Session Time: 4:00pm-5:30pm
Presentation Time: 5:00pm-5:12pm
Location: Room 118-C
Background: CTLA4Ig is an agonist that blocks CD28-B7 costimulation, downregulating T cell immunity, but also appears to negate T cell-dependent B cell activation, thus inhibiting humoral immunity. Previously, we reported that CTLA4Ig inhibits de novo alloantibody response, and we now report that CTLA4Ig can also attenuate recall alloantibody responses. The acting mechanism(s), however, is poorly understood.
Methods: In vivo studies were conducted in a mouse model of HLA.A2 sensitization, in which C57BL/6 mice pre-sensitized with HLA.A2+ skin allografts (SG) were re-immunized with a second HLA.A2+ SG at day 90 Ptx. CTLA4Ig was given to the recipients at days 0, 2, 7 and 14 post-2nd SG. In vitro studies were performed in a culture model utilizing an anti-HLA.A2 IgG1-sereting mouse hybridoma line (PA2.1) to investigate the effects of CTLA4Ig on expression of plasma cell markers, cell growth, and antibody production.
Results: CTLA4Ig treated mice in recall responses to 2nd SG had significantly lower levels of DSA IgG (n=7, MFI: 312.6+-184 at day 14; 331.7+-176.5 at day 21) than that of controls (n=8, MFI: 501.2+-165.9 at day 14, p=0.04; 739.7+-212.5 at day 21, p=0.012). In vitro studies showed that hybridoma PA2.1 cells express surface markers consistent with that of plasma cells, including CD38+, CD138+++, CD28+- CD80+ (B7-1), CD274+ (PDL-1) and CD279+ (PD-1). CD80 expression by PA2.1 cells increases with LPS stimulation and decreases with CTLA4Ig blockage. Cell proliferation experiments showed that CTLA4Ig arrests PA2.1 cell growth in a dose-dependent manner (P<0.01). ELISpot assays demonstrated a decreased in IgG spots in the PA2.1 cells treated with CTLA4Ig in cultures.
Conclusion: B7-1 (CD80) expression by antibody forming cells can be blocked by CTLA4Ig, indicating direct inhibition of CTLA4Ig on CD80 expressed by plasma cells. Furthermore, treatment of PA2.1 cells with CTLA4Ig arrested cell growth and reduced IgG production shown in ELISpots, suggesting that binding of CTLA4Ig to CD80 on antibody-forming cells can exert a negative effect on antibody responses.
To cite this abstract in AMA style:Kim I, Wu G, Chai N-N, Jordan S, Klein A. In Vitro Evidence That CTLA4Ig Attenuates Recall Alloantibody Responses [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/in-vitro-evidence-that-ctla4ig-attenuates-recall-alloantibody-responses/. Accessed April 21, 2019.
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