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Recent Publications

The role of engineered materials in mucosal vaccination strategies

Eshaghi B, Schudel A, Sadeghi I, Chen Z, Lee A, Kanelli  M, Tierney F, Han J, Ingalls B, Francis D, et al. The role of engineered materials in mucosal vaccination strategies. Nature Reviews Materials. 2023. Publisher's VersionAbstract
Mucosal pathogens, as exemplified by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human immunodeficiency virus (HIV) and Mycobacterium tuberculosis, lead to substantial morbidity and mortality worldwide and pose serious threats to global health. Mucosal vaccination is crucial to combating mucosal pathogens because it enables the immune system to directly target and neutralize pathogens at their point of entry. Mucosal vaccines need to penetrate the mucus layer, reach the target tissue and activate robust immune responses in the mucosal tissues. Material-based strategies are necessary to meet these requirements. In this Review, we provide an overview of current mucosal vaccines, categorized by administration route, to highlight the importance of material design in overcoming the existing delivery challenges. We discuss the different classes of materials currently being used as vaccine carriers to induce antigen-specific mucosal immunity, including lipids, natural and synthetic polymers, inorganic materials and pathogen-inspired materials.
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Association between Bisphosphonate use and COVID-19 related outcomes

Thompson J, Wang Y, Dreischulte T, Barreiro O, Gonzalez R, Hanč P, Matysiak C, Neely H, Rottenkolber M, Haskell T, et al. Association between Bisphosphonate use and COVID-19 related outcomes. eLife. 2023. Publisher's VersionAbstract

Background: Although there are several efficacious vaccines against COVID-19, vaccination rates in many regions around the world remain insufficient to prevent continued high disease burden and emergence of viral variants. Repurposing of existing therapeutics that prevent or mitigate severe COVID-19 could help to address these challenges. The objective of this study was to determine whether prior use of bisphosphonates is associated with reduced incidence and/or severity of COVID-19.

Methods: A retrospective cohort study utilizing payer-complete health insurance claims data from 8,239,790 patients with continuous medical and prescription insurance January 1, 2019 to June 30, 2020 was performed. The primary exposure of interest was use of any bisphosphonate from January 1, 2019 to February 29, 2020. Bisphosphonate users were identified as patients having at least one bisphosphonate claim during this period, who were then 1:1 propensity score-matched to bisphosphonate non-users by age, gender, insurance type, primary-care-provider visit in 2019, and comorbidity burden. Main outcomes of interest included: (a) any testing for SARS-CoV-2 infection; (b) COVID-19 diagnosis; and (c) hospitalization with a COVID-19 diagnosis between March 1, 2020 and June 30, 2020. Multiple sensitivity analyses were also performed to assess core study outcomes amongst more restrictive matches between BP users/non-users, as well as assessing the relationship between BP-use and other respiratory infections (pneumonia, acute bronchitis) both during the same study period as well as before the COVID outbreak.

Results: 7,906,603 patients for whom continuous medical and prescription insurance information was available were selected. 450,366 bisphosphonate users were identified and 1:1 propensity score-matched to bisphosphonate non-users. Bisphosphonate users had lower odds ratios (OR) of testing for SARS-CoV-2 infection (OR=0.22; 95%CI:0.21-0.23; p<0.001), COVID-19 diagnosis (OR=0.23; 95%CI:0.22-0.24; p<0.001), and COVID-19-related hospitalization (OR=0.26; 95%CI:0.24-0.29; p<0.001). Sensitivity analyses yielded results consistent with the primary analysis. Bisphosphonate-use was also associated with decreased odds of acute bronchitis (OR=0.23; 95%CI:0.22-0.23; p<0.001) or pneumonia (OR=0.32; 95%CI:0.31-0.34; p<0.001) in 2019, suggesting that bisphosphonates may protect against respiratory infections by a variety of pathogens, including but not limited to SARS-CoV-2.

Conclusions: Prior bisphosphonate-use was associated with dramatically reduced odds of SARS-CoV-2 testing, COVID-19 diagnosis, and COVID-19-related hospitalizations. Prospective clinical trials will be required to establish a causal role for bisphosphonate-use in COVID-19-related outcomes.

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Translational Studies Using the MALT1 Inhibitor (S)-Mepazine to Induce Treg Fragility and Potentiate Immune Checkpoint Therapy in Cancer

Pilato M, Gao Y, Sun Y, Fu A, Grass C, Seeholzer T, Feederle R, Mazo I, Kazer S, Litchfield K, et al. Translational Studies Using the MALT1 Inhibitor (S)-Mepazine to Induce Treg Fragility and Potentiate Immune Checkpoint Therapy in Cancer. J Immunother Precis Oncol. 2023. Publisher's VersionAbstract

Introduction: Regulatory T cells (Tregs) play a critical role in the maintenance of immune homeostasis but also protect tumors from immune-mediated growth control or rejection and pose a significant barrier to effective immunotherapy. Inhibition of MALT1 paracaspase activity can selectively reprogram immune-suppressive Tregs in the tumor microenvironment to adopt a proinflammatory fragile state, which offers an opportunity to impede tumor growth and enhance the efficacy of immune checkpoint therapy (ICT).

Methods: We performed preclinical studies with the orally available allosteric MALT1 inhibitor (S)-mepazine as a single-agent and in combination with anti-programmed cell death protein 1 (PD-1) ICT to investigate its pharmacokinetic properties and antitumor effects in several murine tumor models as well as patient-derived organotypic tumor spheroids (PDOTS).

Results: (S)-mepazine demonstrated significant antitumor effects and was synergistic with anti-PD-1 therapy in vivo and ex vivo but did not affect circulating Treg frequencies in healthy rats at effective doses. Pharmacokinetic profiling revealed favorable drug accumulation in tumors to concentrations that effectively blocked MALT1 activity, potentially explaining preferential effects on tumor-infiltrating over systemic Tregs.

