A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis

Science ◽  
2021 ◽  
Vol 371 (6525) ◽  
pp. 145-153
Author(s):  
Christina Krienke ◽  
Laura Kolb ◽  
Elif Diken ◽  
Michael Streuber ◽  
Sarah Kirchhoff ◽  
...  
Keyword(s):  
T Cells ◽  
Messenger Rna ◽  
Effector T Cells ◽  
Systemic Delivery ◽  
Major Goal ◽  
Autoimmune Encephalomyelitis ◽  
Efficient Delivery ◽  
Costimulatory Signals ◽  
Antigen Presenting ◽  
Experimental Autoimmune

The ability to control autoreactive T cells without inducing systemic immune suppression is the major goal for treatment of autoimmune diseases. The key challenge is the safe and efficient delivery of pharmaceutically well-defined antigens in a noninflammatory context. Here, we show that systemic delivery of nanoparticle-formulated 1 methylpseudouridine-modified messenger RNA (m1Ψ mRNA) coding for disease-related autoantigens results in antigen presentation on splenic CD11c+ antigen-presenting cells in the absence of costimulatory signals. In several mouse models of multiple sclerosis, the disease is suppressed by treatment with such m1Ψ mRNA. The treatment effect is associated with a reduction of effector T cells and the development of regulatory T cell (Treg cell) populations. Notably, these Treg cells execute strong bystander immunosuppression and thus improve disease induced by cognate and noncognate autoantigens.

The immune response to lentiviral-delivered transgene is modulated in vivo by transgene-expressing antigen-presenting cells but not by CD4+CD25+ regulatory T cells

Blood ◽  
2007 ◽  
Vol 110 (6) ◽  
pp. 1788-1796 ◽  
Author(s):  
Andrea Annoni ◽  
Manuela Battaglia ◽  
Antonia Follenzi ◽  
Angelo Lombardo ◽  
Lucia Sergi-Sergi ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Adoptive Transfer ◽  
T Regulatory Cells ◽  
Lentiviral Vector ◽  
Antigen Presenting Cells ◽  
Effector T Cells ◽  
Systemic Delivery ◽  
Antigen Presenting

Abstract Systemic delivery of lentiviral vector (LV) in immunocompetent mice leads to efficient in vivo cell transduction and expression of the encoded protein under the control of the ubiquitous promoter of human cytomegalovirus (CMV). However, antitransgene immune response results in clearance of transduced cells 4 weeks after injection. T regulatory cells (Tregs), which have been demonstrated to control immune responses in vivo, were tested for their ability to suppress antitransgene response leading to stable long-term expression. Adoptive transfer of natural CD4+CD25+ Tregs (nTregs) isolated from wild type (wt) mice or from transgene tolerant transgenic (tg) mice did not suppress the antitransgene immune response after LV delivery. These data demonstrate that neither increasing the endogenous pool of natural Tregs nor transferring nTregs selected in a transgene-expressing thymus can modulate the immune response and mediate sustained transgene expression. Conversely, adoptive transfer of antigen-presenting cells (APCs) isolated from transgene-tolerant tg mice efficiently reduced the immune response leading to stable LV-encoded protein expression in vivo. Reduction of CD8+ effector T cells was observed in LV-treated mice coinjected with transgene-expressing APCs compared with control mice. These data indicate that antitransgene immune response can be modulated by transgene-expressing APCs possibly through deletion of effector T cells.

scholarly journals Modulating lung immune cells by pulmonary delivery of antigen-specific nanoparticles to treat autoimmune disease

2020 ◽  
Vol 6 (42) ◽  
pp. eabc9317
Author(s):  
Eiji Saito ◽  
Stephen J. Gurczynski ◽  
Kevin R. Kramer ◽  
Carol A. Wilke ◽  
Stephen D. Miller ◽  
...  
Keyword(s):  
T Cells ◽  
Autoimmune Disease ◽  
Costimulatory Molecule ◽  
Substantial Reduction ◽  
Pulmonary Delivery ◽  
Autoimmune Encephalomyelitis ◽  
Intratracheal Administration ◽  
The Central Nervous System ◽  
Antigen Presenting ◽  
Experimental Autoimmune

