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Characteristics of donor-specific anti-HLA antibodies in renal transplant recipients
Abstracts / Human Immunology 76 (2015) 38–167
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CHARACTERISTICS OF DONOR-SPECIFIC ANTI-HLA ANTIBODIES IN RENAL TRANSPLANT RECIPIENTS. Salim Ghandorah a, Serdar Yilmaz a, Abdulnaser Abadi a, Taleb Rahmanian b, Jinguo Wang b, Faisal M. Khan a,b, Noureddine Berka a,b. a University of Calgary, Calgary, AB, Canada; b Calgary Laboratory Services, Calgary, AB, Canada. Introduction: Antibody-mediated rejection (AMR) is the major complication of renal transplantation that significantly affects the renal allograft survival. Complement fixation mediated through donor specific anti-Human Leukocyte Antigen (HLA) antibodies (DSA) is the hallmark of AMR. Different methods have been developed to detect harmful DSAs. However, not all DSAs have the same detrimental effect, as different antibody characteristics might trigger distinct immune responses. Aim: In the present study, we assessed various biological (timing of appearance, strength and specificity) and functional (IgG subtype and c1q binding ability) characteristics of DSA in renal transplant patients. Methods: A total of 315 kidney transplant recipients were accrued for this study and 39 patients with de novo DSA were retrospectively analysed for different DSA characteristics. The analyses were carried out using commercially available SAB assay for IgG determination, C1q assay for complement binding capability and modified SAB assay for IgG subclass determination (One Lambda) Results: Important findings of the study were: (1) majority of the DSAs were denovo antibodies (p = 0.0001); primarily against HLA class II antigen (p = 0.0005); and typically developed after one year posttransplant (p = 0.0001). (2) DSA with highest strength were routinely observed against DQB antigens in comparison to other HLA class I and II antigens (p = 0.006). (3) IgG1 was the predominant IgG subclass (49.4%), followed by IgG3 (24.7%), IgG2 (16%), and IgG4 (9.9%). (4) DSA MFI and the IgG1 subclass were strongly correlated with C1q positivity (p = 0.01 and p = 0.009, respectively). Conclusion: Among the functional characteristics, higher MFI of DSA and IgG1 subclass were strongly correlated with C1q positivity. Among the biological characteristics, the majority of DSAs were against HLA class II antigens and developed frequently after one-year post transplantation. Further studies are needed to investigate the clinical relevance of these biological and functional DSA characteristics in predicting renal allograft outcomes.
P175
MYSTERY SENSITIZATION: WHAT HAPPENED IN THE HOSPITAL???. Kelley M. Haarberg, Nancy D. Herrera, Yelena Barabanova, Matthew F. Cusick, Ashley Ruiz, Robert Gordon, Anat R. Tambur. Northwestern University, Chicago, IL, United States. The 26 y/o female, with history of double heart valve replacement, should have had an uneventful heart transplant (txp). The patient (pt) was 0% HLA-Class I, only 12% sensitized to HLA-Class II, and the virtual crossmatch against her donor was negative. Our mystery case, however, had just begun. During the txp, testing of the immediate pre-txp sample revealed the pt was 100% sensitized to HLA-Class I and 24% to Class II, flow crossmatch (FCXM) on the same sample showed strong T and B cell channel shifts, HLA-DSA titered as high as 1:512 and were strongly C1q-binding. This was a surprising increase from results collected one month prior to txp. The clinical txp team was alerted, and while the pt was fine at that time, within 5 h of txp cardiogenic shock and rejection began. Early detection of sensitization allowed the txp team to arrange for plasmapheresis (PP), Thymoglobulin and Eculizumab before the pt crashed. How had the pt become so sensitized? Was there a sample switch? Re-typing of all samples for HLA antigens confirmed they belonged to the pt. Was the patient sensitized between the time of her first sample drawn one month prior to txp and the time of txp? As an inpatient for 3 weeks prior to txp, the clinical team was able to report she had not incurred any sensitizing events. Protocol fresh frozen plasma and Hepatitis B vaccine were given. FCXM on the 1 month pre-txp sample was negative, correlating with the original virtual. DSAs responded quickly to Eculizumab, Bortezomib and PP. Within 4 days post-txp, DSA titers had fallen to 1:8, and a 1 week post-txp right atrium biopsy was C4d negative. This was the most rapid response to therapy we had ever seen, and we speculate that the hyperacute immune response and quick therapy, including PP and complement inhibitors, precluded a mature complement response and C4d deposition. As of 4 months post-txp, DSA titers were maintained below 1:4 on Tacrolimus, Cellcept and Prednisone, and the pt entered cardio rehabilitation. While likely an anamnestic response pointing to a gap in HLA-specificity data collection, perhaps immunization could have served as a sensitizing event in this case. This case highlights the need for close monitoring for HLA-sensitization and antibody specificity changes following hospitalization and vaccination.
