Functional Characterization of Regulatory Macrophages That Inhibit Graft-reactive Immunity

Macrophage accumulation in transplanted organs has long been recognized as a feature of allograft rejection1. Immunogenic monocytes infiltrate the allograft early after transplantation, mount a graft reactive response against the transplanted organ, and initiate organ rejection2. Recent data suggest that suppressive macrophages facilitate successful long-term transplantation3 and are required for the induction of transplantation tolerance4. This suggests a multidimensional concept of macrophage ontogeny, activation, and function, which demands a new roadmap for the isolation and analysis of macrophage function5. Due to the plasticity of macrophages, it is necessary to provide a methodology to isolate and characterize macrophages, depending on the tissue environment, and to define their functions according to different scenarios. Here, we describe a protocol for immune characterization of graft-infiltrating macrophages and the methods we used to functionally evaluate their capacity to inhibit CD8+ T proliferation and to promote CD4+Foxp3+ Treg expansion in vitro.We acknowledge the technical contributions of the Flow Cytometry, Microsurgery, and Bio- repository/Pathology Centers of Research Excellence at Mount Sinai. This work was supported by the COST Action BM1305: Action to Focus and Accelerate Cell Tolerogenic Therapies (A FACTT), the Mount Sinai Recanati/Miller Transplantation Institute developmental funds, Ministerio de Ciencia e Innovacion SAF2013-48834-R and SAF2016-80031-R J.O.S

Myeloid derived suppressor cells and autoimmunity

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Immunotherapy with myeloid cells for tolerance induction

PURPOSE OF REVIEW: Understanding the interplay between myeloid dendritic cells and T cells under tolerogenic conditions, and whether their interactions induce the development of antigen-specific regulatory T cells (Tregs) is critical to uncover the mechanisms involved in the induction of indefinite allograft survival. RECENT FINDINGS: Myeloid dendritic cell-T-cell interactions are seminal events that determine the outcome of the immune response, and multiple in-vitro protocols suggest the generation of tolerogenic myeloid dendritic cells that modulate T-cell responses, and determine the outcome of the immune response to an allograft following adoptive transfer. We believe that identifying specific conditions that lead to the generation of tolerogenic myeloid dendritic cells and Tregs are critical for the manipulation of the immune response towards the development of transplantation tolerance. SUMMARY: We summarize recent findings regarding specific culture conditions that generate tolerogenic myeloid dendritic cells that induce T-cell hyporesponsiveness and Treg development, which represents a novel immunotherapeutic approach to promote the induction of indefinite graft survival prolongation. The interpretations presented here illustrate that different mechanisms govern the generation of tolerogenic myeloid dendritic cells, and we discuss the concomitant therapeutic implications.This work was supported by the Programa Ramón y Cajal RYC-2006-1588, Ministerio de Educa-ción y Ciencia SAF2007-63579, Programa José Castillejo JC2008-00065, and Programa de Investigación de Grupos Emergentes del ISCIII (to J.C.O.), and NIH R01 AI-41428, AI-72039, and the Emerald Foundation (to J.S.B.).S

Tolerogenic Role of Myeloid Suppressor Cells in Organ Transplantation

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature cells of myeloid origin with a specific immune inhibitory function that negatively regulates the adaptive immune response. Since MDSC participate in the promotion of tolerance in the context of organ transplantation, therapeutic strategies that regulate the induction and development of MDSC have been the center of scientist attention. Here we review literature regarding induction of MDSC with demonstrated suppressive function among different types of allografts and their mechanism of action. While manipulation of MDSC represents a potential therapeutic approach for the promotion of donor specific tolerance in solid organ transplantation, further characterization of their specific phenotype, which distinguishes MDSC from non-suppressive myeloid cells, and detailed evaluation of the inhibitory mechanism that determines their suppressive function, is necessary for the realistic application of MDSC as biomarkers in health and disease and their potential use as immune cell therapy in organ transplantation

Alicante-Winter Immunology Symposium in Health (A-Wish) and the Boulle-SEI awards: A collaboration between the Spanish Society for immunology, the University of Alicante and the Jean Boulle Group to honor the Balmis Expedition

• This introduction for the first Alicante-Winter Immunology Symposium in Health (A-WISH) and the Boulle-SEI Awards, seeks to promote the efforts of Spanish scientists in the advancement of the study of immunology, infectious diseases and vaccinology, and also to disseminate the development of novel approaches in diagnosis and therapeutics of diseases that involve the immune system. • On December 16th and 17th 2021 the Spanish Society of Immunology (SEI) and the University of Alicante (UA) joined forces to organize the first A-WISH (https://a-wish.org). • In this first symposium, researchers shared their expertise to address strategies for the COVID-19 response and pandemic preparedness

Review: Ischemia Reperfusion Injury?A Translational Perspective in Organ Transplantation