Antigen-specific particles can treat autoimmunity, and pulmonary delivery may provide for easier delivery than intravenous or subcutaneous routes. The lung is a “hub” for autoimmunity where autoreactive T cells pass before arriving at disease sites. Here, we report that targeting lung antigen-presenting cells (APCs) via antigen-loaded poly(lactide-co-glycolide) particles modulates lung CD4+ T cells to tolerize murine experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Particles directly delivered to the lung via intratracheal administration demonstrated more substantial reduction in EAE severity when compared with particles delivered to the liver and spleen via intravenous administration. Intratracheally delivered particles were associated with lung APCs and decreased costimulatory molecule expression on the APCs, which inhibited CD4+ T cell proliferation and reduced their population in the central nervous system while increasing them in the lung. This study supports noninvasive pulmonary particle delivery, such as inhalable administration, to treat autoimmune disease.

scholarly journals IL-1β enables CNS access to CCR2hi monocytes and the generation of pathogenic cells through GM-CSF released by CNS endothelial cells

2018 ◽  
Vol 115 (6) ◽  
pp. E1194-E1203 ◽  
Author(s):  
Alexandre Paré ◽  
Benoit Mailhot ◽  
Sébastien A. Lévesque ◽  
Camille Juzwik ◽  
Prenitha Mercy Ignatius Arokia Doss ◽  
...  
Keyword(s):  
Spinal Cord ◽  
T Cells ◽  
Endothelial Cells ◽  
Myeloid Cells ◽  
Autoimmune Encephalomyelitis ◽  
Cns Inflammation ◽  
Gm Csf ◽  
Autoimmune Conditions ◽  
Antigen Presenting ◽  
Experimental Autoimmune

Molecular interventions that limit pathogenic CNS inflammation are used to treat autoimmune conditions such as multiple sclerosis (MS). Remarkably, IL-1β–knockout mice are highly resistant to experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Here, we show that interfering with the IL-1β/IL-1R1 axis severely impairs the transmigration of myeloid cells across central nervous system (CNS) endothelial cells (ECs). Notably, we report that IL-1β expression by inflammatory CCR2hi monocytes favors their entry into the spinal cord before EAE onset. Following activation with IL-1β, CNS ECs release GM-CSF, which in turn converts monocytes into antigen-presenting cells (APCs). Accordingly, spinal cord-infiltrated monocyte-derived APCs are associated with dividing CD4+ T cells. Factors released from the interaction between IL-1β–competent myeloid cells and CD4+ T cells are highly toxic to neurons. Together, our results suggest that IL-1β signaling is an entry point for targeting both the initiation and exacerbation of neuroinflammation.

scholarly journals T Cell Costimulation through CD28 Depends on Induction of the Bcl-xγ Isoform

2002 ◽  
Vol 196 (1) ◽  
pp. 87-95 ◽  
Author(s):  
Qunrui Ye ◽  
Barry Press ◽  
Stephan Kissler ◽  
Xiao-Feng Yang ◽  
Linrong Lu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Proteolipid Protein ◽  
Autoimmune Encephalomyelitis ◽  
Activated T Cells ◽  
Impaired Memory ◽  
Cytokine Responses ◽  
Costimulatory Signals ◽  
Dependent Signaling Pathway ◽  
Experimental Autoimmune

The molecular basis of CD28-dependent costimulation of T cells is poorly understood. Bcl-xγ is a member of the Bcl-x family whose expression is restricted to activated T cells and requires CD28-dependent ligation for full expression. We report that Bcl-xγ–deficient (Bcl-xγ−/−) T cells display defective proliferative and cytokine responses to CD28-dependent costimulatory signals, impaired memory responses to proteolipid protein peptide (PLP), and do not develop PLP-induced experimental autoimmune encephalomyelitis (EAE). In contrast, enforced expression of Bcl-xγ largely replaces the requirement for B7-dependent ligation of CD28. These findings identify the Bcl-xγ cytosolic protein as an essential downstream link in the CD28-dependent signaling pathway that underlies T cell costimulation.

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