Many autoimmune disorders such as psoriasis lead to the alteration of skin components which generally manifests as unwanted topical symptoms. One of the most widely approved psoriasis-like animal models is the imiquimod (IMQ)-induced mouse model. This representation mimics various aspects of the complex cutaneous pathology and could be appropriate for testing topical treatment options. We perform a thorough characterization of this model by assessing some parameters that are not fully described in the literature, namely a precise description of skin disruption. It was evaluated by transepidermal water loss measurements and analyses of epidermis swelling as a consequence of keratinocyte hyperproliferation. The extent of neo-angiogenesis and hypervascularity in dermis were highlighted by immunostaining. Moreover, we investigated systemic inflammation through cytokines levels, spleen swelling and germinal centers appearance in draining lymph nodes. The severity of all parameters was correlated to IMQ concentration in skin samples. This study outlines new parameters of interest useful to assess this model. We highlight the skin barrier disruption and report a systemic inflammatory reaction occurring at distance both in spleen and lymph nodes. These newly identified biological endpoints could be exploited to investigate the efficacy of therapeutic candidates for psoriasis and more extensively for several other skin inflammatory diseases.

Vaccines have successfully eradicated a large number of diseases. However, some infectious diseases (such as HIV, Chlamydia trachomatis or Bacillus anthracis) keep spreading since there is no vaccine to prevent them. One way to overcome this issue is the development of new adjuvant formulations which are able to induce the appropriate immune response without sacrificing safety. Lymph nodes are the site of lymphocyte priming by antigen-presenting cells and subsequent adaptive immune response, and are a promising target for vaccine formulations. In this review, we describe the properties of different polymer-based (e.g., poly lactic-co-glycolic acid, poly lactic acid …) particulate adjuvants as innovative systems, capable of co-delivering immunopotentiators and antigens. We point out how these nanoparticles enhance the delivery of antigens, and how their physicochemical properties modify their uptake by antigen-presenting cells and their migration into lymph nodes. We describe why polymeric nanoparticles increase the persistence into lymph nodes and promote a mature immune response. We also emphasize how nanodelivery directs the response to a specific antigen and allows the induction of a cytotoxic immune response, essential for the fight against intracellular pathogens or cancer. Finally, we highlight the interest of the association between polymer-based vaccines and immunopotentiators, which can potentiate the effect of the molecule by directing it to the appropriate compartment and reducing its toxicity.

Pathogen recognition receptor (PRR) agonists are currently being developed and tested as adjuvants in various formulations to optimize the immunogenicity and efficacy of vaccines. Using an original in vitro approach to prime naive precursors from unfractionated human peripheral blood mononuclear cells, we assessed the influence of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), a ligand for the stimulator of interferon genes (STING), on the induction of antigen-specific CD8 ⁺ T cells. We found that 2′3′-cGAMP and 3′3′-cGAMP were especially potent adjuvants in this system, driving the expansion and maturation of functionally replete antigen-specific CD8 ⁺ T cells via the induction of type I IFNs. The biological relevance of these findings was confirmed in vivo using two mouse models, in which 2′3′-cGAMP–adjuvanted vaccination elicited protective antitumor or antiviral CD8 ⁺ T cell responses. These results identify particular isoforms of cGAMP as effective adjuvants that may find utility in the development of novel immunotherapies and vaccines.

MRNA is a blooming technology for vaccination and has gained global attention during the SARS-CoV-2 pandemic. However, the recent clinical trials have highlighted increased reactogenicity when using high mRNA doses. Intending to increase the potency of mRNA therapeutics and to decrease the therapeutic dose, we designed a mRNA backbone and optimized the mRNA purification process. We used the enhanced green fluorescent protein (eGFP) reporter gene flanked by one 5′ untranslated region (UTR) and two 3′ UTRs of the human β-globin as a reference mRNA and identified the most promising mRNA sequence using in vitro and in vivo models. First, we assessed the impact of different poly(A) sizes on translation and selected the most optimal sequence. Then, we selected the best 5′ UTR among synthetic sequences displaying a high ribosome loading. Finally, we evaluated the transfection efficiency of our standard mRNA template after two capping strategies and purification using either double-stranded RNA (dsRNA) depletion or dephosphorylation of 5′PPP RNA or both combined. Double purification was shown to give the best results. Altogether, the use of a newly defined 5′ UTR coupled to post-transcriptional treatments will be of great interest in the mRNA vaccine field, by limiting the amount of the antigen-coding transcript and subsequently the formulation components needed for an efficient vaccination.