Thanks to the development of new, more potent and selective immunosuppressive drugs together with advances in surgical techniques, organ transplantation has emerged from an experimental surgery over fifty years ago to being the treatment of choice for many end-stage organ diseases, with over 139,000 organ transplants performed worldwide in 2019. Inherent to the transplantation procedure is the fact that the donor organ is subjected to blood flow cessation and ischemia during harvesting, which is followed by preservation and reperfusion of the organ once transplanted into the recipient. Consequently, ischemia/reperfusion induces a significant injury to the graft with activation of the immune response in the recipient and deleterious effect on the graft. The purpose of this review is to discuss and shed new light on the pathways involved in ischemia/reperfusion injury (IRI) that act at different stages during the donation process, surgery, and immediate post-transplant period. Here, we present strategies that combine various treatments targeted at different mechanistic pathways during several time points to prevent graft loss secondary to the inflammation caused by IRI

The BCG Vaccine for COVID-19: First Verdict and Future Directions.

Despite of the rapid development of the vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it will take several months to have enough doses and the proper infrastructure to vaccinate a good proportion of the world population. In this interim, the accessibility to the Bacille Calmette-Guerin (BCG) may mitigate the pandemic impact in some countries and the BCG vaccine offers significant advantages and flexibility in the way clinical vaccines are administered. BCG vaccination is a highly cost-effective intervention against tuberculosis (TB) and many low-and lower-middle-income countries would likely have the infrastructure, and health care personnel sufficiently familiar with the conventional TB vaccine to mount full-scale efforts to administer novel BCG-based vaccine for COVID-19. This suggests the potential for BCG to overcome future barriers to vaccine roll-out in the countries where health systems are fragile and where the effects of this new coronavirus could be catastrophic. Many studies have reported cross-protective effects of the BCG vaccine toward non-tuberculosis related diseases. Mechanistically, this cross-protective effect of the BCG vaccine can be explained, in part, by trained immunity, a recently discovered program of innate immune memory, which is characterized by non-permanent epigenetic reprogramming of macrophages that leads to increased inflammatory cytokine production and consequently potent immune responses. In this review, we summarize recent work highlighting the potential use of BCG for the treatment respiratory infectious diseases and ongoing SARS-CoV-2 clinical trials. In situations where no other specific prophylactic tools are available, the BCG vaccine could be used as a potential adjuvant, to decrease sickness of SARS-CoV-2 infection and/or to mitigate the effects of concurrent respiratory infections.The authors' work is supported by National Institutes of Health grants R01 AI139623AI and Ministerio de Ciencia e Innovación PID2019-110015RB-I00 (JO); PID2019-105761RB-100 (EN-V). MG-P is funded from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 860003.S

Experiencia en el seguimiento de la alimentación de población paquistaní diabética

Cartel presentado en la Segunda Conferencia Internacional de Comunicación en Salud, celebrada el 23 de octubre de 2015 en la Universidad Carlos III de MadridIntroducción: Trabajo realizado en el marco de un Ensayo Clínico Aleatorizado multicéntrico desarrollado en 3 Centros de Salud: Besòs y Raval Sud de Barcelona, y Fondo de Santa Coloma de Gramenet, sobre ”Efectividad de una dieta adaptada a los hábitos culinarios de la población paquistaní en el grado de control metabólico de la diabetes”. Objetivos: Conocer la alimentación de la población de origen paquistaní que padece Diabetes Mellitus II (DM II) en tres Áreas Básicas de Salud urbanas; Identificar la cantidad de hidratos de carbono (HC) que ingieren habitualmente; Evaluar si cumplen las recomendaciones sobre raciones de HC según las Guías de Práctica Clínica para la DM II. Metodología: estudio observacional descriptivo. Durante el seguimiento de los pacientes del estudio antes citado, se les pasa diversos cuestionarios socioculturales, familiares y de hábitos alimentarios. En este último y, con el fin de poder cuantificar mejor la cantidad de Hidratos de carbono ingeridos, tomamos como referencia la medida de Chapati (principal alimento rico en HC que consumen. Criterios de inclusión: pacientes adultos de origen paquistaní con DM II y con Hemoglobina glicada >8%. Resultados y conclusiones: Seguimiento de 15 pacientes. Tienen conocimientos sobre su patología y la dieta a seguir. Suelen hacer 3 comidas al día. No realizan suplementos. Existe un alto consumo de HC, principalmente en forma de Chapati (harina integral) y Dhal (legumbre sin piel). Escasez de pescados y huevos. Pocas verduras crudas y lácteos. Alto consumo de té y bebidas edulcoradas. Variabilidad de la dieta en función de las características socioculturales y familiares. Los hombres que conviven sin familia, tienen platos mas monótonos y mezclados en una olla. Existe un consumo excesivo de hidratos de carbono, por encima de las recomendaciones para el buen control metabólico de la DMII

Genetic diversity and signatures of selection of drug resistance in Plasmodium populations from both human and mosquito hosts in continental Equatorial Guinea

