A long-awaited structure offers new information on the rejection of transplanted organs

The rejection of any kind is always difficult to manage, but when the body rejects a valuable organ transplant, the consequences can be devastating. Professor A. Vathsala, co-director of the National University Center for Organ Transplantation at the National University Hospital (NUH) and professor of medicine, explained that between 30% and 40% of transplants kidneys are lost over time. In collaboration with Associate Professor Paul MacAry of the Department of Microbiology and Immunology of NUS Medicine, she decided to collaborate on the resolution of a major clinical problem at NUCOT: how to extend the life of each organ graft?

The introduction of an organ from a donor into a recipient almost always leads the recipient's immune system to recognize the new organ as foreign and to trigger an immune response. The transplant rejection (or transplant) can be clbadified into two main types: cell-mediated rejection and antibody-mediated rejection. Cell-mediated rejection, which occurs more frequently in 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 immunosuppressive drugs such as steroids.

The particularly difficult problem for transplant patients is antibody-induced rejection, which causes chronic rejection. The antibodies in the graft bind to a molecule called human leukocyte antigen (HLA) on the organ of the transplanted donor and stimulate an inflammatory response involving either the immune cells or the complement pathway. A major problem in transplantation is the difficulty in diagnosing and predicting the rejection caused by the antibodies. In addition, doctors discover that rejection occurred when a transplant begins to fail and that they perform a biopsy.

"We found that up to twenty percent of patients had antibodies against their donors.This is not because a patient has antibodies that his rejection will be rejected.Although many transplanted have antibodies, not all antibodies are harmful, is not a good way to predict which antibodies are actually harmful, "said Professor Vathsala.

Another more important problem is that there is no effective treatment against antibody-induced rejection. These patients with antibody-induced rejection end up needing a re-transplant with a fresh organ, which is difficult because of the shortage of donor organs. Therefore, antibody-induced rejection is a major challenge in organ transplantation and is an ideal target for pushing the boundaries of transplantation outcomes.

A critical step in antibody-mediated rejection is the binding of antibodies to a recipient grafted to the donor's HLA molecule. These antibodies are called alloantibodies. However, until now, the mechanism by which these antibodies bind to HLA was not known. In an article published online in Nature Communications On February 21, 2019, Professor MacAry, Professor Vathsala, a partner at Nanyang Technological University and the University of Oxford, announced the creation of the first high-resolution crystalline structure in the world. allo-antibody-HLA interaction.

At this resolution (2.4 angstroms), researchers were able to identify several important pieces of information. First, they identified two amino acids in HLA (90-position aspartic acid and 14-arginine) that were critical for antibody-HLA binding. Second, they found that the antibody binds to a site at the bottom of the HLA protein, at a distance from sites where peptides, T cells, and natural killer cells bind to HLA. This finding was surprising because it indicated that the antibody-stimulated inflammatory response was independent of peptide or immune cell interactions with HLA.

"What was interesting is that the antibody binds to the side of the [HLA] "This allows you to design inhibitors that will clog the interface, because if you stop the binding of antibodies, you prevent these antibodies from causing an immune attack."

In fact, the team has shown that a form of antibody (a subclbad called IgG4) binds to the HLA protein without causing an inflammatory response. Since these antibodies can reduce inflammation by binding to HLA and preventing the binding of other antibody subclbades, they could be developed as treatments for the prevention or treatment of drug-mediated rejection. antibody.

According to Professor Kathryn Wood, Professor Emeritus of Immunology at Oxford University and Professor of Surgery Khoo Oon Teik at NUS Medicine, Project Advisor and co-author of the Nature Communications This document is a "landmark study of which all groups in the world will take note, and this is truly a first in this field".

The crystal structure consists of a single type of HLA called HLA-A * 11: 01, common among Chinese and the most common type among Singaporeans. The team hopes to be able to resolve the structures of all other HLA molecules common to Asians within three to five years.

Professor Vathsala described the project as a fortuitous collaboration of basic science and clinical research aimed at solving a long-standing problem in the clinic. "We [at NUH] have a wonderful campus in our backyard where we can meet experts in microbiology and immunology. The project was born from a random tea where Paul and I met and said: "Let's solve this problem and look at the structural aspects of the antibodies and the antigen." 39; "