Mecanismos moleculares implicados en el modo de acción de alergoides conjugados a manano y tratamientos anti-IgE en células dendríticas humanas

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Bioquímica y Biología Molecular, leída el 21-01-2022Allergy is defined as the unexpected abnormal or exaggerated reaction to an exogenous stimulus (allergen) involving the immune system. Allergic diseases represent a major health problem of increasing prevalence with high socio-economic burden, decreasing the quality of life of many patients. Nowadays, allergen-specific immunotherapy (AIT) is the only treatment with potential long-lasting disease-modifying effects for allergic diseases, and together with biologicals such as monoclonal antibodies (mAbs), represent the most effective therapies for allergic patients when conventional medication is not enough to control the symptoms. However, they still have drawbacks in terms of efficacy, security, long duration or high cost. Therefore, there is an urgent need to develop more effective and safer treatments. Allergoid-mannan conjugates represent next-generation vaccines for AIT targeting dendritic cells (DCs) able to promote the generation of functional regulatory T (Treg) cells. On the other hand, omalizumab, an anti-IgE biological, is approved for the treatment of severe allergic asthma, for chronic spontaneous urticaria (CSU) and for chronic rhinosinusitis with nasal polyps (CRSwNP). Recently, a next-generation anti-IgE mAb (ligelizumab) with significant higher affinity for IgE than omalizumab, has been developed and it is being currently assayed in phase III random clinical trials for CSU...La alergia se define como una reacción exagerada a sustancias externas (alérgenos) mediada por el sistema inmune. Las enfermedades alérgicas constituyen un problema muy importante de salud con una gran carga socioeconómica, disminuyendo la calidad de vida de los pacientes. Actualmente, la inmunoterapia específica de alérgeno (AIT) es el único tratamiento con capacidad potencial para modificar el curso de las enfermedades alérgicas a largo plazo, y junto a los biológicos como los anticuerpos monoclonales (mAbs) dirigidos frente a dianas específicas, representan las terapias más efectivas para los pacientes en los que la medicación convencional no es suficiente para el control de los síntomas. Sin embargo, estos tratamientos aún presentan ciertas limitaciones en cuanto a eficacia, seguridad, larga duración o alto coste, por lo que hay una necesidad urgente de desarrollar tratamientos más efectivos y seguros. Los alergoides conjugados a manano son vacunas de nueva generación para AIT dirigidas frente a células dendríticas (DCs) capaces de inducir células T reguladoras (Treg) funcionales. Por otro lado, omalizumab, un biológico anti-IgE, está aprobado para el tratamiento del asma alérgica grave, de urticaria crónica espontánea (CSU) y de rinosinusitis crónica con pólipos nasales (CRSwNP). Recientemente, se ha desarrollado un nuevo mAb anti-IgE de alta afinidad (ligelizumab) que se encuentra actualmente en fases muy avanzadas para el tratamiento de CSU...Fac. de Ciencias QuímicasTRUEunpu

Allergoid–mannan conjugates reprogram monocytes into tolerogenic dendritic cells via epigenetic and metabolic rewiring

Allergoid–mannan conjugates are novel vaccines for allergen-specific immunotherapy being currently assayed in phase 2 clinical trials. Allergoid–mannan conjugates target dendritic cells (DCs) and generate functional forkhead box P3 (FOXP3)-positive Treg cells, but their capacity to reprogram monocyte differentiation remains unknown

Immune modulation via T regulatory cell enhancement:Disease-modifying therapies for autoimmunity and their potential for chronic allergic and inflammatory diseases-An EAACI position paper of the Task Force on Immunopharmacology (TIPCO)

Therapeutic advances using targeted biologicals and small-molecule drugs have achieved significant success in the treatment of chronic allergic, autoimmune, and inflammatory diseases particularly for some patients with severe, treatment-resistant forms. This has been aided by improved identification of disease phenotypes. Despite these achievements, not all severe forms of chronic inflammatory and autoimmune diseases are successfully targeted, and current treatment options, besides allergen immunotherapy for selected allergic diseases, fail to change the disease course. T cell–based therapies aim to cure diseases through the selective induction of appropriate immune responses following the delivery of engineered, specific cytotoxic, or regulatory T cells (Tregs). Adoptive cell therapies (ACT) with genetically engineered T cells have revolutionized the oncology field, bringing curative treatment for leukemia and lymphoma, while therapies exploiting the suppressive functions of Tregs have been developed in nononcological settings, such as in transplantation and autoimmune diseases. ACT with Tregs are also being considered in nononcological settings such as cardiovascular disease, obesity, and chronic inflammatory disorders. After describing the general features of T cell–based approaches and current applications in autoimmune diseases, this position paper reviews the experimental models testing or supporting T cell–based approaches, especially Treg-based approaches, in severe IgE-mediated responses and chronic respiratory airway diseases, such as severe asthma and COPD. Along with an assessment of challenges and unmet needs facing the application of ACT in these settings, this article underscores the potential of ACT to offer curative options for patients with severe or treatment-resistant forms of these immune-driven disorders

Metabolic pathways in immune senescence and inflammaging: Novel therapeutic strategy for chronic inflammatory lung diseases. An EAACI position paper from the Task Force for Immunopharmacology

