Modulating the T Lymphocyte Immune Response via Secretome Produced miRNA: From Tolerance Induction to the Enhancement of the Anticancer Response

T cells are key mediators of graft tolerance/rejection, development of autoimmunity, and the anticancer response. Consequently, differentially modifying the T cell response is a major therapeutic target. Most immunomodulatory approaches have focused on cytotoxic agents, cytokine modulation, monoclonal antibodies, mitogen activation, adoptive cell therapies (including CAR-T cells). However, these approaches do not persistently reorient the systemic immune response thus necessitating continual therapy. Previous murine studies from our laboratory demonstrated that the adoptive transfer of polymer-grafted (PEGylated) allogeneic leukocytes resulted in the induction of a persistent and systemic tolerogenic state. Further analyses demonstrated that miRNA isolated from the secretome of polymer-modified or control allogeneic responses effectively induced either a tolerogenic (TA1 miRNA) or proinflammatory (IA1 miRNA) response both in vitro and in vivo that was both systemic and persistent. In a murine Type 1 diabetes autoimmune model, the tolerogenic TA1 therapeutic effectively attenuated the disease process via the systemic upregulation of regulatory T cells while simultaneously downregulating T effector cells. In contrast, the proinflammatory IA1 therapeutic enhanced the anticancer efficacy of naïve PBMC by increasing inflammatory T cells and decreasing regulatory T cells. The successful development of this secretome miRNA approach may prove useful treating both autoimmune diseases and cancer

Inhibition of Autoimmune Diabetes in NOD Mice by miRNA Therapy.

Autoimmune destruction of the pancreatic islets in Type 1 diabetes is mediated by both increased proinflammatory (Teff) and decreased regulatory (Treg) T lymphocytes resulting in a significant decrease in the Treg:Teff ratio. The non-obese diabetic (NOD) mouse is an excellent in vivo model for testing potential therapeutics for attenuating the decrease in the Treg:Teff ratio and inhibiting disease pathogenesis. Here we show for the first time that a bioreactor manufactured therapeutic consisting of a complex of miRNA species (denoted as TA1) can effectively reset the NOD immune system from a proinflammatory to a tolerogenic state thus preventing or delaying autoimmune diabetes. Treatment of NOD mice with TA1 resulted in a systemic broad-spectrum upregulation of tolerogenic T cell subsets with a parallel downregulation of Teff subsets yielding a dramatic increase in the Treg:Teff ratio. Moreover, the murine-derived TA1 was highly effective in the inhibition of allorecognition of HLA-disparate human PBMC. TA1 demonstrated dose-responsiveness and exhibited equivalent or better inhibition of allorecognition driven proliferation than etanercept (a soluble TNF receptor). These findings demonstrate that miRNA-based therapeutics can effectively attenuate or arrest autoimmune disease processes and may be of significant utility in a broad range of autoimmune diseases including Type 1 diabetes

HEBAlt: a potent transcriptional regulator of proliferation in developing B cell precursors (83.8)

Abstract The basic helix-loop-helix transcription (bHLH) factor E2A is essential for B cell development, and can act as a homodimer or as a heterodimer with the closely related bHLH factor HEB. We have identified a short form of HEB called HEBAlt, which differs from the long form of HEB in its structure, function, and regulation, and which is conserved in vertebrates, including humans. Within hematopoiesis, HEBAlt is expressed only in developing T cell and B cell precursors. HEBAlt is strongly upregulated in pre-B cells, but is absent in IgM+ B cells. Retroviral expression of HEBAlt in multipotent hematopoietic precursors partially blocks B cell development. However, committed B cell precursors expressing ectopic HEBAlt undergo rapid expansion and exhibit extended survival in culture. HEBAlt-induced expansion arises from a limited number of precursors, indicating that secondary events collaborate with HEBAlt to cause loss of growth control. IL-7R and cyclin D3 are upregulated in HEBAlt-transduced cells, suggesting that HEBAlt normally functions to promote proliferation of early B cell precursors. Furthermore, downregulation of HEBAlt may be required for quiescence during Ig light chain rearrangement. These results suggest that dysregulation of HEBAlt could play an initiating role in the oncogenic transformation of B cell precursors.</jats:p