Targeting macrophages with phosphatidylserine-rich liposomes as a potential antigen-specific immunotherapy for type 1 diabetes.

Type 1 diabetes (T1D) results from a breakdown in immunological tolerance, with pivotal involvement of antigen-presenting cells. In this context, antigen-specific immunotherapies have been developed to arrest autoimmunity, such as phosphatidylserine (PS)-liposomes. However, the role of certain antigen-presenting cells in immunotherapy, particularly human macrophages (Mφ) in T1D remains elusive. The aim of this study was to determine the role of Mφ in antigen-specific immune tolerance and T1D. To that end, we evaluated Mφ ability to capture apoptotic-body mimicking PS-liposomes in mice and conducted a phenotypic and functional characterisation of four human monocyte-derived Mφ (MoMφ) subpopulations (M0, M1, M2a and M2c) after PS-liposomes uptake. Our findings in mice identified Mφ as the most phagocytic cell subset in the spleen and liver. In humans, while phagocytosis rates were comparable between T1D and control individuals, PS-liposome capture dynamics differed among Mφ subtypes, favouring inflammatory (M1) and deactivated (M2c) Mφ. Notably, high nanoparticle concentrations did not affect macrophage viability. PS-liposome uptake by Mφ induced alterations in membrane molecule expression related to immunoregulation, reduced secretion of IL-6 and IL-12, and diminished autologous T-cell proliferation in the context of autoantigen stimulation. These results underscore the tolerogenic effects of PS-liposomes and emphasize their potential to target human Mφ, providing valuable insights into the mechanism of action of this preclinical immunotherapy.

A new platform for autoimmune diseases. Inducing tolerance with liposomes encapsulating autoantigens.

Autoimmune diseases (AIDs) are caused by the loss of self-tolerance and destruction of tissues by the host's immune system. Several antigen-specific immunotherapies, focused on arresting the autoimmune attack, have been tested in clinical trials with discouraging results. Therefore, there is a need for innovative strategies to restore self-tolerance safely and definitively in AIDs. We previously demonstrated the therapeutic efficacy of phosphatidylserine (PS)-liposomes encapsulating autoantigens in experimental type 1 diabetes and multiple sclerosis. Here, we show that PS-liposomes can be adapted to other autoimmune diseases by simply replacing the encapsulated autoantigen. After administration, they are distributed to target organs, captured by phagocytes and interact with several immune cells, thus exerting a tolerogenic and immunoregulatory effect. Specific PS-liposomes demonstrate great preventive and therapeutic efficacy in rheumatoid arthritis and myasthenia gravis. Thus, this work highlights the therapeutic potential of a platform for several autoimmunity settings, which is specific, safe, and with long-term effects.

Impact of Betamethasone Pretreatment on Engrafment of Cord Blood-Derived Hematopoietic Stem Cells.

Hematopoietic stem cell (HSC) transplantation is crucial to cure hematologic malignancies. Umbilical cord blood (UCB) is a source of stem cells, but 90% of UCB units are discarded due to low cellularity. Improving the engraftment capacities of CD34+ stem cells would allow the use of UCB that were so far rejected. Betamethasone induces long-term transcriptomic and epigenomic changes in immune cells through glucocorticoid receptor. We hypothesize that discarded UCB could be used owing to improvements induced by betamethasone. Isolated CD34+ HSC from UCB were exposed to the synthetic glucocorticoids betamethasone and fluticasone for 20 h, and cell phenotype was determined before transplantation. NSG mice were sub-lethally irradiated (1 Gy or 2 Gy) 6 h before intravenously transferring 2-5 × 105 CD34+ HSC. The peripheral blood engraftment levels and the leukocyte subsets were followed up for 20 weeks using flow cytometry. At end point, the engraftment and leukocyte subsets were determined in the spleen and bone marrow. We demonstrated that betamethasone has surprising effects in recovering immune system homeostasis. Betamethasone and fluticasone increase CXCR4 and decrease HLA class II and CD54 expression in CD34+ HSCs. Both glucocorticoids-exposed cells showed a similar engraftment in 2 Gy-irradiated NSG mice. Interestingly, betamethasone-exposed cells showed enhanced engraftment in 1 Gy-irradiated NSG mice, with a trend to increase regulatory T cell percentage when compared to control. Betamethasone induces alterations in CD34+ HSCs and improve the engraftment, leading to a faster immune system recovery, which will contribute to engrafted cells survival.

Antibody Protection against Long-Term Memory Loss Induced by Monomeric C-Reactive Protein in a Mouse Model of Dementia.

Monomeric C-reactive protein (mCRP), the activated isoform of CRP, induces tissue damage in a range of inflammatory pathologies. Its detection in infarcted human brain tissue and its experimentally proven ability to promote dementia with Alzheimer's disease (AD) traits at 4 weeks after intrahippocampal injection in mice have suggested that it may contribute to the development of AD after cerebrovascular injury. Here, we showed that a single hippocampal administration of mCRP in mice induced memory loss, lasting at least 6 months, along with neurodegenerative changes detected by increased levels of hyperphosphorylated tau protein and a decrease of the neuroplasticity marker Egr1. Furthermore, co-treatment with the monoclonal antibody 8C10 specific for mCRP showed that long-term memory loss and tau pathology were entirely avoided by early blockade of mCRP. Notably, 8C10 mitigated Egr1 decrease in the mouse hippocampus. 8C10 also protected against mCRP-induced inflammatory pathways in a microglial cell line, as shown by the prevention of increased generation of nitric oxide. Additional in vivo and in vitro neuroprotective testing with the anti-inflammatory agent TPPU, an inhibitor of the soluble epoxide hydrolase enzyme, confirmed the predominant involvement of neuroinflammatory processes in the dementia induced by mCRP. Therefore, locally deposited mCRP in the infarcted brain may be a novel biomarker for AD prognosis, and its antibody blockade opens up therapeutic opportunities for reducing post-stroke AD risk.

A century later, still fighting back: antigen-specific immunotherapies for type 1 diabetes.

Type 1 diabetes (T1D) is a chronic metabolic disease caused by the autoimmune destruction of insulin-producing ß-cells. Ever since the 1920s, the fate of patients suffering from T1D was dramatically improved owing to the isolation and production of insulin, and the scientific field has largely progressed as a result of the evidence gathered about its underpinnings and mechanisms. The last years have seen this knowledge transformed into actual antigen-specific immunotherapies with potential to restore selectively the breach of tolerance to ß-cell autoantigens and halt the autoimmune aggression. However, so far, the results of both prevention and reversion trials in T1D have been rather discouraging, so there is still an urgent need to optimize those immunotherapies and their associated factors, for example, posology and administration patterns, route and timing. In this review, we look back on what has been achieved in the last century and identify the main autoantigens driving the autoimmune attack in T1D. Then, we take a deep dive into the numerous antigen-specific immunotherapies trialed and the ones still at a preclinical phase, ranging from peptides, proteins and agent combinations to gene transfer, nanoparticles, cell-based strategies and novel approaches exploiting naturally occurring tolerogenic processes. Finally, we provide insight into the several features to be considered in a T1D clinical trial, the ideal time point for intervention and the biomarkers needed for monitoring the successful regulatory effect of the antigen-specific immunotherapy. Although further research and optimization remain imperative, the development of a therapeutic armamentarium against T1D autoimmunity is certainly advancing with a confident step.