Quantifying the importance of pMHC valency, total pMHC dose and frequency on nanoparticle therapeutic efficacy

Abstract

Nanoparticles (NPs) coated with β-cell-specific peptide major histocompatibility complex (pMHC) class I molecules can effectively restore normoglycemia in spontaneously diabetic nonobese diabetic mice. They do so by expanding pools of cognate memory autoreactive regulatory CD8+ T cells that arise from naive low-avidity T-cell precursors to therapeutic levels. Here we develop our previously constructed mathematical model to explore the effects of compound design parameters (NP dose and pMHC valency) on therapeutic efficacy with the underlying hypothesis that the functional correlates of the therapeutic response (expansion of autoregulatory T cells and deletion of autoantigen-loaded antigen-presenting cells by these T cells) are biphasic. We show, using bifurcation analysis, that the model exhibits a 'resonance'-like behavior for a given range of NP dose in which bistability between the healthy state (possessing zero level of effector T-cell population) and autoimmune state (possessing elevated level of the same population) disappears. A heterogeneous population of model mice subjected to several treatment protocols under these new conditions is conducted to quantify both the average percentage of autoregulatory T cells in responsive and nonresponsive model mice, and the average valency-dependent minimal optimal dose needed for effective therapy. Our results reveal that a moderate increase (≥1.6-fold) in the NP-dependent expansion rate of autoregulatory T-cell population leads to a significant increase in the efficacy and the area corresponding to the effective treatment regimen, provided that NP dose ≥8 μg. We expect the model developed here to generalize to other autoimmune diseases and serve as a computational tool to understand and optimize pMHC-NP-based therapies.

Spatiotemporal Dynamics of Insulitis in Human Type 1 Diabetes

“…We have discussed one hypothesis involving the promotion of low avidity T cell clones (Amrani et al, 2000; Khadra et al, 2009). One potential method for doing this is through the intravenous injection of ex vivo -selected and ex vivo -expanded autologous regulatory T cells, such as CD4+ cells (Bluestone et al, 2015), another is to incite the same expansion of regulatory T cells in vivo through the intravenous injection of nanoparticles coated with pMHC (Sugarman et al, 2013). Our modeling framework could easily be extended to include the effect of infusion of either the cells themselves or the nanoparticles to test the spatial aspects of these interventions.…”

Continuum model of T-cell avidity: Understanding autoreactive and regulatory T-cell responses in type 1 diabetes

“…Recent findings have shown that IL-2 promotes the recruitment and function of Tauts, whereas Tregs suppress the generation of Tauts (Shameli et al, 2013). Clinically, these Tauts can be expanded using nanoparticles coated with pMHC class II and I complexes (Clemente-Casares et al, 2011; Khadra et al, 2010b; Sugarman et al, 2013; Tsai et al, 2010). The extended model can thus help unravel the complex homeostatic interplay between all these T-cell pools and to optimize the therapeutic efficacy of nanoparticles in the treatment of the disease.…”

Unraveling the contribution of pancreatic beta-cell suicide in autoimmune type 1 diabetes

“…Some of the parameters of the model have been previously estimated in Khadra et al (2009) and Sugarman et al (2013). Data from non-obese diabetic (NOD) mice, prone to developing insulin-dependent diabetes similar to human T1D, was used to determine the ballpark values of these parameters.…”