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83 Detection of Class I Anti-HLA Antibodies by Luminex Pre-Transplant Predicts Poor Outcomes Following Lung Transplantation
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The Journal of Heart and Lung Transplantation, Vol 30, No 4S, April 2011
patients (n⫽28), there was a significant drop in Abs to Col-V (from 23/28 to 12/28) and K␣1T (from 25/28 to 14/28, p ⬍0.01). However, among DSA cleared BOS⫹ patients (n⫽10) there was minimal decline of autoAbs (anti-Col-V: from 10/10 to 7/10, and anti- K␣1T: from 10/10 to 8/10 p⫽ 0.21). Among those with persistent DSA (n⫽23) and BOS⫹ (n⫽14) the drop in auto-Abs following therapy was insignificant. Cytokine analysis on the therapy group demonstrated that among patients who cleared DSA and who were free from BOS had decreased levels of pro-inflammatory cytokines (namely IL-1 (3.2 fold decrease), IL-17 (3.0), IFN-␥ (2.3)) and a concomitant increase in anti-inflammatory cytokine IL-10 (3.7 fold increase, p⬍0.01 for all) within 6 months of administration of therapy. Conclusions: Our results demonstrate that antibody directed therapy results in decreased circulating levels of pro inflammatory cytokines and development of auto-Abs and increased freedom from BOS.
every 3 months for class I and II DSA with ELISA and Luminex-based assays in conjunction with surveillance and clinical bronchoscopies. The primary outcome was time from transplant to the development of BOS or death with a study endpoint of 9/1/2010. Associations were assessed with student t-tests and freedom from BOS and survival were assessed with Kaplan Meier estimates with log rank analysis. Results: A total of 343 patients were included with a mean follow-up time of 3.3 ⫾ 1.9 years. 51 (14.8%) patients developed DSA at a median time of 435 (IQR 697) days from transplantation. 41 (80.4%) patients with DSA developed BOS during the study period versus 79 (27.1%) of patients without DSA. The mean onset to BOS in patients with DSA was 787.5 (SD 390) days versus 978.3 (SD 532) days in those patients without DSA (p ⬍0.05). Patients with DSA also had a higher mortality than patients without DSA at study end (54.9% vs. 32.1%; p⫽0.004).
83 Detection of Class I Anti-HLA Antibodies by Luminex Pre-Transplant Predicts Poor Outcomes Following Lung Transplantation G.P. Westall,1 L. Mitchell,1 B. Levvey,1 F. Hudson,2 L. Cantwell,2 G. Snell.1 1Lung Transplant Unit, Alfred Hospital, Melbourne, VIC, Australia; 2Victorian Transplantation and Immunogenetics Service, Australian Red Cross Blood Service, Melbourne, VIC, Australia. Purpose: Solid phase assays detect anti-HLA antibodies with high accuracy and sensitivity, however debate continues on how these results should be interpreted in the setting of lung transplantation. Methods and Materials: We performed a retrospective analysis of pretransplant anti-HLA antibody levels detected using a solid-phase HLA microbead assay (Luminex) in 80 patients undergoing lung transplantation at a single centre between 1/1/09 and 1/5/10. All patients underwent prospective T- and B-cell crossmatches (complement-dependent cytotoxicity assays) prior to transplantation. Outcome variables analyzed included acute cellular and antibody-mediated rejection, BOS and survival. Results: Pre-transplant class I and class II anti-HLA antibodies were present in 31/80 (38%) and 13/80 (10%) patients, respectively, but did not predict a positive T- or B-cell crossmatch which was weekly positive in 1/80 and 14/80 patients, respectively. HLA class I and II donor-specific antibodies (DSA) were present pre-transplant in 13 and 7 patients, respectively. The presence pre-transplant of class I DSA, irrespective of a negative prospective T- and B-cell crossmatch predicted for a poor outcome (Odds ratio for BOS/death 4.6, p ⫽ 0.03). Pre-transplant DSA was not associated with the subsequent development of either acute cellular or antibody-mediated rejection. Only two patients developed clinically significant antibody-mediated rejection. Both developed DSA following transplant having not been present pre-transplant. Conclusions: Identifying DSA pre-transplant predicts poor outcomes posttransplant and provides prognostic information beyond that which has been historically provided by a negative prospective crossmatch. Future studies need to focus on defining the level of pre-transplant DSA as measured using solid phase assays that predict for adverse outcomes following lung transplantation. 