BACKGROUND: In Plasmodium, the high level of genetic diversity and the interactions established by co-infecting parasite populations within the same host may be a source of selection on pathogen virulence and drug resistance. As different patterns have already been described in humans and mosquitoes, parasite diversity and population structure should be studied in both hosts to properly assess their effects on infection and transmission dynamics. This study aimed to characterize the circulating populations of Plasmodium spp and Plasmodium falciparum from a combined set of human blood and mosquito samples gathered in mainland Equatorial Guinea. Further, the origin and evolution of anti-malarial resistance in this area, where malaria remains a major public health problem were traced. METHODS: Plasmodium species infecting humans and mosquitoes were identified by nested-PCR of chelex-extracted DNA from dried blood spot samples and mosquitoes. Analysis of Pfmsp2 gene, anti-malarial-resistance associated genes, Pfdhps, Pfdhfr, Pfcrt and Pfmdr1, neutral microsatellites (STR) loci and Pfdhfr and Pfdhps flanking STR was undertaken to evaluate P. falciparum diversity. RESULTS: Prevalence of infection remains high in mainland Equatorial Guinea. No differences in parasite formula or significant genetic differentiation were seen in the parasite populations in both human and mosquito samples. Point mutations in all genes associated with anti-malarial resistance were highly prevalent. A high prevalence was observed for the Pfdhfr triple mutant in particular, associated with pyrimethamine resistance.Analysis of Pfdhps and Pfdhfr flanking STR revealed a decrease in the genetic diversity. This finding along with multiple independent introductions of Pfdhps mutant haplotypes suggest a soft selective sweep and an increased differentiation at Pfdhfr flanking microsatellites hints a model of positive directional selection for this gene. CONCLUSIONS: Chloroquine is no longer recommended for malaria treatment in Equatorial Guinea but sulphadoxine-pyrimethamine (SP) remains in use in combination with artesunate and is the only drug recommended in preventive chemotherapy in pregnancy. The high prevalence of point mutations in Pfdhfr and Pfdhps points to the danger of an eventual reduction in the efficacy of SP combined therapy in P. falciparum populations in Equatorial Guinea and to the essential continuous monitoring of these two genes.This study was supported by PEst-OE/SAU/LA0018/2011 - Proj. Estratégico LA0018 2011/2012 (http://cmdt.ihmt.unl.pt/index.php/pt/) and PTDC/SAU-EPI/113326/2009, “Fundacão para a Ciência e Tecnologia/Ministério da Educação e Ciência”, FCT/MEC (http://alfa.fct.mctes.pt/index.phtml.pt), Portugal and by “Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación”, Madrid, Spain. C. Mendes and P. Salgueiro hold FCT grants (SRFH/BD/41473/2007 and SFRH/BPD/72532/2010, respectively).S

Induction of High Levels of Specific Humoral and Cellular Responses to SARS-CoV-2 After the Administration of Covid-19 mRNA Vaccines Requires Several Days

Objectives: In the context of the Covid-19 pandemic, the fast development of vaccines with efficacy of around 95% preventing Covid-19 illness provides a unique opportunity to reduce the mortality associated with the pandemic. However, in the absence of efficacious prophylactic medications and few treatments for this infection, the induction of a fast and robust protective immunity is required for effective disease control, not only to prevent the disease but also the infection and shedding/transmission. The objective of our study was to analyze the level of specific humoral and cellular T-cell responses against the spike protein of SARS-CoV-2 induced by two mRNA-based vaccines (BNT162b2 and mRNA-1273), but also how long it takes after vaccination to induce these protective humoral and cellular immune responses. Methods: We studied in 40 healthy (not previously infected) volunteers vaccinated with BNT162b2 or mRNA-1273 vaccines the presence of spike-specific IgG antibodies and SARS-CoV-2-specific T cells at 3, 7 and 14 days after receiving the second dose of the vaccine. The specific T-cell response was analyzed stimulating fresh whole blood from vaccinated volunteers with SARS-CoV-2 peptides and measuring the release of cytokines secreted by T cells in response to SARS-CoV-2 stimulation. Results: Our results indicate that the immunization capacity of both vaccines is comparable. However, although both BNT162b2 and mRNA-1273 vaccines can induce early B-cell and T-cell responses, these vaccine-mediated immune responses do not reach their maximum values until 14 days after completing the vaccination schedule. Conclusion: This refractory period in the induction of specific immunity observed after completing the vaccination could constitute a window of higher infection risk, which could explain some emerging cases of SARS-CoV-2 infection in vaccinated people.This work was supported by grants co-funded by ERDF (FEDER) Funds from the European Commission “A way of making Europe” from the Instituto de Salud Carlos III (ISCIII) COV20-00668 to RCR and PI18/00506 to MP. It was also partially financed by a grant from “Fundación Familia Alonso” (FFA-FIBHGM-2019) and the consortium ACT4COVID, funded by Cellnex-Telecom. SG-M was supported by the Youth Employment Program co-financed by the Madrid community and FEDER Funds (PEJ-2020-AI/BMD-17954). JO has received funding from the European Union Horizon 2020 research and innovation program VACCELERATE under grant agreement No [101037867]. The funders had no role in study design, data collection, or analysis; the decision to publish; or the preparation of the manuscript.S