Tolerogenic Nanoparticles Impacting B and T Lymphocyte Responses Delay Autoimmune Arthritis in K/BxN Mice

Abstract

Current treatments for unwanted antibody responses largely rely on immunosuppressive drugs compromising overall immunity. New approaches to achieve antigen-specific tolerance are desirable to avoid unwanted side effects. Several nanoparticle-based approaches that utilize different mechanisms to tolerize the B or T cell arms of the humoral immune response have shown promise for induction of antigen-specific tolerance, raising the possibility that they could work synergistically if combined. Earlier we showed that Siglec-engaging tolerance-inducing antigenic liposomes (STALs) that display both an antigen (Ag) and glycan ligands of the inhibitory co-receptor CD22 (CD22L) lead to robust antigen-specific B cell tolerance to protein antigens in naive mice. In another approach, administration of free Ag with poly­(lactic-co-glycolic acid)–rapamycin nanoparticles (PLGA-R) induced robust antigen-specific tolerance through production of regulatory T cells. Here we illustrate that coadministration of STALs together with PLGA-R to naive mice induced more robust tolerance to multiple antigen challenges than either nanoparticle alone. Moreover, in K/BxN mice that develop spontaneous autoimmune arthritis to the self-antigen glucose-6-phosphate-isomerase (GPI), co-delivery of GPI-LP-CD22L and PLGA-R delayed onset of disease and in some mice prevented the disease indefinitely. The results show synergy between B cell-tolerizing STALs and T cell-tolerizing PLGA-R and the potential to induce tolerance in early stage autoimmune disease.

Suppressing Immune Responses Using Siglec Ligand-Decorated Anti-receptor Antibodies

“…Because Siglecs are primarily expressed on immune cells, they are recognized as attractive targets for cell-specific therapies that can enhance desired immune responses or suppress unwanted immune responses. − As one strategy to suppress unwanted immune responses by B cells and mast cells, we developed Siglec tolerizing antigenic liposomes (STALs) that display both an antigen (or allergen) and glycan ligands of inhibitory Siglecs. For B cells, the antigen is recognized by a B-cell receptor (BCR) comprising membrane-bound IgM and/or IgD and a high affinity ligand of a B-cell Siglec (CD22 or Siglec-G/10). ,− When administered in vivo, STALs suppress activation of B cells that recognize the antigen and cause apoptosis of the B cells, resulting in tolerance to subsequent antigen challenge.…”

“…Because Siglecs are primarily expressed on immune cells, they are recognized as attractive targets for cell-specific therapies that can enhance desired immune responses or suppress unwanted immune responses. − As one strategy to suppress unwanted immune responses by B cells and mast cells, we developed Siglec tolerizing antigenic liposomes (STALs) that display both an antigen (or allergen) and glycan ligands of inhibitory Siglecs. For B cells, the antigen is recognized by a B-cell receptor (BCR) comprising membrane-bound IgM and/or IgD and a high affinity ligand of a B-cell Siglec (CD22 or Siglec-G/10). ,− When administered in vivo, STALs suppress activation of B cells that recognize the antigen and cause apoptosis of the B cells, resulting in tolerance to subsequent antigen challenge. For mast cells, the STALs display an allergen, recognized by an IgE bound to the FcεRI receptor, and a high-affinity ligand of a mast cell inhibitory Siglec such as CD33/Siglec-3 or Siglec-8. , When injected into a mouse sensitized to an anti-allergen IgE, mast cell degranulation mediated by the allergen is suppressed by recruitment of the Siglec, preventing severe systemic anaphylaxis and desensitizing the animal to subsequent allergen challenge. , …”

Suppression of Autoimmune Rheumatoid Arthritis with Hybrid Nanoparticles That Induce B and T Cell Tolerance to Self-Antigen

“…While the K/BxN mice are genetically programed to develop anti-GPI antibodies, in the studies reported here, CD22L-NP­(R)-GPI was administered prior to the onset of disease, as defined by joint swelling. However, we have previously shown that by using a two NP strategy combining CD22L liposomes (GPI-STALs) targeting B cells with PLGA (RAPA), the administration to K/BxN mice after disease onset could delay and in a few cases reverse disease progression, demonstrating the potential for studying treatment in a setting of ongoing disease . Future studies will be aimed at evaluation of this hybrid NP approach to suppress ongoing autoimmune responses.…”

“…More recently, while investigating treatment of the K/BxN model of rheumatoid arthritis caused by reaction to the autoantigen glucose-6-phospate isomerase (GPI), Srivastava et al combined PLGA-RAPA NPs with Siglec-tolerizing antigenic liposomes (STALs). STALs had been previously developed to induce antigen-specific tolerance in B cells through a surface display of both the antigen and a glycan ligand for the inhibitory co-receptor CD22/Siglec-2 (CD22L) on liposomal nanoparticles (LPs).…”

“…When a B cell that recognizes the antigen is contacted by STALs, CD22 is recruited to the immunological synapse to suppress activation and ultimately causes apoptosis, removing it from the B cell repertoire. It was found that a combination of antigenic liposomal STALs (antigen-LP-CD22L) and rapamycin-loaded PLGA NPs (PLGA-RAPA) exhibited improved immune tolerance over either particle alone . When this combination was used in the K/BxN arthritis mouse model, treatment with GPI-LP-CD22L and PLGA-RAPA delayed the progression of disease.…”