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Recent Progress in the Pathology of AMR and CAV

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Brandon T. Larsen, MD, PhD
University of Arizona College of Medicine
Tucson, Arizona, USA

At times, the rapid pace of new developments can be overwhelming to the practicing physician, and this is certainly true in the field of heart and lung transplantation pathology! In the November 2015 issue of Links, our Council highlighted many of the key pathology publications from the last year, to help busy pathologists stay abreast of our rapidly evolving field. But time flies even faster, as we all know, necessitating another ISHLT Links update from the Pathology Council.

In the last 3 months since our last update, we've already seen several new studies published that advance our understanding of allograft pathology. As in recent years, antibody-mediated rejection (AMR) and cardiac allograft vasculopathy (CAV) remain a strong focus of our Council's discussions and research efforts. If you missed the November update, it might be worth checking out too, for a more extensive review of our field's recent progress. In the present update, only 2 very recent papers will be highlighted that are likely of broadest interest, but this is certainly an incomplete list and many others are deserving of review, too.

Progress in Pulmonary AMR
Despite being a focus of intense interest and investigation, pulmonary AMR and its pathologic characteristics remain poorly understood. As you all know, in an effort to focus research efforts in pulmonary AMR, the Pathology Council published a summary statement in 2012 with recommendations for pathologic evaluation of AMR, which included suggestions for protocol biopsies and serologic evaluation for DSA, in order to accumulate data and begin to unravel the details of the pathology of this phenomenon.

This data is finally beginning to emerge, spurred on by efforts of our Council members and others. In January, Dr. Wallace and colleagues published a blinded multi-institutional study investigating pathologic changes in a large number of lung allograft biopsies, to see whether any statistically significant findings correlate with the presence of DSAs (http://www.ncbi.nlm.nih.gov/pubmed/26601715). They found that capillary inflammation, acute lung injury, and endotheliitis each correlate significantly with the presence of DSAs. On the other hand, they observed no significant correlation between the presence of staining for C4d and the presence of DSAs, reaffirming what many of us have experienced with our C4d stains, and again suggesting that C4d is of limited utility in the pathologic evaluation of the lung allograft.

Certainly, the story of pulmonary AMR is not over, as the transbronchial biopsy remains an imperfect tool, fraught with numerous technical and interpretive challenges, and additional studies and advances in technology are sorely needed. Perhaps the cryobiopsy will begin to shed light on this vexing problem as it becomes more widely adopted. In any case, we can expect a lively discussion on the topic in Washington next month!

Progress in CAV
Data on cardiac AMR and CAV continues to accumulate, but the nature of the association between cardiac AMR and the eventual development of CAV remains poorly understood, and this potential link continues to be hotly debated.

In January, Dr. Loupy and colleagues in France reported their findings in an interesting multi-center study of late failing cardiac allografts, where they investigated the pathology of CAV and its association with AMR (http://www.ncbi.nlm.nih.gov/pubmed/26588356). They also correlated these findings with endomyocardial biopsies obtained between allograft implantation and explantation. In their study, they observed evidence of antibody-mediated injury in 62% of allografts with pure arteriosclerosis or mixed arteriosclerosis and atherosclerosis, but not in allografts with pure atherosclerosis only. The authors concluded that AMR is operating in a substantial fraction of failing cardiac allografts, and is associated with severe coronary arteriosclerosis, the histologic hallmark of CAV.

This study adds to the growing body of indirect evidence suggesting a causal link between cardiac AMR and CAV. Nevertheless, much remains to be learned about the pathogenesis, tempo, and treatment of CAV, and its relationship to cardiac AMR. Don't miss the stimulating discussions on this topic that will certainly occur at the Annual Meeting next month!

2016 Annual Meeting & Scientific Sessions in Washington, DC.
Please join us for the following pathology-oriented sessions in Washington:

Unraveling "Chronic Rejection" in the Heart, where the controversy and ambiguity surrounding chronic rejection in the heart will be discussed. What does "chronic" really mean? And are the changes we observe truly rejection? Speakers will address the myocardial alterations (beyond CAV) seen after years of repetitive rejection episodes, novel mechanisms of CAV development, the role of complement and other mechanisms in potentiating late graft damage, analogues of chronic rejection in other organs, and animal models of late graft loss.

Controversies in Heart Transplantation: Past, Present and Future, where the current status of rejection surveillance and utility of endomyocardial biopsy will be hotly debated.

Big Data to Answer Big Questions: Biobanking to "Omics" to Personalized Medicine in Thoracic Organ Transplantation, where renowned investigators will discuss the process of biobanking and proper utilization of banked specimens for research, and the promise of Big Data as a tool that will revolutionize future clinical practice.

A 2016 Focused Update on AMR in Cardiac Transplantation: Immunologic Diagnostics and the Treatment of Refractory AMR, where the current state of cardiac AMR will be addressed, including a discussion of endomyocardial biopsy features in AMR and emerging molecular technologies for detection of AMR.

Endotypes of CLAD and Novel Treatment Strategies, where our current understanding of the different CLAD phenotypes will be reviewed, including their clinical diagnosis, radiology, pathology, prognosis, and treatment.

For more details about these and other exciting symposia, please visit the 2016 Preliminary Program at http://www.ishlt.org/meetings/annualMeeting.asp.

See you all soon! ■

Disclosure Statement: The author has no conflicts of interest to disclose.

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