Mechanisms of Allograft Rejection: Insights from Behind the Scenes

Dr. Remi Shih, Thoa Nong, Dr. Jar-How Lee and their team at the Terasaki Innovation Center in California have recently discovered novel mechanisms behind allograft rejection. Their research has revealed a previously unrecognized complexity in antibody-mediated rejection, highlighting the dynamic interaction between major histocompatibility complex (MHC)-bound peptides and epitopes targeted by human leukocyte antigens (HLA) alloantibodies. Concurrently, their investigation into the immunogenicity of unique DQβ:DRα heterodimers in kidney transplant recipients has revealed novel pathways of immune recognition with potential implications for clinical outcomes. Here, we offer exclusive insights from these scientists in their recent contributions in immunology and transplantation.

Peptide Variations Shape Antibody Specificity in Transplantation

In 1969, donor-specific HLA antibodies were first discovered by Dr. Terasaki, but their accurate detection has remained a challenging obstacle in organ transplantation. Bead-based assays have advanced antibody identification, yet disparities with traditional methods highlight the necessity for more complete information in this regard to ensure accurate and precise compatibility assessments for transplant patients.

Antibodies targeting HLA pose challenges for transplantation patients. Despite efforts to match antibodies using single-antigen bead (SAB) assays, some reactivities remain unexplained. Recent findings from a publication in Nature Communications have shed light on the relationship between MHC-bound peptides and epitopes that are recognized by HLA alloantibodies. This finding revealed a previously unrecognized component that directly affects antibody-mediated rejection. Essentially, the unexplained reactivities of the HLA class II molecule DQβ0603:DQα0103 were explored, and it was found that peptides from specific regions of the HLA class I molecule bind to DQβ0603:DQα0103, which is what affects antibody reactivity. These findings suggest that HLA class I peptides can contribute to antibody binding to HLA class II proteins, and provide more clarity in mechanisms surrounding transplant immunology and adaptive immunity.

Dr. Remi Shih, the Science Director at Terasaki Innovation Center in Los Angeles, California and co-first author of the paper, has provided insightful commentary on their findings. “The basic point of this research is that when HLA lab directors encounter this phenomenon, some may lack clarity on how to report these findings,” Dr. Shih emphasized. “In certain cases, these antibodies may be disregarded due to challenges in confirming their presence, leading to decisions made without utilizing critical data.” Dr. Shih stressed the significance of their research in affirming the existence of these antibodies, urging HLA lab directors to consider this data in their decision-making processes to avoid unforeseen consequences. Furthermore, Thoa Nong, the Director of Laboratory Operations at the Terasaki Innovation Center and co-first author of the paper, went on to discuss how these findings could potentially improve current methods of detecting and treating antibody-mediated rejection in transplant patients. “This discovery enhances our comprehension of the immune system’s response to transplanted organs, and offers another alternative for this phenomenon. Future HLA research directions are fluid, and we only offer the awareness of our discoveries to the industries.” Thoa and the team all shared the sentiment that the discoveries of the article were a surprise, and would provide valuable information into the  complexities of antibody reactivity in transplantation.

Targeting Unique HLA Protein Complexes 

The HLA gene cluster on chromosome 6 encodes proteins important for immune responses, especially in organ transplants. These proteins, known as HLA class I and II molecules, play a key role in recognizing and responding to harmful invaders. However, if there are differences in these proteins, the body might produce antibodies against foreign HLA proteins, which can pose significant challenges for patients needing transplants. 

In a second innovative study now published in Transplantation, the team at the Terasaki Innovation Center demonstrated the stable formation of hybrid HLA class II molecules, specifically the rarely observed DQβ:DRα heterodimers. Their investigation aimed to explore the role of these molecules in immune responses and their relevance for organ transplantation. The research found that differences in certain immune proteins, called HLA class I and II antigens, affect how they interact with different amino acids. This influences their ability to show small pieces of proteins to the immune system. Specifically, certain combinations of genetic factors (DQB1 alleles) were better at forming these protein complexes on cell surfaces. By utilizing SABs, the team identified patient sera that reacted with these heterodimers, indicating their potential clinical significance. The discovery of these stable protein complexes (DQβ:DRα interisotypic heterodimers) opens up new avenues for studying how they affect the immune system, especially in kidney transplants. Overall, this research provides new opportunities to understand how these protein complexes impact transplant success.

In the context of this investigation titled “Identification of Antibodies to DQβ:DRα Interisotypic Heterodimers in Human Sera,” Dr. Jar-How Lee, Chief Scientific Officer at Terasaki Innovation Center and corresponding author provided his commentary on the implications of this research. When asked about using their discoveries to improve immune compatibility through genetic engineering, the response highlighted that natural genetic differences already affect how proteins are expressed on cell surfaces. “There is no genetic engineering in the HLA variants. They naturally exist,” Dr. Lee clarified. “We only provide the understanding.” Co-first authors of the paper, Dr. Shih, Thoa Nong and Dr. Mayra Lopez-Cepero all stressed the significance of understanding antibodies’ core mechanisms in optimizing transplant outcomes.  “We don’t know the long-term impact to the industry,” noted Thoa. “This research is all about understanding antibodies. We’re offering new explanations, but we’re not sure yet how they’ll affect the industry in the long run.” Dr. Lopez-Cepero stressed that “These antibodies have always been around; we’re just now discovering more about them. Because this is all quite new, we’ll have to wait to see the full impact.” Additionally, the discussion explored the broader implications of successful heterodimer assembly, suggesting potential applications in autoimmune or infectious diseases. “Our paper offers explanations that antibodies can be either allo-, auto- or both,” Dr. Shih remarked. “It is up to the transplantation industries to decide if they want to implement this into their diagnostic/screening routines.”

Given the complexity of this work, it is remarkable to observe the reaching effects of this content across the board, opening the door for further research into the role of antibody reactivity and the influence of hybrid molecules in transplantation.

Author

Bernice Lottering