84 The Impact of Donor Specific HLA Antibodies in Lung Transplantation after Induction with Alemtuzumab M.R. Morrell,1 K. Spichty,3 C.J. Gries,1 M.M. Crespo,1 B. Johnson,1 J.M. Pilewski,1 Y. Toyoda,2 C.A. Bermudez,2 J.K. Bhama,2 D. Zaldonis,2 A. Zeevi.3 1Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA; 2Division of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA; 3Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA. Purpose: Donor specific HLA antibodies (DSA) have been associated with poor outcomes after lung transplantation including bronchiolitis obliterans (BOS). We sought to evaluate the relationship between DSA, freedom from BOS and survival in a cohort of consecutive lung transplant recipients who received induction with alemtuzumab. Methods and Materials: A cross-sectional study of patients from 20032007 was performed. Per protocol, patients were screened at 2 weeks and
Conclusions: After induction with alemtuzumab, the incidence of DSA in lung transplant recipients is lower in comparison with previous reports. Patients with DSA are at a higher risk of early BOS and mortality. Further studies are needed to assess the significance of antibody-directed therapy to improve allograft function and overall survival. 85 Antibody-Mediated Rejection after Lung Transplantation R.R. Hachem,1 J.P. Ritter,2 R.D. Yusen,1 A.R. Wills,3 J.A. Iuppa,3 D. Byers,1 T. Mohanakumar,4 A. Patterson,5 E.P. Trulock.1 1Pulmonary & Critical Care, Washington University School of Medicine, St. Louis, MO; 2Pathology & Immunology, Washington University School of Medicine, St. Louis, MO; 3Pharmacy, Barnes-Jewish Hospital, St. Louis, MO; 4Surgery, Washington University School of Medicine, St. Louis, MO; 5Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, MO. Purpose: Antibody-mediated rejection (AMR) after lung transplantation (LTX) remains enigmatic and there is no consensus on the diagnostic features or management. In this study, we review a case series of AMR and propose a definition. Methods and Materials: We conducted a retrospective cohort study and used the following criteria proposed by the National Conference to Assess AMR in Solid Organ TX: DSA, C4d deposition, tissue pathology, and graft dysfunction to identify cases. We reviewed recipients’ records between 1/06 and 7/10 and identified 16 cases that fulfilled these criteria. Results: There were 8 men and 8 women; 5 had COPD, 5 had IPF, 4 had CF, 1 had sarcoid, and 1 had a re-TX for BOS. 5 were sensitized pre-TX but all 16 had a negative direct crossmatch. All were treated with ATG (n⫽7) or basiliximab (n⫽9) for induction and tacrolimus, azathioprine, and prednisone. Recipients developed AMR a mean 283 d after LTX and 11
The Journal of Heart and Lung Transplantation, Vol 30, No 4S, April 2011
patients (n⫽28), there was a significant drop in Abs to Col-V (from 23/28 to 12/28) and K␣1T (from 25/28 to 14/28, p ⬍0.01). However, among DSA cleared BOS⫹ patients (n⫽10) there was minimal decline of autoAbs (anti-Col-V: from 10/10 to 7/10, and anti- K␣1T: from 10/10 to 8/10 p⫽ 0.21). Among those with persistent DSA (n⫽23) and BOS⫹ (n⫽14) the drop in auto-Abs following therapy was insignificant. Cytokine analysis on the therapy group demonstrated that among patients who cleared DSA and who were free from BOS had decreased levels of pro-inflammatory cytokines (namely IL-1 (3.2 fold decrease), IL-17 (3.0), IFN-␥ (2.3)) and a concomitant increase in anti-inflammatory cytokine IL-10 (3.7 fold increase, p⬍0.01 for all) within 6 months of administration of therapy. Conclusions: Our results demonstrate that antibody directed therapy results in decreased circulating levels of pro inflammatory cytokines and development of auto-Abs and increased freedom from BOS.
every 3 months for class I and II DSA with ELISA and Luminex-based assays in conjunction with surveillance and clinical bronchoscopies. The primary outcome was time from transplant to the development of BOS or death with a study endpoint of 9/1/2010. Associations were assessed with student t-tests and freedom from BOS and survival were assessed with Kaplan Meier estimates with log rank analysis. Results: A total of 343 patients were included with a mean follow-up time of 3.3 ⫾ 1.9 years. 51 (14.8%) patients developed DSA at a median time of 435 (IQR 697) days from transplantation. 41 (80.4%) patients with DSA developed BOS during the study period versus 79 (27.1%) of patients without DSA. The mean onset to BOS in patients with DSA was 787.5 (SD 390) days versus 978.3 (SD 532) days in those patients without DSA (p ⬍0.05). Patients with DSA also had a higher mortality than patients without DSA at study end (54.9% vs. 32.1%; p⫽0.004).
