institutes of Health under award number RO1-DK113504.

Adora Lin

Funding will help uncover immune system differences that trigger food allergies

Adora Lin

“When it comes to food allergies, we really don’t know how they develop. We don’t know how to best differentiate between a child who can safely eat a potential allergen, like peanuts, compared with a child who cannot safely eat peanuts.” says Adora A. Lin, M.D., Ph.D.

Adora A. Lin, M.D., Ph.D., an attending physician in Children’s department of Allergy and Immunology, was awarded $240,000 to improve understanding of how children’s immune systems tolerate or react to certain food allergens – sometimes triggering a cascade of side effects that can be fatal.

The three-year American Academy of Allergy, Asthma & Immunology (AAAAI) Foundation award will underwrite Dr. Lin’s ongoing research into the regulation of the antibody Immunoglobulin E (IgE), which plays a pivotal role in these allergic responses.

“Our immune system maintains a delicate balance, working just enough to ward off potential invaders and pathogens, but not so much that it triggers problems of its own making,” Dr. Lin says. “When it comes to food allergies, we really don’t know how they develop. We don’t know how to best differentiate between a child who can safely eat a potential allergen, like peanuts, compared with a child who cannot safely eat peanuts.”

Food allergies have become a growing problem and affect about 1 in 13 U.S. children, or about two per classroom. Food items such as eggs, milk, peanuts, tree nuts, soy and wheat trigger allergic reactions that can include itching, swelling, hives and difficulty breathing. As children’s immune systems react to exposure to such allergens, their B-cells produce IgE antibodies.

Apart from avoiding these foods and carrying rescue medications, which must be used immediately after accidental exposure, there is no way to treat food allergies effectively. That makes it essential to better understand how the immune system works in order to innovate new and better food allergy treatments and diagnostics.

Dr. Lin’s work involves isolating immune cells from blood samples, culturing them and stimulating an immune response to known food allergy triggers. B-cells make IgE, but additional clarity is needed about what turns on the “make IgE” signal as well as which signals indicate it’s time to stop making IgE. Ultimately, the aim is to identify biomarkers that are akin to the “check engine” light that illuminates to warn of a potential problem long before a car stalls in traffic.

“I’m very excited about this funding,” Dr. Lin adds. “Our field has done an exceptional job with clinical work to help children with food allergies. This award recognizes the importance of the mechanistic side of the equation. I’m excited to help make that contribution to the research.”

As it stands now, blood tests are sensitive to food-related IgE, but are not specific. Only 30 to 55 percent of children who have IgE to common food allergens have an allergic reaction after eating the food, which means that 45 to 70 percent are merely sensitized and could tolerate eating the food. Current tests cannot distinguish between sensitized and allergic children.

“Our hope is to identify biomarkers that would serve as the ‘check engine’ light that tell us in advance which child’s immune system will react strongly to that food. Right now, there is no way to tell. This project will help uncover those differences,” she says.

Dr. Lin was one of three recipients of the AAAAI Foundation’s faculty development award, which was presented during a March 3, 2018, award ceremony held during the organization’s business meeting.