Judy Hopfield

Protective immunity remains intact after antibody removal by means of proteasome inhibition.

Background. Proteasome inhibition abrogates donor-specific anti-human leukocyte antigen (HLA) antibody (DSA) in patients posttransplant. However, its effects on protective humoral immunity to vaccine antigens remain unknown. Herein, we report on bortezomibs safety regarding protective immunity in patients who have experienced HLA antibody reduction/removal. Methods. Thirteen living donor renal transplant patients were treated with bortezomib one to two cycles (1.3 mg/m2×4 doses) and plasmapheresis in 2008 to remove HLA antibodies posttransplant. Serial measurements of HLA antibody were conducted weekly before, during, and after treatment by means of single antigen bead on Luminex (One Lambda Inc., Canoga Park, CA). Measles and tetanus toxoid IgGs were measured quantitatively by using ELISA (American Research Products Inc., Belmont, MA). Results. All patients treated with bortezomib/plasmapheresis resulted in a primary DSA reduction of more than 50%. In 10 of 13 patients, complete DSA removal (to below 1000 mean fluorescent intensity) occurred. At 1 year posttreatment, antibody intensity remains significantly depressed in the group as a whole. Despite the significant effect on antibody production, tetanus toxoid and measles IgG levels remained unchanged and above the level of protection at 1 year posttreatment. Conclusion. These data indicate that proteasome inhibitors plus plasmapheresis results in prolonged reduction of HLA antibodies while leaving protective immunity intact.

Higher Risk of Kidney Graft Failure in Patients with Rejection Episodes in the Presence of Anti-Angiotensin II Type 1 Receptor Antibodies: 2168

Rejection Episodes in the Presence of AntiAngiotensin II Type 1 Receptor Antibodies Taniguchi M., Rebellato L.M., Catrou P.G., Briley K.P., Hopfield J., Terasaki P.I. One Lambda, Inc., Los Angeles, United States, East Carolina University, Brody School of Medicine, Greenville, United States, Terasaki Foundation Laboratory, Los Angeles, United States Purpose: Anti-Angiotensin II Type 1 Receptor (AT1R) antibodies have been shown in patients with acute rejection of kidney and chronic rejection of heart transplants. In this study, we sought to determine if AT1R antibodies are associated with graft failure. Methods: The study subjects were 132 kidney transplant recipients (transplanted between 1999 and 2007) having biopsy-proven rejection episodes. Sera from these patients collected during rejection episodes were tested for the presence of both anti-AT1R and HLA antibodies. The detection of AT1R antibodies was done using ELISA (cell based), and the detection of HLA antibodies with LABScreen Single Antigen. The anti-AT1R level was categorized into three: high (>16.5 IU/ml), moderate (16.5 9.5 IU/ml), and low (< 9.5 IU/ml). Results: The high and moderate AT1R antibody levels were observed in 24% (32/132) of the patients with rejection episodes (12% high and 12% moderate). Co-occurrence of positive HLA antibodies was 78%. In the patients with high anti-AT1R, (i) biopsy-proven chronic rejection was more prevalent than biopsy-proven acute rejection (50% vs. 31%); (ii) co-occurrence of HLA-donor specific antibodies (DSA) was higher than the patients with low anti-AT1R (50% vs. 33%). The graft survival of the patients with high anti-AT1R was the worst compared with the patients with moderate and low anti-AT1R (Log-rank P=0.007, Figure 1). Moreover, the lowest survival was observed with high anti-AT1R alone, followed by concurrence of high anti-AT1R and HLA-DSA, HLA-DSA alone and absence of both antibodies (P=0.005, Figure 2)

PROTECTIVE IMMUNITY REMAINS INTACT FOLLOWING ANTIBODY REMOVAL VIA PROTEASOME INHIBITION: 803

M.J. Everly1, P.I. Terasaki2, H.L. Trivedi3, J. Hopfield4, H. Kaneku5 1, One Lambda Inc, Canoga Park/CA/UNITED STATES OF AMERICA, 2, Terasaki Foundation Laboratory, Los Angeles/UNITED STATES OF AMERICA, 3Institute Of Transplantation Sciences, Institute of Kidney Disease and Research Centre, Ahmedabad/INDIA, 4Research Ii, One Lambda Inc, Canoga Park/UNITED STATES OF AMERICA, 5, Terasaki Foundation Laboratory, Los Angeles/California/UNITED STATES OF AMERICA