Polymer-Based Production of miRNA-Based Immune Modulators
Using bioreactor systems, the 'immunocamouflage' of leukocytes can be used to generate microRNA (miRNA) that can be administered in vitro or in vivo to induce either tolerance of a proinflammatory state. These miRNA biologics are stable and highly effective. the miRNA biologics modulate the immune system by regulating the Treg:Teff ratio.
miRNA regulation is complex in that a SINGLE miRNA can regulate 10-100's of genes and a SINGLE gene can be regulated by 10-100's of miRNA. Hence, the change of a SINGLE miRNA (up/down) is UNLIKELY to exert a potent systemic biological response due to the inherent complexity of miRNA expression, targeting and fidelity. Moreover, biological responses likely arise as a consequence of a PATTERN OF miRNA CHANGES that include unchanged, increased and decreased expression of MULTIPLE miRNAs. Thus, one must think of PATTERNS OF CHANGES. Our miRNA APPROACH has been to replicate the complex biologic miRNA patterns of change necessary to induce either a systemic pro-tolerogenic (TA1) or pro-inflammatory (IA1) state in the treated individual
Wang, D., Toyofuku, W.M., Chen, A.M. and Scott, M.D. Induction of Immunotolerance via mPEG Grafting to Allogeneic Leukocytes. Biomaterials 32:9494-9503 (2011).
Wang, D., Toyofuku, W.M. Kyluik, D.L. and Scott, M.D. Chapter 7: Use of Flow Cytometry In The In Vitro and In Vivo Analysis of Tolerance/Anergy Induction By Immunocamouflage. In: Flow Cytometry-Recent Perspectives, (Editor: Schmid, I.) InTech, ISBN 979-953-307-355-1. (2012). Pages 133-150. Link: Intech Web Page
Wang, D., Shanina , I., Toyofuku, W.M., Horwitz, M.S. and Scott, M.D. Inhibition of Autoimmune Diabetes in NOD Mice by miRNA Therapy. PLoS ONE 10(12): e0145179. doi:10.1371/journal. pone.0145179 (2015). Link: Plosone Paper
Kyluik-Price D.L., Li, L. and Scott, M.D. Effects of Methoxypoly (Ethylene Glycol) Mediated Immunocamouflage on Leukocyte Surface Marker Detection, Cell Conjugation, Activation and Alloproliferation. Biomaterials 74(1):167-177 (2016).
TA1: Tolerogenic miRNA therapeutic that induces an systemic immunoquiescent state inhibiting the onset or progression of autoimmune disease. May also improve transplantion outcome by inhibiting host-versus-graft disease (HVGD).
IA1: miRNA-based therapetuic that enhances the immune response to abnormal cells (e.g., cancer).
Our miRNA APPROACH has been to replicate the complex biologic miRNA patterns of change necessary to induce either a systemic pro-tolerogenic (TA1) or pro-inflammatory (IA1) state in the treated individual.
Wang, D., Shanina , I., Toyofuku, W.M., Horwitz, M.S. and Scott, M.D. Inhibition of Autoimmune Diabetes in NOD Mice by miRNA Therapy. PLoS ONE 10(12): e0145179. doi:10.1371/journal. pone.0145179 (2015).
Autoimmune Type 1 Diabetes Reduced by TA1 Treatment
Pancreatic Islet Morphology is Significantly Improved in TA1 Treated Mice
TA Treatment INCREASES the ratio of T Regulatory (Treg) to T Effector (Teff; e.g., Th17) Lymphocytes
Utility of TA1 Therapy in NOD (Diabetic) Mice