2013 - ISBTS 2013 Symposium
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Mini-Oral Communications 2
26.360 - A dose-dependent in vitro Inhibition of HLA Antibody Complement Activation by C1 Esterase Inhibitor (Berinert®) in sensitized small bowel transplant candidates
Presenter: Guilherme, Costa, , United States
Authors: Guilherme Costa1, John Lunz1, George Mazariegos1, Rakesh Sindhi1, Kyle Soltys1, Geoffrey Bond1, Hiroshi Sogawa1, Judith Vensak2, Mel Berger2, Adrianna Zeevi1
A dose-dependent in vitro Inhibition of HLA Antibody Complement Activation by C1 Esterase Inhibitor (Berinert®) in sensitized small bowel transplant candidates
Guilherme Costa1, John Lunz1, George Mazariegos1, Rakesh Sindhi1, Kyle Soltys1, Geoffrey Bond1, Hiroshi Sogawa1, Judith Vensak2, Mel Berger2, Adrianna Zeevi1
1Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States; 2CSL Behring, King of Prussia, PA, United States
Introduction:Complement activation due to donor-specific HLA antibody (DSA) is associated with allograft acute antibody (Ab) mediated rejection (AMR). New modalities to inhibit complement activation are currently under investigation for use in transplantation including Berinert®, a plasma-derived concentrate of C1 Esterase Inhibitor (C1-INH) (CSL Behring). The current standard of DSA monitoring uses Luminex single antigen beads (L-IgG) but does not determine complement activating status. A modified Luminex-based assay detecting C1q binding HLA Ab (L-C1q), defines complement activating HLA Ab, correlates with complement dependent crossmatch (CDC-XM) status and early AMR in solid allograft transplant recipients.
Aim:The objective of this study was to develop an assay to evaluate the in vitro inhibition of complement-binding HLA Ab by C1-INH in highly sensitized small bowelltransplant candidates.
Methods:We evaluated in vitro C1-INH inhibition of complement binding of HLA Ab in T and B-cell CDC-XM and L-C1q assays. CDC assay was performed with sera from sensitized small bowel (n=4) candidates in the presence or absence of C1H-INH at various concentrations (0.4U/ml to 0.025U/ml) using either a panel of T and B cells or HLA matched specific target cells. L-C1q assay was also performed with or without 0.4U/ml C1H-INH and inhibition was determined for each HLA specificity. As a control, Human α1-proteinase inhibitor (Zemaira®) was introduced in both assays to demonstrate C1-INH inhibition specificity.
Results: C1-INH inhibited T and B cell CDC-XM positivity in a dose dependent manner at concentrations of 0.4U/ml to 0.025U/ml. Similarly, in the L-C1q assay an 80%-100% reduction in the MFI of C1q-positive HLA Ab was seen. HLA Ab that were C1q positive at a high titer(>1:16) were less effected by C1-INH compared to lower titer Ab(<1:4). Reducing the HLA Ab titer by diluting the sera resulted in 100% inhibition of L-C1q assay. The addition of the control protein Zemaira® had no effect in CDC and L-C1q assays.
Conclusion: The in vitro efficacy of C1-INH to inhibit complement activating HLA Ab in both CDC and Luminex C1q assays was dependent on the level of C1q reactive IgG antibodies. These methods may potentially be able to define HLA Ab that would be susceptible to C1-INH therapy and increase the potential donor pool in sensitized small bowel candidates.
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