83 Detection of Class I Anti-HLA Antibodies by Luminex Pre-Transplant Predicts Poor Outcomes Following Lung Transplantation G.P. Westall,1 L. Mitchell,1 B. Levvey,1 F. Hudson,2 L. Cantwell,2 G. Snell.1 1Lung Transplant Unit, Alfred Hospital, Melbourne, VIC, Australia; 2Victorian Transplantation and Immunogenetics Service, Australian Red Cross Blood Service, Melbourne, VIC, Australia. Purpose: Solid phase assays detect anti-HLA antibodies with high accuracy and sensitivity, however debate continues on how these results should be interpreted in the setting of lung transplantation. Methods and Materials: We performed a retrospective analysis of pretransplant anti-HLA antibody levels detected using a solid-phase HLA microbead assay (Luminex) in 80 patients undergoing lung transplantation at a single centre between 1/1/09 and 1/5/10. All patients underwent prospective T- and B-cell crossmatches (complement-dependent cytotoxicity assays) prior to transplantation. Outcome variables analyzed included acute cellular and antibody-mediated rejection, BOS and survival. Results: Pre-transplant class I and class II anti-HLA antibodies were present in 31/80 (38%) and 13/80 (10%) patients, respectively, but did not predict a positive T- or B-cell crossmatch which was weekly positive in 1/80 and 14/80 patients, respectively. HLA class I and II donor-specific antibodies (DSA) were present pre-transplant in 13 and 7 patients, respectively. The presence pre-transplant of class I DSA, irrespective of a negative prospective T- and B-cell crossmatch predicted for a poor outcome (Odds ratio for BOS/death 4.6, p ⫽ 0.03). Pre-transplant DSA was not associated with the subsequent development of either acute cellular or antibody-mediated rejection. Only two patients developed clinically significant antibody-mediated rejection. Both developed DSA following transplant having not been present pre-transplant. Conclusions: Identifying DSA pre-transplant predicts poor outcomes posttransplant and provides prognostic information beyond that which has been historically provided by a negative prospective crossmatch. Future studies need to focus on defining the level of pre-transplant DSA as measured using solid phase assays that predict for adverse outcomes following lung transplantation. 84 The Impact of Donor Specific HLA Antibodies in Lung Transplantation after Induction with Alemtuzumab M.R. Morrell,1 K. Spichty,3 C.J. Gries,1 M.M. Crespo,1 B. Johnson,1 J.M. Pilewski,1 Y. Toyoda,2 C.A. Bermudez,2 J.K. Bhama,2 D. Zaldonis,2 A. Zeevi.3 1Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA; 2Division of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA; 3Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA. Purpose: Donor specific HLA antibodies (DSA) have been associated with poor outcomes after lung transplantation including bronchiolitis obliterans (BOS). We sought to evaluate the relationship between DSA, freedom from BOS and survival in a cohort of consecutive lung transplant recipients who received induction with alemtuzumab. Methods and Materials: A cross-sectional study of patients from 20032007 was performed. Per protocol, patients were screened at 2 weeks and
Conclusions: After induction with alemtuzumab, the incidence of DSA in lung transplant recipients is lower in comparison with previous reports. Patients with DSA are at a higher risk of early BOS and mortality. Further studies are needed to assess the significance of antibody-directed therapy to improve allograft function and overall survival. 85 Antibody-Mediated Rejection after Lung Transplantation R.R. Hachem,1 J.P. Ritter,2 R.D. Yusen,1 A.R. Wills,3 J.A. Iuppa,3 D. Byers,1 T. Mohanakumar,4 A. Patterson,5 E.P. Trulock.1 1Pulmonary & Critical Care, Washington University School of Medicine, St. Louis, MO; 2Pathology & Immunology, Washington University School of Medicine, St. Louis, MO; 3Pharmacy, Barnes-Jewish Hospital, St. Louis, MO; 4Surgery, Washington University School of Medicine, St. Louis, MO; 5Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, MO. Purpose: Antibody-mediated rejection (AMR) after lung transplantation (LTX) remains enigmatic and there is no consensus on the diagnostic features or management. In this study, we review a case series of AMR and propose a definition. Methods and Materials: We conducted a retrospective cohort study and used the following criteria proposed by the National Conference to Assess AMR in Solid Organ TX: DSA, C4d deposition, tissue pathology, and graft dysfunction to identify cases. We reviewed recipients’ records between 1/06 and 7/10 and identified 16 cases that fulfilled these criteria. Results: There were 8 men and 8 women; 5 had COPD, 5 had IPF, 4 had CF, 1 had sarcoid, and 1 had a re-TX for BOS. 5 were sensitized pre-TX but all 16 had a negative direct crossmatch. All were treated with ATG (n⫽7) or basiliximab (n⫽9) for induction and tacrolimus, azathioprine, and prednisone. Recipients developed AMR a mean 283 d after LTX and 11