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Antibody Mediated Rejection

David Iturbe, MD
Hospital Universitario Marqués de Valdecilla
Santander, Spain

Lung transplantation (LT) is a treatment option for patients with end-stage lung disease. Long-term survival, however, remains significantly worse in comparison to other solid organ transplants. Outcomes are limited by recurrent immunologic events contributing to chronic lung allograft dysfunction (CLAD), the very specifics of which remain unknown to this day.

Antibody-mediated rejection (AMR) is recognized as a form of rejection following kidney and heart transplantation with well-established diagnostic criteria regarding histopathology, immunopathology and serology, however, such strong evidence is somewhat lacking in regards to LT.

Some studies have identified the development of "de novo" Donor Specific Antibodies (DSA) as a significant predictor of poor outcomes. The presence of DSA is related to Bronchiolitis Obliterans (BO) and acute cellular rejection (ACR), specifically high grade and persistent-recurrent ACR (1-5). An In vitro study demonstrated that class I anti-HLA antibodies can induce airway epithelial cell proliferation, release of fibrogenic growth factors, and epithelial cell apoptosis. This process may lead to the activation of lung fibroblasts resulting in tissue remodeling and fibrous tissue proliferation observed during BO development [6].

The incidence of DSA remains unknown. Studies have described widely ranging results from 10 to more than 50% [7]. This inconsistency is largely due to significant differences in laboratory techniques and recipient variables, therefore definitive conclusions are difficult to draw. Moreover, tests are aimed to mainly identify HLA antibodies, neglecting other antigens that may have a pathogenic role in the humoral response such as collagen, vimentin, angiotensin-receptor and alpha-tubulin, minor histocompatibility antigens (MICA/MICB), as well as others that are yet to be defined.

Histopathologic and immunophenotypic criteria of AMR in LT have neither been described nor accepted. Unlike renal and cardiac transplant, they weren´t addressed in the 1990 and 1996 ISHLT classification of LT rejection and were not clearly established in the 2007 revision. The Pathology Council's update, provided in 2012 [8], described a broad list of patterns that would suggest AMR warranting immunopathologic evaluation. This list includes more specific terms such as neutrophilic capillaritis or neutrophilic septal margination, but also others like high-grade or persistent/recurrent cellular rejection, obliterative bronchiolitis and diffuse alveolar damage, which are found in processes like bacterial/viral infection, graft preservation injury and many others that are quite distant from AMR. In conclusion, there is no typical histopathologic pattern that would be considered specific for AMR, leaving clinicians without a reliable marker. The same is also true regarding exclusion criteria since presence of an absolutely healthy tissue is the only certain criterion for absence of AMR.

The bound antibody induces the complement cascade, leading to cleavage and activation of C4d protein. Thus, the presence of this complement protein in interstitial capillary is considered a marker of humoral damage of the allograft. This is used as a tenet in the AMR diagnosis algorithm, however many aspects of this phenomena remain unknown. Furthermore, the complement cascade can be activated by bacterial infection and other inflammatory processes, rendering this marker somewhat unspecific. There are few published schemes for grading distribution or intensity of C4d staining in pulmonary AMR. Usually immunoreactivity higher than 50% of interstitial capillaries is used as a threshold; however, as mentioned previously, there is a big gap of knowledge owing to scarcity of studies and heterogeneity in methods and results amongst them. We are still far away from fully understanding the true role of staining complement proteins and the best way to measure them.

Banff criteria defined AMR as an unexplained graft dysfunction, "de novo" DSA, neutrophilic capillaritis and positive C4d staining in biopsy [9]. Unlike renal or cardiac transplant, it is very uncommon to find patients who fulfill all the criteria. As discussed above, AMR is presented by a large spectrum of histopathologic patterns that are established in nearly all lung biopsy samples and normal tissue is the only true evidence for exclusion of AMR. C4d is still far from being sensitive or specific enough to be considered as an irrefutable marker. DSA presence should be considered as a mainstay of this process, however they may be adsorbed within the allograft, leading to falsely negative results [10]. As in cellular rejection, patients may develop acute respiratory symptoms or remain totally asymptomatic with normal pulmonary function tests. Therefore we still need to define a diagnostic algorithm for AMR that fits this lung idiosyncrasy.

Response to treatment and long-term outcomes are two important areas needing further investigation. Few small trials have been published with unclear and heterogeneous results. Therapies are based on combinations of plasmapheresis, intravenous immunoglobulins, high dose glucocorticoids and Rituximab. Some centers used Bortezomib or Eculizumab in complex cases.

In conclusion, there are numerous vitally important knowledge gaps in AMR, LT failure, and management. First, we need to develop a concrete definition and diagnostic criteria for AMR. Only then we could perform large multicenter and well-designed trials to evaluate therapies as well as short and long-term outcomes.

In this author's opinion, we are only beginning to realize the magnitude of this medical complication, whether it´s just an isolated condition, only important to a small cohort of patients, or the presence of a humoral response determines immunologic/inflammatory processes that may contribute to the development of CLAD. It is prudent to ask new questions, seek answers to them, and investigate those answers in the hopes of progressing the very science and medicine of lung transplantation and improving our patient's long-term outcomes. ■

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


  1. Sundaresan S, Mohanakumar T, Smith MA, Trulock EP, Lynch J, Phelan D, et al. HLA-A locus mismatches and development of antibodies to HLA after lung transplantation correlate with the development of bronchiolitis obliterans syndrome. Transplantation. 1998;65(5):648-53.
  2. Jaramillo A, Smith MA, Phelan D, et al. Development of ELISA-detected anti-HLA antibodies precedes the development of bronchiolitis obliterans syndrome and correlates with progressive decline in pulmonary function after lung transplantation. Transplantation. 1999;67(8):1155-61.
  3. Girnita AL, McCurry KR, Iacono AT, et al. HLA-specific antibodies are associated with high-grade and persistent-recurrent lung allograft acute rejection. J heart lung Transplant. 2004;23(10):1135-41.
  4. Girnita AL, Duquesnoy R, Yousem SA, et al. HLA-specific antibodies are risk factors for lymphocytic bronchiolitis and chronic lung allograft dysfunction. Am J Transplant. 2005;5(1):131-8.
  5. Jaramillo A, Smith CR, Maruyama T, et al. Anti-HLA class I antibody binding to airway epithelial cells induces production of fibrogenic growth factors and apoptotic cell death: a possible mechanism for bronchiolitis obliterans syndrome. Hum Immunol. 2003;64(5):521-9.
  6. Jaramillo A, Fernandez FG, Kuo EY,et al. Immune mechanisms in the pathogenesis of bronchiolitis obliterans syndrome after lung transplantation. Pediatr Transplantation. 2005;9(1):84-93.
  7. Hachem RR, Yusen RD, Meyers BF, et al. Anti-human leukocyte antigen antibodies and preemptive antibody-directed therapy after lung transplantation. J heart lung Transplant.. 2010;29(9):973-80.
  8. Berry G, Burke M, Andersen C, et al. Pathology of pulmonary antibody-mediated rejection: 2012 update from the Pathology Council of the ISHLT. J heart lung Transplant. 2013;32(1):14-21.
  9. Racusen LC, Colvin RB, Solez K, et al. Antibody-mediated rejection criteria - an addition to the Banff 97 classification of renal allograft rejection. Am J Transplant. 2003;3(6):708-14.
  10. Westall GP, Snell GI. Antibody-mediated rejection in lung transplantation: fable, spin, or fact? Transplantation. 2014;98(9):927-30.

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