Date: Tuesday, May 5, 2015
Session Time: 5:30pm-6:30pm
Presentation Time: 5:30pm-6:30pm
Location: Exhibit Hall E
Background CTLA4Ig (Belatacept) is a novel anti-rejection therapy aimed at costimulatory blockade. Clinical data suggest that post-transplant alloantibody formation is also reduced in patients treated with CTLA4Ig. However, the efficacy and mechanism(s) by which CTLA4Ig modulates T-dependent alloantibody responses are poorly understood. Here, we explored the effects of CTLA4Ig in a mouse model of allosensitization.
Methods C57BL/6 mice were sensitized with a HLA.A2+ skin allograft and treated with abatacept (500ug/dose by IP injection) at days 0, 2, 7, 14, 21 post-1st skin grafting (P1SG). To study the long-term impact of CTLA4Ig on recall antibody responses, mice receiving primary SG were re-immunized with a second HLA.A2+ skin graft at Day 90 P1SG. Donor-specific antibody (DSA) levels were measured in a flow-cytometric antibody binding assay.
Results Control mice developed peak levels of HLA.A2-specific IgM (35 +-7 MFI; mean fluorescence intensity) at day 14 PTx while the CTLA4Ig treated mice had low levels of DSA IgM (12.8+-0.5 MFI, p=0.007). Control mice developed HLA.A2-specific IgG antibodies, beginning at day 14 (582.09+-144.26 MFI) and reached peak levels at day 21 (714.9+-217.6 MFI). In contrast, mice in the treatment group had persistently low levels of HLA.A2 specific IgG at day 14 (11.77+-0.64 MFI, p=2.6E-10 ), day 21 (26.15+-16.39 MFI, p=9.2E-9) and day 28 (18.2+-9.7 MFI, p=2.44E-8), indicating a potent suppression of de novo IgG alloantibodies. Furthermore, recall DSA IgG responses to 2nd SG were significantly reduced in the mice receiving CTLA4Ig treatment during primary skin transplantation (216.3+-112.9 vs. control 473+-263.5 MFI, p<0.05).
Conclusion CTLA4Ig is a potent inhibitor of de novo alloantibody responses through blocking CD28-B7 costimulation to negate T-cell dependent B cell activation. CTLA4Ig, when administered during T cell priming with alloantigen could significantly reduce recall DSA antibody levels, suggesting a potential long term effect on HLA antibody formation.
To cite this abstract in AMA style:Wu G, Kim I, Chai N-N, Jordan S, Klein A. CTLA4Ig Administered During T-Cell Priming Negates de novo Alloantibody Responses and Modulates Recall Antibody Production [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/ctla4ig-administered-during-t-cell-priming-negates-de-novo-alloantibody-responses-and-modulates-recall-antibody-production/. Accessed May 6, 2021.
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