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P174
CHARACTERISTICS OF DONOR-SPECIFIC ANTI-HLA ANTIBODIES IN RENAL TRANSPLANT RECIPIENTS. Salim Ghandorah a, Serdar Yilmaz a, Abdulnaser Abadi a, Taleb Rahmanian b, Jinguo Wang b, Faisal M. Khan a,b, Noureddine Berka a,b. a University of Calgary, Calgary, AB, Canada; b Calgary Laboratory Services, Calgary, AB, Canada. Introduction: Antibody-mediated rejection (AMR) is the major complication of renal transplantation that significantly affects the renal allograft survival. Complement fixation mediated through donor specific anti-Human Leukocyte Antigen (HLA) antibodies (DSA) is the hallmark of AMR. Different methods have been developed to detect harmful DSAs. However, not all DSAs have the same detrimental effect, as different antibody characteristics might trigger distinct immune responses. Aim: In the present study, we assessed various biological (timing of appearance, strength and specificity) and functional (IgG subtype and c1q binding ability) characteristics of DSA in renal transplant patients. Methods: A total of 315 kidney transplant recipients were accrued for this study and 39 patients with de novo DSA were retrospectively analysed for different DSA characteristics. The analyses were carried out using commercially available SAB assay for IgG determination, C1q assay for complement binding capability and modified SAB assay for IgG subclass determination (One Lambda) Results: Important findings of the study were: (1) majority of the DSAs were denovo antibodies (p = 0.0001); primarily against HLA class II antigen (p = 0.0005); and typically developed after one year posttransplant (p = 0.0001). (2) DSA with highest strength were routinely observed against DQB antigens in comparison to other HLA class I and II antigens (p = 0.006). (3) IgG1 was the predominant IgG subclass (49.4%), followed by IgG3 (24.7%), IgG2 (16%), and IgG4 (9.9%). (4) DSA MFI and the IgG1 subclass were strongly correlated with C1q positivity (p = 0.01 and p = 0.009, respectively). Conclusion: Among the functional characteristics, higher MFI of DSA and IgG1 subclass were strongly correlated with C1q positivity. Among the biological characteristics, the majority of DSAs were against HLA class II antigens and developed frequently after one-year post transplantation. Further studies are needed to investigate the clinical relevance of these biological and functional DSA characteristics in predicting renal allograft outcomes.
P175
MYSTERY SENSITIZATION: WHAT HAPPENED IN THE HOSPITAL???. Kelley M. Haarberg, Nancy D. Herrera, Yelena Barabanova, Matthew F. Cusick, Ashley Ruiz, Robert Gordon, Anat R. Tambur. Northwestern University, Chicago, IL, United States. The 26 y/o female, with history of double heart valve replacement, should have had an uneventful heart transplant (txp). The patient (pt) was 0% HLA-Class I, only 12% sensitized to HLA-Class II, and the virtual crossmatch against her donor was negative. Our mystery case, however, had just begun. During the txp, testing of the immediate pre-txp sample revealed the pt was 100% sensitized to HLA-Class I and 24% to Class II, flow crossmatch (FCXM) on the same sample showed strong T and B cell channel shifts, HLA-DSA titered as high as 1:512 and were strongly C1q-binding. This was a surprising increase from results collected one month prior to txp. The clinical txp team was alerted, and while the pt was fine at that time, within 5 h of txp cardiogenic shock and rejection began. Early detection of sensitization allowed the txp team to arrange for plasmapheresis (PP), Thymoglobulin and Eculizumab before the pt crashed. How had the pt become so sensitized? Was there a sample switch? Re-typing of all samples for HLA antigens confirmed they belonged to the pt. Was the patient sensitized between the time of her first sample drawn one month prior to txp and the time of txp? As an inpatient for 3 weeks prior to txp, the clinical team was able to report she had not incurred any sensitizing events. Protocol fresh frozen plasma and Hepatitis B vaccine were given. FCXM on the 1 month pre-txp sample was negative, correlating with the original virtual. DSAs responded quickly to Eculizumab, Bortezomib and PP. Within 4 days post-txp, DSA titers had fallen to 1:8, and a 1 week post-txp right atrium biopsy was C4d negative. This was the most rapid response to therapy we had ever seen, and we speculate that the hyperacute immune response and quick therapy, including PP and complement inhibitors, precluded a mature complement response and C4d deposition. As of 4 months post-txp, DSA titers were maintained below 1:4 on Tacrolimus, Cellcept and Prednisone, and the pt entered cardio rehabilitation. While likely an anamnestic response pointing to a gap in HLA-specificity data collection, perhaps immunization could have served as a sensitizing event in this case. This case highlights the need for close monitoring for HLA-sensitization and antibody specificity changes following hospitalization and vaccination.
163