Anti-human leukocyte antigen antibodies and preemptive antibody-directed therapy after lung transplantation

Ramsey R Hachem, Roger D Yusen, Bryan F Meyers, Aviva A Aloush, Thalachallour Mohanakumar, G Alexander Patterson, Elbert P Trulock, Ramsey R Hachem, Roger D Yusen, Bryan F Meyers, Aviva A Aloush, Thalachallour Mohanakumar, G Alexander Patterson, Elbert P Trulock

Abstract

Background: Because the development of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) after lung transplantation has been associated with acute and chronic rejection, we implemented a clinical protocol to screen all transplant recipients for DSA and preemptively treat those who developed DSA with rituximab and intravenous immune globulin (IVIG), or IVIG alone.

Methods: We conducted a prospective observational study of this protocol and used the LABScreen Single Antigen assay to detect DSA after transplantation. We compared the incidence of acute rejection, lymphocytic bronchiolitis, and bronchiolitis obliterans syndrome (BOS) between those who developed DSA and those who did not using Cox proportional hazards models. We used the Kaplan-Meier method to compare freedom from BOS and survival between those who had persistent DSA and those who had successful depletion of DSA.

Results: Among 116 recipients screened, DSA developed in 65 during the study period. Those who developed DSA and received antibody-directed therapy had a similar incidence of acute rejection, lymphocytic bronchiolitis, and BOS as those who did not develop DSA. Furthermore, recipients who had successful depletion of DSA had greater freedom from BOS and better survival than those who had persistent DSA. Finally, those treated for DSA had a similar incidence of infectious complications as those who did not develop DSA.

Conclusions: The development of DSA is surprisingly common after lung transplantation. Antibody-directed therapy may reduce the risk of rejection associated with DSA, but a randomized controlled trial is necessary to critically evaluate the efficacy of this treatment protocol.

Conflict of interest statement

DISCLOSURE STATEMENT

None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.

Copyright 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1
Figure 1
Distributions of mean fluorescence intensity (MFI) and ratio of donor-specific anti-HLA antibody (DSA) MFI to positive control MFI for recipients who developed DSA. Boxes extend from the 25th to the 75th percentiles and whiskers extend to the largest and smallest values within 1.5 box lengths. The line within the boxes represents the median. The solid circles represent outlier cases between 1.5 and 3 box lengths from the upper edge of the boxes.
Figure 2
Figure 2
Flowchart of the study, treatments, and possible outcomes.
Figure 3
Figure 3
Freedom from bronchiolitis obliterans syndrome (BOS). There was no significant difference in freedom from BOS between those who developed DSA and were treated with intravenous immune globulin (IVIG) and rituximab and those who were treated with IVIG alone (A). There was no significant difference in freedom from BOS between those who developed DSA to Class I, Class II, or both Class I and Class II antigens (B). Recipients who had persistent DSA were significantly more likely to develop BOS than those who cleared the DSA (C).
Figure 4
Figure 4
Survival. Recipients who developed DSA and were treated with IVIG alone had a significantly worse survival than those treated with IVIG and rituximab (A). There was no significant survival difference between those who developed DSA to Class I, Class II, or both Class I and Class II antigens (B). Recipients who had persistent DSA had a significantly worse survival than those who cleared the DSA (C).
Figure 5
Figure 5
Causes of death. BOS was the most frequent cause of death, followed by pneumonia.

References

    1. Christie JD, Edwards LB, Aurora P, et al. Registry of the International Society for Heart and Lung Transplantation: Twenty-fifth official adult lung and heart/lung transplantation report – 2008. J Heart Lung Transplant. 2008;27:957–969.
    1. Burton CM, Carlsen J, Mortensen J, Andersen CB, Milman N, Iversen M. Long-term survival after lung transplantation depends on development and severity of bronchiolitis obliterans syndrome. J Heart Lung Transplant. 2007;26:681–686.
    1. Lingaraju R, Pochettino A, Blumenthal NP, et al. Lung transplant outcomes in white and African American recipients: Special focus on acute and chronic rejection. J Heart Lung Transplant. 2009;28:8–13.
    1. Valentine VG, Robbins RC, Berry GJ, et al. Actuarial survival of heart-lung and bilateral sequential lung transplant recipients with obliterative bronchiolitis. J Heart Lung Transplant. 1996;15:371–383.
    1. Sundaresan S, Mohanakumar T, Smith MA, 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):648–653.
    1. Smith MA, Sundaresan S, Mohanakumar T, et al. Effect of development of antibodies to HLA and cytomegalovirus mismatch on lung transplantation survival and development of bronchiolitis obliterans syndrome. J Thorac Cardiovac Surg. 1998;116(5):812–820.
    1. Palmer SM, Davis RD, Hadjiliadis D, et al. Development of an antibody specific to major histocompatibility antigens detectable by flow cytometry after lung transplant is associated with bronchiolitis obliterans syndrome. Transplantation. 2002;74(6):799–804.
    1. 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;23:1135–1141.
    1. 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;5:131–138.
    1. Jaramillo A, Smith CR, Maruyama T, Zhang L, Patterson GA, Mohanakumar T. 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;64:521–529.
    1. Maruyama T, Jaramillo A, Narayanan K, Higuchi T, Mohanakumar T. Induction of obliterative airway disease by anti-HLA class I antibodies. Am J Transplant. 2005;5:2126–2134.
    1. Fukami N, Ramachandran S, Saini D, et al. Antibodies to MHC class I induce autoimmunity: role in the pathogenesis of chronic rejection. J Immunol. 2009;182:309–318.
    1. Morris GP, Phelan DL, Jendrisak MD, Mohanakumar T. Virtual crossmatch by identification of donor-specific anti-human leukocyte antigen antibodies by solid-phase immunoassay: a 30-month analysis in living donor kidney transplantation. Hum Immunol. 2010;71:268–273.
    1. Yousem SA, Berry GJ, Cagle PT, et al. Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group. J Heart Lung Transplant. 1996;15:1–15.
    1. Estenne M, Maurer JR, Boehler A, et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant. 2002;21:297–310.
    1. Tait BD, Hudson F, Cantwell L, et al. Review article: luminex technology for HLA antibody detection in organ transplantation. Nephrology. 2009;14:247–254.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever