Assessment of DQ Risk Epitope Mismatch in Lung Transplantation as a Predictor of Chronic Lung Allograft Dysfunction

Ennis, Samantha; Malouf, M.A.; Plit, M.; Benzimra, M.; Havryk, A.; Thomson, Claire; Pearson, Rebecca; Glanville, Allan R.; Walton, D.C.; Watson, Narelle; Darley, D.R.

doi:10.1016/j.healun.2020.01.1246

Cited by 3 publications

(5 citation statements)

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“…These observations resonated with our clinical experience in which DQα05-heterodimers are not only a frequent occurrence when monitoring for DSAs posttransplantation but are also often the ones exhibiting the highest inhibition (prozone phenomenon) and demonstrating highest titers (up to 1:65,536 39 ). Increased frequency of DQα05-heterodimers was observed also in studies of heart and lung transplant recipients 40,41 as well as in pediatric kidney transplant recipients. 42 Importantly, our observation emphasizes the contribution of the DQα to the full heterodimer, as molecules that have the same DQβ chain (and are considered serologically equivalent) but different DQα chain have quite different EMS-3D scores (Figure 6).…”

Section: Discussionmentioning

confidence: 64%

“…These observations resonated with our clinical experience in which DQα05‐heterodimers are not only a frequent occurrence when monitoring for DSAs posttransplantation but are also often the ones exhibiting the highest inhibition (prozone phenomenon) and demonstrating highest titers (up to 1:65,536 39 ). Increased frequency of DQα05‐heterodimers was observed also in studies of heart and lung transplant recipients 40,41 as well as in pediatric kidney transplant recipients 42 …”

Section: Discussionmentioning

confidence: 81%

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Qualitative, rather than quantitative, differences between HLA‐DQ alleles affect HLA‐DQ immunogenicity in organ transplantation

Maguire,

Crivello,

Fleischhauer

et al. 2024

HLA

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Prolonging the lifespan of transplanted organs is critical to combat the shortage of this life‐saving resource. Chronic rejection, with irreversible demise of the allograft, is often caused by the development of donor‐specific HLA antibodies. Currently, enumerating molecular (amino acid) mismatches between recipient and donor is promoted to identify patients at higher risk of developing HLA antibodies, for use in organ allocation, and immunosuppression‐minimization strategies. We have counseled against the incorporation of such approaches into clinical use and hypothesized that not all molecular mismatches equally contribute to generation of donor‐specific immune responses. Herein, we document statistical shortcomings in previous study design: for example, use of individuals who lack the ability to generate donor‐specific‐antibodies (HLA identical) as part of the negative cohort. We provide experimental evidence, using CRISPR‐Cas9‐edited cells, to rebut the claim that the HLAMatchmaker eplets represent “functional epitopes.” We further used unique sub‐cohorts of patients, those receiving an allograft with two HLA‐DQ mismatches yet developing antibodies only to one mismatch (2MM1DSA), to interrogate differential immunogenicity. Our results demonstrate that mismatches of DQα05‐heterodimers exhibit the highest immunogenicity. Additionally, we demonstrate that the DQα chain critically contributes to the overall qualities of DQ molecules. Lastly, our data proposes that an augmented risk to develop donor‐specific HLA‐DQ antibodies is dependent on qualitative (evolutionary and functional) divergence between recipient and donor, rather than the mere number of molecular mismatches. Overall, we propose an immunological mechanistic rationale to explain differential HLA‐DQ immunogenicity, with potential ramifications for other pathological processes such as autoimmunity and infections.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 81%

Qualitative, rather than quantitative, differences between HLA‐DQ alleles affect HLA‐DQ immunogenicity in organ transplantation

Maguire,

Crivello,

Fleischhauer

et al. 2024

HLA

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“…Reducing the level of HLA mismatching, in either T-cell or B-cell epitopes, electrostatic differences or amino acid was shown to improve outcomes following LTx as HLA-DRB1345 matching was associated with freedom from RAS and HLA-DQ matching was associated with reduced donor-specific antibody (DSA) development and therefore indirectly also reduced CLAD development [25]. This was specifically confirmed for high-risk epitope mismatch found in DQA1Ã05 þ DQB1Ã02/DQB1Ã03 : 01, which was associated with DSA and CLAD development [26].…”

