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
View: Text | PDF
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

×

Figure 2

STALs strongly inhibit BCR signaling and cause apoptosis.

Options: View larger image (or click on image) Download as PowerPoint
STALs strongly inhibit BCR signaling and cause apoptosis. (A) Calcium fl...
(A) Calcium flux in IgMHEL B cells stimulated with the indicated liposomes. (B) CD86 upregulation of IgMHEL B cells 24 hours after stimulation with the indicated liposomes. (C) In vitro proliferation of CTV-labeled IgMHEL B cells 3 days after simulation with the indicated liposomes. (D) Annexin V versus PI staining of IgMHEL B cells treated for 24 hours with the indicated liposomes. For quantification over time, the percentages of annexinV–PI– (live) cells are expressed relative to the controls treated with naked liposomes normalized to 100% at each time point and plotted as the mean ± SEM (n = 3). (E) In vivo proliferation of adoptively transferred CFSE-labeled IgMHEL B cells 4 days after immunization with the indicated liposomes. The same number of total splenocytes was analyzed for each condition (1 × 106) and gated through the IgMa+Ly5a+ population. (F) Analysis of the number of adoptively transferred Ly5a+IgMHEL B cells remaining in the spleen of recipient mice 12 days after immunization with the indicated liposomes. Quantitation represents mean ± SEM (n = 4). *P < 0.05.