Combination Treatment with Antigen-Specific Dual-Sized Microparticle System Plus Anti-CD3 Immunotherapy Fails to Synergize to Improve Late-Stage Type 1 Diabetes Prevention in Nonobese Diabetic Mice.
J M StewartA L PosgaiJ J LeonM J HallerBenjamin G KeselowskyPublished in: ACS biomaterials science & engineering (2020)
Type 1 diabetes (T1D) pathophysiology, while incompletely understood, has in part been attributed to aberrant presentation of self-antigen plus proinflammatory costimulation by professional antigen-presenting cells (APCs). Therapies targeting dendritic cells (DCs) offer an avenue to restore antigen-specific tolerance by promoting presentation of self-antigen in an anti-inflammatory or suppressive context. Here, we describe a subcutaneously administered, dual-sized biodegradable microparticle (MP) platform that includes phagocytosable (∼1 μm) and nonphagocytosable (∼30 μm) MPs to deliver pro-tolerogenic factors both intra- and extracellularly, as well as the T1D-associated autoantigen, insulin, to DCs for amelioration of autoimmunity. This MP platform resulted in increased recruitment of DCs, suppressive skewing of DC phenotype with diminished expression of CD86 and MHC-II, increased regulatory T cell (Treg) frequency, and upregulated expression of the checkpoint inhibitor programmed cell death protein 1 (PD-1) on T cells. When administered concomitantly with anti-CD3 antibody, which provides transient T cell depletion while preserving Treg populations, in 12-week-old nonobese diabetic (NOD) mice, regulatory immune populations persisted out to 20 weeks of age; however, combination anti-CD3 and dual-sized MP (dMP) therapy failed to synergistically inhibit diabetes onset.
Keyphrases
- type diabetes
- dendritic cells
- glycemic control
- anti inflammatory
- poor prognosis
- cardiovascular disease
- case report
- regulatory t cells
- immune response
- induced apoptosis
- nk cells
- randomized controlled trial
- drug delivery
- stem cells
- metabolic syndrome
- transcription factor
- binding protein
- cell death
- small molecule
- oxidative stress
- high throughput
- cancer therapy
- long non coding rna
- study protocol
- clinical trial
- cerebral ischemia
- replacement therapy
- pi k akt
- signaling pathway