AsianScientist (Mar. 25, 2019) – In a study published in Nature Communications, scientists in Singapore have obtained the structure of a protein complex involved in organ rejection. Their finding could pave the way for better organ transplant outcomes in patients.
Introducing an organ from a donor into a recipient almost always leads to the recipient’s immune system recognizing the new organ as foreign, resulting in an immune response in the recipient. There are two main types of transplant rejection: cell-mediated rejection and antibody-mediated rejection.
Cell-mediated rejection, which occurs more commonly within the first year after a transplant, is caused by immune cells called T cells attacking the transplant. This type of rejection responds well to treatment with non-specific immunosuppressants such as steroids. The particularly thorny issue for transplant patients is antibody-mediated rejection, which is chronic and caused by alloantibodies in the transplant patient binding to a molecule called human leukocyte antigen (HLA) on the transplanted donor organ.
In the present study, scientists led by Professor A. Vathsala at the National University Hospital, Singapore, assembled the high-resolution crystal structure of alloantibody-HLA interaction. At a resolution of 2.4 angstroms, the researchers were able to identify two amino acids in HLA—aspartic acid at position 90 and arginine at position 14—that were critical for the antibody-HLA binding.
The team also discovered that the antibody bound to a site at the bottom of the HLA protein, some distance away from the sites at which peptides, T cells and natural killer cells bind to HLA. This finding was surprising because it indicated that the inflammatory response stimulated by the antibody was independent of the interactions of peptides or immune cells with HLA.
“What was interesting is that the antibody binds to the side of the [HLA] molecule,” explained Associate Professor Paul MacAry at the National University of Singapore, a co-author on the paper. “What this allows you to do is design inhibitors that are going to obstruct the interface because if you stop the antibodies binding, you stop those antibodies from engendering the immune attack.”
In fact, the team showed that one form of the antibody, a subclass called IgG4, bound to the HLA protein without causing an inflammatory response. Since these antibodies are able to reduce inflammation by binding to HLA and preventing other antibody subclasses from binding, they could be developed as therapies for prevention or treatment of antibody-mediated rejection.
The article can be found at: Gu et al. (2019) Defining the Structural Basis for Human Alloantibody Binding to Human Leukocyte Antigen Allele HLA-A*11:01.
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Source: National University of Singapore; Photo: Pixabay.
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