Conclusions: The MALT1 inhibitor (S)-mepazine showed single-agent anticancer activity and presents a promising opportunity for combination with PD-1 pathway-targeted ICT. Activity in syngeneic tumor models and human PDOTS was likely mediated by induction of tumor-associated Treg fragility. This translational study supports ongoing clinical investigations (ClinicalTrials.gov Identifier: NCT04859777) of MPT-0118, (S)-mepazine succinate, in patients with advanced or metastatic treatment-refractory solid tumors.

Keywords: MALT1; cancer immunotherapy; fragile Tregs; interferon-γ; regulatory T cells.

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Multimodal control of dendritic cell functions by nociceptors

Hanč P, Gonzalez R, Mazo I, Wang Y, Lambert T, Ortiz G, Miller E, von Andrian UH. Multimodal control of dendritic cell functions by nociceptors. Science. 2023.Abstract
It is known that interactions between nociceptors and dendritic cells (DCs) can modulate immune responses in barrier tissues. However, our understanding of the underlying communication frameworks remains rudimentary. Here, we show that nociceptors control DCs in three molecularly distinct ways. First, nociceptors release the calcitonin gene-related peptide that imparts a distinct transcriptional profile on steady-state DCs characterized by expression of pro-interleukin-1β and other genes implicated in DC sentinel functions. Second, nociceptor activation induces contact-dependent calcium fluxes and membrane depolarization in DCs and enhances their production of proinflammatory cytokines when stimulated. Finally, nociceptor-derived chemokine CCL2 contributes to the orchestration of DC-dependent local inflammation and the induction of adaptive responses against skin-acquired antigens. Thus, the combined actions of nociceptor-derived chemokines, neuropeptides, and electrical activity fine-tune DC responses in barrier tissues.
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Control of myeloid cell functions by nociceptors

Hanč P, Messou M-A, Wang Y, von Andrian UH. Control of myeloid cell functions by nociceptors. Frontiers in Immunology. 2023. Publisher's VersionAbstract
The immune system has evolved to protect the host from infectious agents, parasites, and tumor growth, and to ensure the maintenance of homeostasis. Similarly, the primary function of the somatosensory branch of the peripheral nervous system is to collect and interpret sensory information about the environment, allowing the organism to react to or avoid situations that could otherwise have deleterious effects. Consequently, a teleological argument can be made that it is of advantage for the two systems to cooperate and form an “integrated defense system” that benefits from the unique strengths of both subsystems. Indeed, nociceptors, sensory neurons that detect noxious stimuli and elicit the sensation of pain or itch, exhibit potent immunomodulatory capabilities. Depending on the context and the cellular identity of their communication partners, nociceptors can play both pro- or anti-inflammatory roles, promote tissue repair or aggravate inflammatory damage, improve resistance to pathogens or impair their clearance. In light of such variability, it is not surprising that the full extent of interactions between nociceptors and the immune system remains to be established. Nonetheless, the field of peripheral neuroimmunology is advancing at a rapid pace, and general rules that appear to govern the outcomes of such neuroimmune interactions are beginning to emerge. Thus, in this review, we summarize our current understanding of the interaction between nociceptors and, specifically, the myeloid cells of the innate immune system, while pointing out some of the outstanding questions and unresolved controversies in the field. We focus on such interactions within the densely innervated barrier tissues, which can serve as points of entry for infectious agents and, where known, highlight the molecular mechanisms underlying these interactions.
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High-Fat Diet Rapidly Modifies Trafficking, Phenotype, and Function of Plasmacytoid Dendritic Cells in Adipose Tissue

Stutte S, Ishikawa-Ankerhold H, Lynch L, Eickhoff S, Nasiscionyte S, Guo C, van den Heuvel D, Setzensack D, Colonna M, Maier-Begandt D, et al. High-Fat Diet Rapidly Modifies Trafficking, Phenotype, and Function of Plasmacytoid Dendritic Cells in Adipose Tissue. Immunology. 2022. Publisher's VersionAbstract

Plasmacytoid dendritic cells (pDCs) display an increased abundance in visceral adipose tissue (VAT) of humans with obesity. In the current study, we set out to decipher the molecular mechanisms of their recruitment to VAT and the functional relevance of this process. We observed increased pDC numbers in murine blood, liver, spleen, and VAT after feeding a high-fat diet (HFD) for 3 wk when compared with a standard diet. pDCs were enriched in fat-associated lymphoid clusters representing highly specific lymphoid regions within VAT. HFD led to an enlargement of fat-associated lymphoid clusters with an increased density and migratory speed of pDCs as shown by intravital multiphoton microscopy. For their recruitment into VAT, pDCs employed P-selectin with E-selectin and L-selectin being only critical in response to HFD, indicating that the molecular cues underlying pDC trafficking were dependent on the nutritional state. Subsequent recruitment steps required α4β1 and α4β7 integrins and engagement of CCR7. Application of fingolimod (FTY720) abrogated egress of pDCs from VAT, indicating the involvement of sphingosine-1-phosphate in this process. Furthermore, HFD altered pDC functions by promoting their activation and type 1 IFN expression. Blocking pDC infiltration into VAT prevented weight gain and improved glucose tolerance during HFD. In summary, a HFD fundamentally alters pDC biology by promoting their trafficking, retention, and activation in VAT, which in turn seems to regulate metabolism.

Copyright © 2022 by The American Association of Immunologists, Inc.

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What We Do

The von Andrian lab conducts basic research in immunology using a broad range of molecular cellular and whole animal approaches. We focus on the molecular mechanisms of immune cell migration and homing in lymphoid and non-lymphoid tissues using intravital microscopy techniques.