Perspective
Antibody-mediated rejection in lung transplantation: Myth or reality?

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Whether antibody-mediated rejection after lung transplantation exists as an entity is debated by immunologists, histopathologists, and clinicians, without a strong consensus regarding diagnostic characteristics despite an increasing body of evidence that attests to a significant role in other solid organ transplant disciplines. Evidence for and against the protean manifestations of antibody-mediated rejection after lung transplantation is discussed, with special reference to hyperacute pulmonary allograft rejection as well as acute and chronic pulmonary allograft rejection, emphasizing the potential role of complement and antibodies to human leukocyte antigens and anti-endothelial antigens. A well-described clinical phenotype exists for hyperacute pulmonary allograft rejection with low-level evidence for efficacy of therapy with intravenous immunoglobulin, plasmapheresis, and anti-CD20 monoclonal antibodies plus supportive care, if instituted early in the evolution of the process. The clinical phenotype of acute antibody-mediated rejection is now better defined, if not widely diagnosed, and a similar treatment protocol appears effective. The role of antibody-mediated rejection in the development of chronic pulmonary allograft rejection remains an exciting area for further study based on some compelling preliminary work to date. Antibody-mediated rejection after lung transplantation remains a major area for research. In the clinical domain, experience suggests antibody-mediated rejection should be considered a potential cause of graft dysfunction, whether concomitant acute cellular rejection is diagnosed or not, and especially where resistance to corticosteroid therapy is encountered.

Section snippets

Hyperacute rejection

Evidence for the concept of AMR presenting with hyperacute rejection, albeit a rare phenomenon, is more compelling. In 1996 Frost et al8 described the first convincing case of clinical hyperacute rejection, which was corroborated by a positive, donor–antigen-specific immunoglobulin (Ig) G-mediated lymphocytotoxic crossmatch, and compatible histopathologic, immunofluorescent, and electron microscopic features. Features of diffuse alveolar damage, neutrophilic infiltrates, and endothelial and

Acute rejection

Evidence for the role of AMR as a potential modality of acute rejection is conflicted and relies on the histopathologic definition of changes that can be ascribed to AMR vs those that are deemed compatible with ACR. Capillaritis, or more correctly, capillary injury, appears to be one of the most definitive findings suggestive of AMR in the literature, the concerns of the current LRSG notwithstanding. Of course, the level of concordance between pathologists in grading AMR is untested. In 1996

Chronic rejection

In concert with other solid organ transplants, it remains probable that AMR is indeed a lead candidate for an etiologic role in the insidious onset and progression of graft dysfunction categorized as chronic rejection, which in the lung is manifest as bronchiolitis obliterans syndrome (BOS). A number of authors have postulated that BOS is the result of humoral and cellular immune responses developed against major histocompatibility complex molecules expressed by airway epithelial cells of the

Non-HLA antibodies

If HLA mismatch and anti-HLA antibodies demonstrate a small effect, it is possible that non-HLA antibodies may have a significant effect. An early, exciting report in 1995 by Smith et al25 from Harefield showed that anti-epithelial cell antibodies (AECAs) detectable in a microcytotoxicity assay (but not by Western blotting) before single-lung transplantation were associated with a decrease in 1-year graft survival of 56% for AECA-positive recipients vs 78% for AECA-negative recipients (p =

The role of complement

AMR is a better-defined cause for cardiac and renal graft dysfunction, where C4d deposition, a stable component of complement activation, inversely correlates with graft survival. Magro et al30 examined biopsy specimens from 23 lung transplant recipients in an attempt to correlate clinical status and morphologic findings with the pattern of C4d deposition. In patients with symptomatic acute rejection, all specimens showed light microscopic and immunofluorescent evidence compatible with AMR. The

Conclusion

Although some questions are unanswered regarding the true incidence, severity, and significance of AMR after lung transplantation, biologically plausible clinical phenotypes have been described for hyperacute and acute AMR. Other causes of acute lung injury such as aspiration pneumonitis and hemorrhagic viral infection must be excluded in the acute circumstance, but prompt action to manage potentially life-threatening graft dysfunction is critical for the practitioner, who must be guided by the

Disclosure statement

Allan R. Glanville is the global principal investigator for the CeMyLungs Investigator Driven study, for which his institution will receive grant support to conduct the study from Novartis Pharmaceuticals (not to exceed €2.4 million).

References (34)

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