One mission of the NIH is to ??better understand, treat, and ultimately prevent?? autoimmune diseases such as type 1 diabetes, multiple sclerosis, and rheumatoid arthritis. All of these diseases are currently managed by broadly immunosuppressing drugs. The objective of this proposal is to develop an effective method for delivering components of an antigen-specific treatment that tolerizes both dendritic cells (DC) and T cells in situ without the requirement for ex vivo manipulation of patient immune cells. For this, the major animal model of multiple sclerosis (MS) will be used. MS in both people and rodents is an autoimmune disease caused by abnormal T cells that, having escaped thymic deletion, destroy the myelin sheath, and eventually the neuronal axons, of motor neurons. The mouse model is called experimental allergic encephalomyelitis (EAE) and is inducible by injection of animals with components of the CNS, especially myelin oligodendrocyte glycoprotein (MOG) and its most antigenic epitope, MOG35-55. EAE has excellent kinetics for providing access to the cells that initiate the disease. Our strategy is to develop injectable biomaterial scaffolds that act in the subdermal layer to attract and tolerize DCs and then release tolerogenic DCs to restrain the ongoing autoimmunity in the host. This goal will be achieved by using our fabricated biocompatible alginate scaffold that is porous, injectable, and can release granulocyte macrophage colony-stimulating factor for recruiting a large number of DCs. To program the recruited DCs inside the scaffold, we will fabricate polymeric nanoparticles carrying 2-(1?H-indole-3?-carbonyl)- thiazole-4-carboxylic acid methyl ester (ITE), which is an endogenous ligand of the intracellular aryl hydrocarbon receptor (AhR) of DCs and T cells. ITE is known to induce tolerogenic DCs and regulatory T cell expansion. We will attempt to make this process antigen-specific by incorporating MOG35-55 peptide, which should be taken up and presented by the DCs to MOG-reactive T cells in the periphery. This interaction in turn should lead to anergy or deletion of the pathogenic T cells and conversion of nave CD4+ T cells to regulatory T cells. Our scaffolds incorporating polymeric nanoparticles will be tested in induced EAE models. In this manner we will determine if and when DC tolerizing occurs in the scaffolds, where the released DC travel, and if and how the process quells ongoing autoimmunity in the host.
Multiple sclerosis is a common but incurable autoimmune disease that is difficult to control and cannot be reliably predicted or prevented in people. This proposed research aims to develop a novel injectable biomaterial scaffold that contains a mixture of molecules to recruit and train immune cells in situ for inducing specific tolerance of the pathogenic T cells that cause the disease. It is a proposal at an early stage of development that has a risk but very high potential payoff in the form of new, highly selective treatments for a number of autoimmune diseases.
|Li, Peter Y; Fan, Zhiyuan; Cheng, Hao (2018) Cell Membrane Bioconjugation and Membrane-Derived Nanomaterials for Immunotherapy. Bioconjug Chem 29:624-634|
|Qi, Hao; Zhou, Hao; Tang, Qiyun et al. (2018) Block copolymer crystalsomes with an ultrathin shell to extend blood circulation time. Nat Commun 9:3005|