Commentary on review: Forming new perspective approaches to determination of donor compatibility

Clarke and Nadat (2024) provide an overview of techniques currently used to detect HLA antigens and antibodies and describe approaches that attempt to quantify incompatibility between a transplant recipient and her/his donor per their HLA typing. They proceed to mention assays investigating qualities of the antibodies such as affinity and avidity as well as glycosylation state and describe approaches to study T and B lymphocytes’ clonality and receptor repertoires. Lastly, they briefly talk about tests to assess allo-immune memory and mention some assays to assess graft injury.

I applaud the authors for providing a condensed menu of tests available for transplant immunologists. I do, however, fear that if the task was to provide new perspective on evaluating compatibility between recipient and donor, this review misses the forest for the trees.

Immune mechanisms are controlled by thousands of genes that drive much of the variability in immune responses, whether those are to pathogens, susceptibility to autoimmune diseases, or susceptibility to allo-stimulation. Each of these genes had evolved and diverged through mechanisms of essentiality, redundancy, and adaptability to provide diverse routes for the best protection to different populations under their own local threats (Quintana-Murci, 2019). These evolutionary forces also necessitated the generation of pathways for redundancy in immune pathways, such that inhibition of one path would not lead to the demise of the individual/population. This means that testing for one, or even a few, pathways will not necessarily correlate with the overall composite response. We should further consider that beyond the ‘pure’ immune genes, additional variables participate in orchestrating an immune response including factors such as age and gender, and environmental exposures. Thus, the landscape of genes and molecules associated with immune activation is vast and polymorphic. We can opt to develop and validate more and more assays to assess allo-immunity as described in the aforementioned review, or we can direct our attention to the elephant in the room—better understanding of the underlying mechanisms leading to differential immunogenicity.

As Histocompatibility and Immunogenetics (H&I) professionals, we appreciate that much of the adaptive immune response (and at least some of the innate response) is guided by the individual's specific HLA molecules. Those are the molecules that control much of our thymic education, that are instrumental for antigen processing and presentation, and that are involved in the most crucial steps of immune activation. The first step in a decision-making tree is ‘identify the problem’. In the context of allo-stimulation, we must therefore first understand why one's immune system perceives one HLA mismatch as more immunogenic and another mismatch as less immunogenic. With this information, deciphering immune activation should be less complex.

Following this rationale, the transformative software brought on by Rene Duquesnoy—HLA Matchmaker—attempted to provide a numeric histo-incompatibility risk stratification metric. Members of our community hastily adopted this approach, succumbing to the colloquial use of the term epitope and the implicit immune significance it invoked. Unfortunately, when questioning the immunologic basis of this approach, significant limitations were unveiled (Tambur & Das, 2023). A basic illustration of flaws in the HLA Matchmaker rationale is evident when analysing individual patients who received a donor with two HLA mismatches at a given locus (DQ in the example referenced; Tambur, 2019). The informative cohort among these patients consists of those recipients who developed de novo donor-specific antibody (dnDSA) to one of the HLA mismatches but not the other mismatch. These patients represent a unique cohort in which each patient serves as its own control, where all external variables (such as levels of immunosuppression; other immune genes; gender; age; and other environmental exposures) are held constant, and the only variable is the quality of the HLA allele mismatch. One allele is clearly more immunogenic as it led to generation of dnDSA, and the other allele is evidently less immunogenic because it did not lead to DSA formation, even though the patient's immune system was robust enough to generate a response against the other mismatch. This cohort, studied in Tambur (2019), clearly showed that the more immunogenic allele was not always the allele with the highest mismatches, counted by HLA Matchmaker. Follow-up studies suggest that evolutionary and functional divergence of the mismatched alleles from the recipient's own HLA background is more aligned with generation of dnDSA (Maguire et al., 2024). While this line of investigation must be confirmed by others, the logic behind it is in par with our understanding of the evolution of the HLA system, its extra ordinary polymorphism, and the natural selection processes that took place primarily due to infectious pathogens (e.g. Hill, 1991). It stands to reason that some HLA alleles diverged in common paths, responding to similar selection pressure, while others diverged in opposing paths. The more immunologically divergent HLA alleles are, the more likely they are to be recognised as foreign.

I therefore believe that the role of H&I community is to first and foremost understand the evolutionary divergence within the HLA system, and how it is guiding differential immunogenicity between recipient and donor in the context of transplantation. Only with this fundamental understanding can we build coherent assessment of other genes and processes within the immune response.

The author declares no conflicts of interest.