Generation of human memory stem T cells after haploidentical T-replete hematopoietic stem cell transplantation

Memory stem T cells (TSCM) have been proposed as key determinants of immunologic memory. However, their exact contribution to a mounting immune response, as well as the mechanisms and timing of their in vivo generation, are poorly understood. We longitudinally tracked TSCM dynamics in patients undergoing haploidentical hematopoietic stem cell transplantation (HSCT), thereby providing novel hints on the contribution of this subset to posttransplant immune reconstitution in humans. We found that donor-derived TSCM are highly enriched early after HSCT. We showed at the antigen-specific and clonal level that TSCM lymphocytes can differentiate directly from naive precursors infused within the graft and that the extent of TSCM generation might correlate with interleukin 7 serum levels. In vivo fate mapping through T-cell receptor sequencing allowed defining the in vivo differentiation landscapes of human naive T cells, supporting the notion that progenies of single naive cells embrace disparate fates in vivo and highlighting TSCM as relevant novel players in the diversification of immunological memory after allogeneic HSCT

Profiling Antibody Response Patterns in COVID-19: Spike S1-Reactive IgA Signature in the Evolution of SARS-CoV-2 Infection

This contribution explores in a new statistical perspective the antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 141 coronavirus disease 2019 (COVID-19) patients exhibiting a broad range of clinical manifestations. This cohort accurately reflects the characteristics of the first wave of the SARS-CoV-2 pandemic in Italy. We determined the IgM, IgA, and IgG levels towards SARS-CoV-2 S1, S2, and NP antigens, evaluating their neutralizing activity and relationship with clinical signatures. Moreover, we longitudinally followed 72 patients up to 9 months postsymptoms onset to study the persistence of the levels of antibodies. Our results showed that the majority of COVID-19 patients developed an early virus-specific antibody response. The magnitude and the neutralizing properties of the response were heterogeneous regardless of the severity of the disease. Antibody levels dropped over time, even though spike reactive IgG and IgA were still detectable up to 9 months. Early baseline antibody levels were key drivers of the subsequent antibody production and the long-lasting protection against SARS-CoV-2. Importantly, we identified anti-S1 IgA as a good surrogate marker to predict the clinical course of COVID-19. Characterizing the antibody response after SARS-CoV-2 infection is relevant for the early clinical management of patients as soon as they are diagnosed and for implementing the current vaccination strategies

Case report: Ponatinib as a bridge to CAR-T cells and subsequent maintenance in a patient with relapsed/refractory Philadelphia-like acute lymphoblastic leukemia

Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) constitutes a heterogeneous subset of ALL with a uniformly unfavorable prognosis. The identification of mutations amenable to treatment with tyrosine kinase-inhibitors (TKIs) represents a promising field of investigation. We report the case of a young patient affected by relapsed/refractory Ph-like ALL treated with chimeric antigen receptor T (CAR-T) cells after successful bridging with compassionate-use ponatinib and low-dose prednisone. We restarted low-dose ponatinib maintenance three months later. Twenty months later, measurable residual disease negativity and B-cell aplasia persist. To the best of our knowledge, this is the first case reporting the use of ponatinib in Ph-like ALL as a bridge to and maintenance after CAR-T cell therapy

Planck 2015 results: XXV. Diffuse low-frequency Galactic foregrounds

We discuss the Galactic foreground emission between 20 and 100 GHz based on observations by Planck and WMAP. The total intensity in this part of the spectrum is dominated by free-free and spinning dust emission, whereas the polarized intensity is dominated by synchrotron emission. The Commander component-separation tool has been used to separate the various astrophysical processes in total intensity. Comparison with radio recombination line templates verifies the recovery of the free-free emission along the Galactic plane. Comparison of the high-latitude H\u3b1 emission with our free-free map shows residuals that correlate with dust optical depth, consistent with a fraction (\ue2\u2030 30%) of H\u3b1 having been scattered by high-latitude dust. We highlight a number of diffuse spinning dust morphological features at high latitude. There is substantial spatial variation in the spinning dust spectrum, with the emission peak (in I\u3bd) ranging from below 20 GHz to more than 50 GHz. There is a strong tendency for the spinning dust component near many prominent H ii regions to have a higher peak frequency, suggesting that this increase in peak frequency is associated with dust in the photo-dissociation regions around the nebulae. The emissivity of spinning dust in these diffuse regions is of the same order as previous detections in the literature. Over the entire sky, the Commander solution finds more anomalous microwave emission (AME) than the WMAP component maps, at the expense of synchrotron and free-free emission. This can be explained by the difficulty in separating multiple broadband components with a limited number of frequency maps. Future surveys, particularly at 5-20 GHz, will greatly improve the separation by constraining the synchrotron spectrum. We combine Planck and WMAP data to make the highest signal-to-noise ratio maps yet of the intensity of the all-sky polarized synchrotron emission at frequencies above a few GHz. Most of the high-latitude polarized emission is associated with distinct large-scale loops and spurs, and we re-discuss their structure. We argue that nearly all the emission at 40deg > l >-90deg is part of the Loop I structure, and show that the emission extends much further in to the southern Galactic hemisphere than previously recognised, giving Loop I an ovoid rather than circular outline. However, it does not continue as far as the "Fermi bubble/microwave haze", making it less probable that these are part of the same structure. We identify a number of new faint features in the polarized sky, including a dearth of polarized synchrotron emission directly correlated with a narrow, roughly 20deg long filament seen in H\u3b1 at high Galactic latitude. Finally, we look for evidence of polarized AME, however many AME regions are significantly contaminated by polarized synchrotron emission, and we find a 2\u3c3 upper limit of 1.6% in the Perseus region

