Tolerance induction using nanoparticles bearing HY peptides in bone marrow transplantation

Abstract

Allogeneic cell therapies have either proven effective or have great potential in numerous applications, though the required systemic, life-long immunosuppression presents significant health risks. Inducing tolerance to allogeneic cells offers the potential to reduce or eliminate chronic immunosuppression. Herein, we investigated antigen-loaded nanoparticles for their ability to promote transplant tolerance in the minor histocompatibility antigen sex-mismatched C57BL/6 model of bone marrow transplantation. In this model, the peptide antigens Dby and Uty mediate rejection of male bone marrow transplants by female CD4+ and CD8+ T cells, respectively, and we investigated the action of nanoparticles on these T cell subsets. Antigens were coupled to or encapsulated within poly(lactide-co-glycolide) (PLG) nanoparticles with an approximate diameter of 500 nm. Delivery of the CD4-encoded Dby epitope either coupled to or encapsulated within PLG particles prevented transplant rejection, promoted donor-host chimerism, and suppressed proliferative and IFN-γ responses in tolerized recipients. Nanoparticles modified with the Uty peptide did not induce tolerance. The dosing regimen was investigated with Dby coupled particles, and a single dose delivered the day after bone marrow transplant was sufficient for tolerance induction. The engraftment of cells was significantly affected by PD-1/PDL-1 costimluation, as blockade of PD-1 reduced engraftment by ~50%. In contrast, blockade of regulatory T cells did not impact the level of chimerism. The delivery of antigen on PLG nanoparticles promoted long-term engraftment of bone marrow in a model with a minor antigen mismatch in the absence of immunosuppression, and this represents a promising platform for developing a translatable, donor-specific tolerance strategy.

Biodegradable antigen-associated PLG nanoparticles tolerize Th2-mediated allergic airway inflammation pre- and postsensitization

“…Ag-NPs inhibit Th2 responses without Th1/Th17 skewing because i.v. injection of PLG(Ag) induces protective and therapeutic tolerance in Th1/ Th17-mediated EAE models and transplant rejection (11). We posit that abrogation of immune responses as induced by PLG(Ag) is preferable to the induction of a competitive inflammatory phenotype and represents a "true" state of tolerance.…”

“…PLG(Ag) allows for the potential delivery of larger amounts of Ag while retaining a free particle surface for further modification. Such particles are effective for the treatment of a variety of immune disorders, including EAE and allograft rejection, and can be prepared and lyophilized in advance to minimize end-user manipulation (11). PLG(Ag) had a diameter of 703.5 ± 84.28 nm.…”

Improving Vaccine and Immunotherapy Design Using Biomaterials

“…No evidence of systemic toxicity was observed with either formulation. Other work has loaded peptide antigens in PLG NPs to improve long-term engraftment of bone marrow in mice by changing how the antigen is processed [97], while MPs containing an immunosuppressive drug have been coated with LN-targeting antibodies to prolong survival in a heart allograft model [98]. …”

Tolerogenic Nanoparticles to Treat Islet Autoimmunity

“…Both antigen-conjugated and antigen-encapsulating particles have been used in Th1/Th17-mediated EAE [116••, 117••, 118••], Th2-mediated allergic airway inflammation [98•], and minor antigen mismatched bone marrow transplant [119•]. The exact mechanisms behind the tolerance induction in this model are still under investigation, but it is thought that intravenous administration leads to uptake of the carboxylated PLG nanoparticles by splenic marginal zone macrophages via the MARCO scavenger receptor, thereafter triggering various tolerogenic pathways including cell-intrinsic anergy and the activation of Foxp3 + Tregs and IL-10-producing Tr1 cells.…”

“…a Nanoparticles targeting APCs. Top : MARCO receptor dependent uptake of antigen-coupled and antigen-encapsulating PLG [98•, 116••, 117••, 118••, 119•, 120••, 121•, 122]. Middle : PLG encapsulating both antigen and rapamycin [109, 110].…”