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Altered inflammation and tissue remodeling are cardinal features of cardiovascular disease and cardiac transplant rejection. Neutrophils have increasingly been understood to play a critical role in acute rejection and early allograft failure; however, discrete mechanisms that drive this damage remain poorly understood. Herein, we demonstrate that early acute cardiac rejection increases allograft prolyl endopeptidase (PE) in association with de novo production of the neutrophil proinflammatory matrikine proline-glycine-proline (PGP). In a heterotopic murine heart transplant model, PGP production and PE activity were associated with early neutrophil allograft invasion and allograft failure. Pharmacologic inhibition of PE with Z-Pro-prolinal reduced PGP, attenuated early neutrophil graft invasion, and reduced proinflammatory cytokine expression. Importantly, these changes helped preserve allograft rejection-free survival and function. Notably, within 2 independent patient cohorts, both PGP and PE activity were increased among patients with biopsy-proven rejection. The observed induction of PE and matrikine generation provide a link between neutrophilic inflammation and cardiovascular injury, represent a potential target to reduce allogenic immune responses, and uncover a mechanism of cardiovascular disease that has been previously unrecognized to our knowledge.

Background: Allograft dysfunction due to presumed antibody-mediated rejection (pAMR) is one of the most serious complications of heart transplantation. Combination therapies of high-dose steroids, intravenous immune globulin, and/or therapeutic plasma exchange (TPE) are often used in this setting., Methods: We performed a 9-year retrospective review of all episodes of pAMR treated with TPE at our institution. pAMR diagnosis was based on clinical and pathologic findings. Left ventricular ejection fraction (LVEF) was measured at baseline, prior to initiation of TPE, and during the course of treatment., Results: There were 42 patients with 47 episodes of pAMR treated with TPE. The majority of episodes were treated with three TPE; however, eight required only two TPE and five episodes required >3 TPE. All episodes of pAMR had LVEF measured before and after the series of TPEs. The mean pre-TPE LVEF was 38% compared with a post-therapy mean LVEF of 50% (P < 0.0001). In 16 episodes of pAMR, for which LVEF was measured following each apheresis, there was significant improvement of allograft function after the first TPE (pre-TPE mean LVEF of 31% and post-first TPE mean LVEF of 37%; P = 0.02). Incremental and significant improvement in allograft function continued following each TPE. Changes in human leukocyte antigen-donor specific antibodies and fibrinogen did not correlate with ejection fraction response., Conclusions: The rapid improvement in allograft function in our patients is most likely due to TPE as other pharmacologic interventions have longer onset. TPE should be considered a first-line intervention in the setting of pAMR., (© 2014 Wiley Periodicals, Inc.)

Background: The problem of AMR remains unsolved because standardized schemes for diagnosis and treatment remains contentious. Therefore, a consensus conference was organized to discuss the current status of antibody-mediated rejection (AMR) in heart transplantation., Methods: The conference included 83 participants (transplant cardiologists, surgeons, immunologists and pathologists) representing 67 heart transplant centers from North America, Europe, and Asia who all participated in smaller break-out sessions to discuss the various topics of AMR and attempt to achieve consensus., Results: A tentative pathology diagnosis of AMR was established, however, the pathologist felt that further discussion was needed prior to a formal recommendation for AMR diagnosis. One of the most important outcomes of this conference was that a clinical definition for AMR (cardiac dysfunction and/or circulating donor-specific antibody) was no longer believed to be required due to recent publications demonstrating that asymptomatic (no cardiac dysfunction) biopsy-proven AMR is associated with subsequent greater mortality and greater development of cardiac allograft vasculopathy. It was also noted that donor-specific antibody is not always detected during AMR episodes as the antibody may be adhered to the donor heart. Finally, recommendations were made for the timing for specific staining of endomyocardial biopsy specimens and the frequency by which circulating antibodies should be assessed. Recommendations for management and future clinical trials were also provided., Conclusions: The AMR Consensus Conference brought together clinicians, pathologists and immunologists to further the understanding of AMR. Progress was made toward a pathology AMR grading scale and consensus was accomplished regarding several clinical issues., (Copyright © 2011 International Society for Heart and Lung Transplantation. All rights reserved.)

Background: Photopheresis therapy (photo) has been advocated as a therapy to improve outcome after recalcitrant or severe rejection, but objective evidence of a beneficial effect has been elusive. This study examined the hypothesis that photo provides protection against rejection, rejection with hemodynamic compromise (HC), and death from rejection after cardiac transplantation., Methods: Between 1990 and 2003, 36 adult patients (from 343 adult transplant recipients) received at least 3 months of photo (2-day treatment every 3 to 6 weeks for a target of 18 months) after HC rejection (n = 12), recurrent/recalcitrant rejection (n = 20), or as prophylaxis in the presence of anti-donor antibodies (n = 4). Survival and risk factors were examined by analysis using multivariate hazard function modulated renewal function., Results: Patients selected for photo were at greater risk for rejection (p < 0.0001) and HC rejection (p < 0.0001) than non-photo patients. After 3 months of photo therapy, rejection risk was decreased (p = 0.04). More importantly, the hazard for subsequent HC rejection or rejection death was significantly reduced toward the risk-adjusted level of lower-risk non-photo patients (p = 0.006)., Conclusions: This study provides objective evidence that photo reduces the risk of subsequent HC rejection and/or death from rejection when initiated for patients with high rejection risk. Photopheresis is recommended as an important therapeutic modality after rejection with hemodynamic compromise, although further studies are needed to define the precise mechanism of the effect and the potential for benefit in other patient sub-sets.