Section: Clinical Risk Factorsmentioning

confidence: 90%

The diagnosis and management of chronic lung allograft dysfunction

Verleden,

Hendriks,

Verleden

2024

Current Opinion in Pulmonary Medicine

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Purpose of review Chronic lung allograft dysfunction (CLAD) remains a life-threatening complication following lung transplantation. Different CLAD phenotypes have recently been defined, based on the combination of pulmonary function testing and chest computed tomography (CT) scanning and spurred renewed interests in differential diagnosis, risk factors and management of CLAD. Recent findings Given their crucial importance in the differential diagnosis, we will discuss the latest development in assessing the pulmonary function and chest CT scan, but also their limitations in proper CLAD phenotyping, especially with regards to patients with baseline allograft dysfunction. Since no definitive treatment exists, it remains important to timely identify clinical risk factors, but also to assess the presence of specific patterns or biomarkers in tissue or in broncho alveolar lavage in relation to CLAD (phenotypes). We will provide a comprehensive overview of the latest advances in risk factors and biomarker research in CLAD. Lastly, we will also review novel preventive and curative treatment strategies for CLAD. Summary Although this knowledge has significantly advanced the field of lung transplantation, more research is warranted because CLAD remains a life-threatening complication for all lung transplant recipients.

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“…A pre-LTx virtual cross match has proved robust at alerting clinicians to particularly adverse combinations. 81,82 Where there is uncertainty a solid-phase Hallifaster crossmatch assessment can add further prognostic information. 80 Great skill and collaboration with Tissue Typing Services is needed to navigate difficult sensitized cases in critically ill potential recipients.…”

Section: Abo Matchingmentioning

confidence: 99%

“…The immunologic LTx focus for the last decade has been avoid matching a recipient to a specific donor where significant DSAs to that donor's HLA are already present. A pre‐LTx virtual cross match has proved robust at alerting clinicians to particularly adverse combinations 81,82 . Where there is uncertainty a solid‐phase Hallifaster crossmatch assessment can add further prognostic information 80 .…”

Section: Lung Donor and Recipient Matching And Compatibilitymentioning

confidence: 99%

Advances in lung transplantation: 60 years on

Paraskeva,

Snell

2024

Respirology

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Lung transplantation is a well‐established treatment for advanced lung disease, improving survival and quality of life. Over the last 60 years all aspects of lung transplantation have evolved significantly and exponential growth in transplant volume. This has been particularly evident over the last decade with a substantial increase in lung transplant numbers as a result of innovations in donor utilization procurement, including the use donation after circulatory death and ex‐vivo lung perfusion organs. Donor lungs have proved to be surprisingly robust, and therefore the donor pool is actually larger than previously thought. Parallel to this, lung transplant outcomes have continued to improve with improved acute management as well as microbiological and immunological insights and innovations. The management of lung transplant recipients continues to be complex and heavily dependent on a tertiary care multidisciplinary paradigm. Whilst long term outcomes continue to be limited by chronic lung allograft dysfunction improvements in diagnostics, mechanistic understanding and evolutions in treatment paradigms have all contributed to a median survival that in some centres approaches 10 years. As ongoing studies build on developing novel approaches to diagnosis and treatment of transplant complications and improvements in donor utilization more individuals will have the opportunity to benefit from lung transplantation. As has always been the case, early referral for transplant consideration is important to achieve best results.

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Assessment of DQ Risk Epitope Mismatch in Lung Transplantation as a Predictor of Chronic Lung Allograft Dysfunction

Cited by 3 publications

References 0 publications

Qualitative, rather than quantitative, differences between HLA‐DQ alleles affect HLA‐DQ immunogenicity in organ transplantation

Qualitative, rather than quantitative, differences between HLA‐DQ alleles affect HLA‐DQ immunogenicity in organ transplantation

The diagnosis and management of chronic lung allograft dysfunction

Advances in lung transplantation: 60 years on

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