Antigenic liposomes displaying CD22 ligands induce antigen-specific B cell apoptosis
Matthew S. Macauley, Fabian Pfrengle, Christoph Rademacher, Corwin M. Nycholat, Andrew J. Gale, Annette von Drygalski, James C. Paulson
Matthew S. Macauley, Fabian Pfrengle, Christoph Rademacher, Corwin M. Nycholat, Andrew J. Gale, Annette von Drygalski, James C. Paulson
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Research Article

Antigenic liposomes displaying CD22 ligands induce antigen-specific B cell apoptosis

Abstract

Antibodies confer humoral immunity but can also be harmful when they target an autoantigen, alloantigen, allergen, or biotherapeutic. New strategies are needed for antigen-specific suppression of undesired antibody responses, particularly to T cell–dependent protein antigens, because they elicit T cell help. Here we show that liposomal nanoparticles, displaying both antigen and glycan ligands of the inhibitory coreceptor CD22, induce a tolerogenic program that selectively causes apoptosis in mouse and human B cells. These SIGLEC-engaging tolerance-inducing antigenic liposomes (STALs, where SIGLEC is defined as sialic acid–binding Ig-like lectin) induced robust antigen-specific tolerance to protein antigens in mice, preventing subsequent immune response to challenge with the same antigen. Since development of inhibitory antibodies to FVIII is a serious problem in treatment of hemophilia A patients, we investigated the potential of this approach for inducing tolerance to FVIII in a hemophilia mouse model. STALs prevented formation of inhibitory FVIII antibodies, allowing for effective administration of FVIII to hemophilia mice to prevent bleeding. These findings suggest that STALs could be used to eliminate or prevent harmful B cell–mediated immune responses.

Authors

Matthew S. Macauley, Fabian Pfrengle, Christoph Rademacher, Corwin M. Nycholat, Andrew J. Gale, Annette von Drygalski, James C. Paulson

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Figure 5

Immune tolerization to FVIII prevents bleeding in FVIII-deficient mice.

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Immune tolerization to FVIII prevents bleeding in FVIII-deficient mice. ...
(A) WT or FVIII-deficient mice were dosed on days 0 and 15 with immunogenic liposomes (Immunogen), STALs, or left untreated. On day 30, mice were reconstituted with rhFVIII at 50 U/kg or saline. FVIII-deficient mice treated with STALs had significantly less blood loss (μl/g) over 20 minutes following tail clip than mice initially treated with immunogenic liposomes. Percentage of bleeding protection (dashed line) represents blood loss of less than 9.9 μl/g as defined by mean + 3 SDs in WT BALB/c mice. (B) FVIII titers in the 3 reconstituted groups demonstrate that bleeding prevention is accompanied by a significant reduction in anti-FVIII antibodies. Data represent mean ± SEM. A 2-tailed Student’s t test was used to establish the level of significance. NS is defined by a P value greater than 0.05.