The accumulation of senescent cells drives inflammaging and increases morbidity of chronic inflammatory lung diseases. Immune responses are built upon dynamic changes in cell metabolism that supply energy and substrates for cell proliferation, differentiation, and activation. Metabolic changes imposed by environmental stress and inflammation on immune cells and tissue microenvironment are thus chiefly involved in the pathophysiology of allergic and other immune‐driven diseases. Altered cell metabolism is also a hallmark of cell senescence, a condition characterized by loss of proliferative activity in cells that remain metabolically active. Accelerated senescence can be triggered by acute or chronic stress and inflammatory responses. In contrast, replicative senescence occurs as part of the physiological aging process and has protective roles in cancer surveillance and wound healing. Importantly, cell senescence can also change or hamper response to diverse therapeutic treatments. Understanding the metabolic pathways of senescence in immune and structural cells is therefore critical to detect, prevent, or revert detrimental aspects of senescence‐related immunopathology, by developing specific diagnostics and targeted therapies. In this paper, we review the main changes and metabolic alterations occurring in senescent immune cells (macrophages, B cells, T cells). Subsequently, we present the metabolic footprints described in translational studies in patients with chronic asthma and chronic obstructive pulmonary disease (COPD), and review the ongoing preclinical studies and clinical trials of therapeutic approaches aiming at targeting metabolic pathways to antagonize pathological senescence. Because this is a recently emerging field in allergy and clinical immunology, a better understanding of the metabolic profile of the complex landscape of cell senescence is needed. The progress achieved so far is already providing opportunities for new therapies, as well as for strategies aimed at disease prevention and supporting healthy aging

Human dendritic cells activated with MV130 induce Th1, Th17 and IL-10 responses via RIPK2 and MyD88 signalling pathways

Recurrent respiratory tract infections (RRTIs) are the first leading cause of community-and nosocomial-acquired infections. Antibiotics remain the mainstay of treatment, enhancing the potential to develop antibiotic resistances. Therefore, the development of new alternative approaches to prevent and treat RRTIs is highly demanded. Daily sublingual administration of the whole heat-inactivated polybacterial preparation (PBP) MV130 significantly reduced the rate of respiratory infections in RRTIs patients, however, the immunological mechanisms of action remain unknown. Herein, we study the capacity of MV130 to immunomodulate the function of human dendritic cells (DCs) as a potential mechanism that contribute to the clinical benefits. We demonstrate that DCs from RRTIs patients and healthy controls display similar ex vivo immunological responses to MV130. By combining systems biology and functional immunological approaches we show that MV130 promotes the generation of Th1/Th17 responses via receptor-interacting serine/threonine-protein kinase-2 (RIPK2)-and myeloid-differentiation primary-response gene88 (MyD88)-mediated signalling pathways under the control of IL-10. In vivo BALB/c mice sublingually immunized with MV130 display potent systemic Th1/Th17 and IL-10 responses against related and unrelated antigens. We elucidate immunological mechanisms underlying the potential way of action of MV130, which might help to design alternative treatments in other clinical conditions with high risk of recurrent infections.This work was supported by grant IPT-2012-0639-090000 from INNPACTO and MINECO, Spain to Inmunotek S.L. The authors' laboratories are supported by grants SAF2014-52706-R to O.P. from MINECO, Spain, and SAF2016-79040R to D.S. from MINECO and European Fund for Regional Development, Spain. O.P. is a Ramon y Cajal Scholar funded by MINECO and the European Social Fund. L.C. is a recipient of a European Respiratory Society Fellowship (RESPIRE2-2013-3708). We thank to Juan Lopez-Relano and Sarai Martinez-Cano for excellent technical assistance with mice experiments.S

Allergoid-mannan conjugates imprint tolerogenic features in human macrophages

MINECOMinisterio de Ciencia e InnovaciónCDTIDepto. de Bioquímica y Biología MolecularFac. de Ciencias QuímicasTRUEpu

Omalizumab restores the ability of human plasmacytoid dendritic cells to induce Foxp3+Tregs

IgE-FcεR1 cross-linking on human pDCs impairs their capacity to generate regulatory T-cells and in vitro omalizumab restores this ability. These findings may pave the way for novel biomarkers to assess omalizumab clinical efficacy and responder patients.Secretaría de Estado de Investigación, Desarrollo e InnovaciónNovartisMINECODepto. de Bioquímica y Biología MolecularFac. de Ciencias QuímicasTRUEpu

MV140, a sublingual polyvalent bacterial preparation to treat recurrent urinary tract infections, licenses human dendritic cells for generating Th1, Th17, and IL-10 responses via Syk and MyD88

Recurrent urinary tract infections (RUTIs) are one of the most common bacterial infectious diseases, especially in women. Antibiotics remain the mainstay of treatment, but their overuse is associated with antibiotic-resistant infections and deleterious effects in the microbiota. Therefore, alternative approaches are fully demanded. Sublingual immunization with MV140 (Uromune), a polyvalent bacterial preparation (PBP) of whole heat-inactivated bacteria, demonstrated clinical efficacy for the treatment of RUTIs, but the involved immunological mechanisms remain unknown. Herein, we demonstrated that MV140 endorses human dendritic cells (DCs) with the capacity to generate Th1/Th17 and IL-10-producing T cells by mechanisms depending on spleen tyrosine kinase (Syk)- and myeloid differentiation primary response gene 88 (MyD88)-mediated pathways. MV140-induced activation of nuclear factor κB (NF-κB) and p38 in human DCs is essential for the generated Th1/Th17 and IL-10 immune responses whereas c-Jun N-terminal Kinase (JNK) and extracellular-signal regulated kinase (ERK) contribute to Th1 and IL-10 responses, respectively. Sublingual immunization of BALB/c mice with MV140 also induces potent systemic Th1/Th17 and IL-10 responses in vivo. We uncover immunological mechanisms underlying the way of action of MV140, which might well also contribute to understand the rational use of specific PBPs in other clinical conditions with potential high risk of recurrent infections.MINECODepto. de Bioquímica y Biología MolecularFac. de Ciencias QuímicasTRUEpu