The undesired destruction of healthy cells by the immune system results in the loss of tissue function and complicates strategies to restore tissue function. The current standard therapy for autoimmune disease involves generalized immunosuppression, which is in most cases is not clinically efficacious and leads to numerous undesired side effects. Dr. Stephen Miller, (co-PI) pioneered an approach in which splenocytes were crosslinked with specific autoantigens, and their delivery to the spleen induced tolerance specifically to the autoantigen. The use of cellular carriers for tolerance induction in the clinical arena is challenging due to the considerable ex-vivo laboratory manipulation that is required, which is expensive, increases the number of donor cells needed and introduces further opportunity for technical error. Our long-term goal is to develop a particle-based platform that can be an off-the-shelf product for induction of tolerance to specific antigens to inhibit the specific undesired immune response while not altering the remaining elements of the immune response. In this proposal, we develop particles that target the spleen following intravenous delivery, and would subsequently be internalized by 'tolerogenic'antigen presenting cells to present the antigens without T cell activation thereby inducing tolerance rather than an immune response. Most strategies targeting the immune system focus on inducing a specific immune response (vaccines), whereas this system aims to do the opposite by inducing tolerance to specific antigens. We hypothesize that peptide-linked particles will be internalized by tolerogenic host splendid APCs which subsequently induce immune tolerance through the coordinate induction of T cell energy and activation of regulatory T cells that limit T cell responses. We have selected biocompatible and biodegradable materials whose physical properties can be controlled to influence their distribution, and can be modified with functional groups to promote internalization, target specific APC populations or receptors, and can release bioactive proteins to enhance the tolerogenic response. The following aims will be investigated:
Specific Aim 1 will investigate particle design for splenic homing and antigen presentation in tolerance induction.
Specific Aim 2 will investigate the innate cellular mechanisms that mediate interactions with antigen-linked particles that lead to tolerance.
Specific Aim 3 will investigate mechanisms of particle-initiated inactivation of effectors T cell functions mediating tolerance induction including clonal deletion, energy/immune deviation, and Treg activation. Successful completion of these studies would identify particles that are novel, safe, efficient and clinically relevant tools to inhibit antigen-specific T- cells for therapy of autoimmune diseases. This innovative approach has far reaching implications for applications in which decreasing specific immune responses could be beneficial, such as the autoimmune diseases, rejection of transplanted cells, and allergies to food antigens or airborne particulates.
In autoimmune diseases, such as multiple sclerosis, the immune system attacks healthy cells resulting in the loss of tissue function, and also complicates strategies to restore cells that could provide that function. We propose to develop biodegradable, biocompatible particles that can induce tolerance and thereby specifically prevent the attack by cells of the immune system. This innovative approach has far reaching implications for applications in which decreasing specific immune responses could be beneficial, such as the autoimmune diseases, rejection of transplanted cells in regenerative medicine, and allergies to food antigens or airborne particulates.
|Prasad, Suchitra; Neef, Tobias; Xu, Dan et al. (2018) Tolerogenic Ag-PLG nanoparticles induce tregs to suppress activated diabetogenic CD4 and CD8 T cells. J Autoimmun 89:112-124|
|Skoumal, Michael; Woodward, Kyle B; Zhao, Hong et al. (2018) Localized immune tolerance from FasL-functionalized PLG scaffolds. Biomaterials 192:271-281|
|Neef, Tobias; Miller, Stephen D (2017) Tolerogenic Nanoparticles to Treat Islet Autoimmunity. Curr Diab Rep 17:84|
|Pearson, Ryan M; Casey, Liam M; Hughes, Kevin R et al. (2017) Controlled Delivery of Single or Multiple Antigens in Tolerogenic Nanoparticles Using Peptide-Polymer Bioconjugates. Mol Ther 25:1655-1664|
|Kuo, Robert; Saito, Eiji; Miller, Stephen D et al. (2017) Peptide-Conjugated Nanoparticles Reduce Positive Co-stimulatory Expression and T Cell Activity to Induce Tolerance. Mol Ther 25:1676-1685|
|Pearson, Ryan M; Casey, Liam M; Hughes, Kevin R et al. (2017) In vivo reprogramming of immune cells: Technologies for induction of antigen-specific tolerance. Adv Drug Deliv Rev 114:240-255|
|Jeong, Su Ji; Cooper, John G; Ifergan, Igal et al. (2017) Intravenous immune-modifying nanoparticles as a therapy for spinal cord injury in mice. Neurobiol Dis 108:73-82|
|McCarthy, Derrick P; Yap, Jonathan Woon-Teck; Harp, Christopher T et al. (2017) An antigen-encapsulating nanoparticle platform for TH1/17 immune tolerance therapy. Nanomedicine 13:191-200|
|Smarr, Charles B; Yap, Woon Teck; Neef, Tobias P et al. (2016) Biodegradable antigen-associated PLG nanoparticles tolerize Th2-mediated allergic airway inflammation pre- and postsensitization. Proc Natl Acad Sci U S A 113:5059-64|
|Ifergan, Igal; Chen, Siqi; Zhang, Bin et al. (2016) Cutting Edge: MicroRNA-223 Regulates Myeloid Dendritic Cell-Driven Th17 Responses in Experimental Autoimmune Encephalomyelitis. J Immunol 196:1455-1459|
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