02 Sep 2021
Discovery could lead to new approaches for treating antibiotic and anti-inflammatory sulfa-drug allergies
Peer review: PNAS
Funding: Australian Research Council, National Health and Medical Research Council of Australia, Allergy and Immunology Foundation of Australasia (AIFA), University of Melbourne Early Career Researcher Grant 2021 UoM, and NHMRC and ARC and NIH -National Institutes of Health, USA.
Researchers have discovered a mechanism that activates part of the body’s immune system through a class of molecules that structurally resemble sulfa-drugs, opening the door to advance research into dealing with allergic reactions commonly associated with sulfa-drugs.
Sulfa-drugs have been a mainstay of anti-inflammatory therapeutics and antibiotics for decades, used to treat and prevent serious conditions such as skin and soft-tissue infections and urinary tract infections.
Allergic reactions to these drugs, that range from a minor rash to severe anaphylaxis, represent a major clinical problem, with five per cent of the population and 30 per cent of immunocompromised individuals experiencing adverse reactions.
This new research, led by the Peter Doherty Institute for Infection and Immunity (Doherty Institute) in collaboration with University of Melbourne’s Bio21 Institute and Harvard Medical School (USA), and published in PNAS, has uncovered a mechanism that stimulates specific immune cells, called natural killer T (NKT) cells, which may play a role in sulfa-drug allergic reactions.
Usually, NKT cells respond to lipids (fat molecules) derived from foreign pathogens when these are bound by protein, called CD1d, which presents them to NKT cells. They can also sense and respond to the alterations in the self-lipid-composition of the host’s (human) cells that are often associated to disease.
What the team has shown is that sulfa-drug-like compounds can also bind to CD1d, and that some NKT cells can sense them in association with a self-lipid molecule bound by CD1d.
This interferes with normal NKT cell immune surveillance, leading to activation of these cells and potentially eliciting an unwanted immune response.
First author on this study, University of Melbourne Dr Catarina Almeida, a Post-doctoral Research Fellow at the Doherty Institute, explained that the study represents a breakthrough in the field of immunology as it presents a mechanism by which sulfa-drugs may initiate an immune response and challenges the paradigm that NKT cells only react to lipid molecules.
“These white blood cells were believed to only be involved in lipid-molecule-surveillance,” Dr Almeida said.
“We’ve been able to show that these non-lipid-molecules, which are structurally similar to sulfa-drugs, can activate a previously unexplored subset of NKT cells in humans.”
“Most research to address the problem of sulfa-drug allergies has unsuccessfully focused on other types of white blood cells.”
The discovery opens an entirely new avenue of research into how these cells function and their potential role in sulfa-drug allergic reactions.
Professor Dale Godfrey, senior author on the paper and head of the laboratory where this research was performed at the Doherty Institute explained that whilst NKT cells have been shown to play an important role in cancer, infection, autoimmunity and allergy, their role in drug-induced allergies remains unexplored.
“We hope that our novel investigations may open a new line of research and help address a long-standing problem that can increase the safety of these important drugs,” Professor Godfrey said.