The impact of HLA antibodies in Lung Transplantation Adriana Zeevi PhD University of Pittsburgh Thomas E Starzl Transplantation Institute
Introduction • The negative impact of donor-specific HLA antibodies (DSA) in renal and heart transplantation is well documented in large multi-center studies. • Circulating DSA post lung transplantation has been linked to: • a) persistent and high grade cellular rejection • b) the development of bronchiolitisobliterans (BOS) • The role of antibody mediated rejection (AMR) and its morphologic manifestation in the lung is still controversial because of non-alloreactive factors that may contribute to the lung injury.
14th International HLA and Immunogenetics Workshop: Report on the prospective chronic rejection project (Ozawa et al Tissue Antigens 2007) Frequency of human leukocyte antigen antibodies post-transplant by organ, n = 5219.
14th International HLA and Immunogenetics Workshop: Report on the prospective chronic rejection project (Ozawa et al Tissue Antigens 2007) LUNG TRANSPLANT SUMMARY • One year after testing, 48% graft loss was reported among the 13 LTx patients with HLA antibodies, while only 17.6% had graft loss in 34 LTx patients who had no antibodies, and this was highly significant despite the small numbers (P = 0.00008). • Patients with HLA Class II antibodies had marginally higher graft failure rate than ones who had only Class I antibodies, but the highest fail rate was seen in patients with both Class I and Class II antibodies.
Lung transplant recipients with DSA are at higher risk of graft loss than patients without DSA • 445 LTx • Follow-up 3.3+1.9y • 14.8% had DSA • 41/58 with DSA Developed BOS Morrell, Pilewski, Zeevi 2011 ISHLT
Implications for Human Leukocyte AntigenAntibodies After Lung TransplantationA 10-Year Experience in 441 Patients • HLA antibodies after lung transplant are associated with • increased risk for BOS and worse survival, • DSA is associated with worse survival. • HLA antibodies appear to be an integral part of the immune response to the allograft both preceding graft dysfunction and after allograft dysfunction. • A key question to address in further analysis is if the decrease or elimination of these antibodies correlates with improved outcomes Laurie D Snyder et al Chest 2013: 144(1) 226-233
Anti-human leukocyte antigen antibodies and preemptive antibody-directed therapy after lung transplantation BOS was more likely to develop in recipients who had persistent DSA than in those who cleared the DSA. Ramsey R. Hachem, MD, et al J Heart Lung Transplant 2010;29:973–80
HLA Antibody Determination Luminex SAB Titer HLA-Ab Complement Binding IgG Subtypes Sensitizing Events
Risk Assessment for AMR Luminex Single Antigen Bead Luminex C1q Test Sensitivity and Specificity AMR STRENGTH MFI Complement Binding Graft Dysfunction
Correlation C1q+DSA with C4d deposition in LTx patient during AMR During ACR (early) DSA Class I +, C1q- Native Lung ACR/AMR DSA Class I+II C1q + Quiescence 2y Dr. Sam Yousem
Post LTx de-novo DSA is 72% DQ-specific (DQB, DQA and DQB/DQA pairs) Donor-Specific Class II HLA-DQ Complement Binding Antibody is Associated with Severe Rejection in Lung Transplantation * IST- Immunosuppression Treatment Zeevi et al ISHLT 2013
Correlation between DSA patterns pre- and post- treatment for AMR: Loss of L-C1q DSA was associated with response to treatment while L-IgG DSA remained strong Severe ACR/AMR MFI DSA DQA1*03 L-IgG Months Post LTx Ritux PP/IVIG Campath
What is the future for AMR diagnosis in Lung Transplantation • A better understanding of the role of DSA in lung transplantation will likely be gained by using the more sensitive, functional assays with results correlated to the pathology and clinical graft function. • A multi-disciplinary approach to develop criteria for lung transplant AMR diagnosis has been initiated at the Banff meeting in Brazil 2013. • In the next ISHLT meeting (San Diego, April 2014) an AMR working group consisting of surgeons, pulmonologists, pathologists and immunologists will meet to summarize the current literature and provide updated guidelines.