Stem Cell Transplantation for Muscular Dystrophy: The Challenge of Immune Response

Treating muscle disorders poses several challenges to the rapidly evolving field of regenerative medicine. Considerable progress has been made in isolating, characterizing, and expanding myogenic stem cells and, although we are now envisaging strategies to generate very large numbers of transplantable cells (e.g., by differentiating induced pluripotent stemcells), limitations directly linked to the interaction between transplanted cells and the host will continue to hamper a successful outcome. Among these limitations, host inflammatory and immune responses challenge the critical phases after cell delivery, including engraftment, migration, and differentiation. Therefore, it is key to study the mechanisms and dynamics that impair the efficacy of cell transplants in order to develop strategies that can ultimately improve the outcome of allogeneic and autologous stemcell therapies, in particular for severe disease such as muscular dystrophies. In this review we provide an overview of the main players and issues involved in this process and discuss potential approaches that might be beneficial for future regenerative therapies of skeletal muscle

A longitudinal analysis of humoral, T cellular response and influencing factors in a cohort of healthcare workers: Implications for personalized SARS-CoV-2 vaccination strategies

IntroductionSARS-CoV-2 mRNA vaccinations elicit both virus-specific humoral and T-cell responses, but a complex interplay of different influencing factors, such as natural immunity, gender, and age, guarantees host protection. The present study aims to assess the immune dynamics of humoral, T-cell response, and influencing factors to stratify individual immunization status up to 10 months after Comirnaty-vaccine administration.MethodsTo this aim, we longitudinally evaluated the magnitude and kinetics of both humoral and T-cell responses by serological tests and enzyme-linked immunospot assay at 5 time points. Furthermore, we compared the course over time of the two branches of adaptive immunity to establish an eventual correlation between adaptive responses. Lastly, we evaluated putative influencing factors collected by an anonymized survey administered to all participants through multiparametric analysis. Among 984 healthcare workers evaluated for humoral immunity, 107 individuals were further analyzed to describe SARS-CoV-2-specific T-cell responses. Participants were divided into 4 age groups: <40 and ≥40 years for men, <48 and ≥48 years for women. Furthermore, results were segregated according to SARS-CoV-2-specific serostatus at baseline.ResultsThe disaggregated evaluation of humoral responses highlighted antibody levels decreased in older subjects. The humoral responses were higher in females than in males (p=0.002) and previously virus-exposed subjects compared to naïve subjects (p<0.001). The vaccination induced a robust SARS-CoV-2 specific T-cell response at early time points in seronegative subjects compared to baseline levels (p<0.0001). However, a contraction was observed 6 months after vaccination in this group (p<0.01). On the other hand, the pre-existing specific T-cell response detected in natural seropositive individuals was longer-lasting than the response of the seronegative subjects, decreasing only 10 months after vaccination. Our data suggest that T-cell reactiveness is poorly impacted by sex and age. Of note, SARS-CoV-2-specific T-cell response was not correlated to the humoral response at any time point.DiscussionThese findings suggest prospects for rescheduling vaccination strategies by considering individual immunization status, personal characteristics, and the appropriate laboratory tests to portray immunity against SARS-CoV-2 accurately. Deepening our knowledge about T and B cell dynamics might optimize the decision-making process in vaccination campaigns, tailoring it to each specific immune response

The Effect of Removable Orthodontic Appliances on Oral Microbiota: A Systematic Review

Background (1): Removable orthodontic appliances may favor plaque accumulation and oral microbe colonization. This might be associated with intraoral adverse effects on enamel or periodontal tissues. The proposed systematic review was carried out to evaluate qualitatively and quantitatively the microbiological changes occurring during orthodontic therapy with removable orthodontic appliances. Methods (2): PubMed, Cochrane Library, Embase, Web of Science, Scopus, Ovid Medline, and Dentistry and Oral Sciences Source were searched. The research included every article published up to January 2020. The Preferred Reporting Items for Reporting Systematic reviews and Meta Analyses (PRISMA) protocol and the “Swedish Council on Technology Assessment in Health Care Criteria for Grading Assessed Studies” (SBU) method were adopted to conduct this systematic review. Results (3): The current study has a moderate evidence, demonstrating that removable appliances do influence the oral microbiota. Significant alterations occur just 15 days after the beginning of therapy, independently from the type of appliance. Furthermore, the levels of oral pathogens decrease significantly or even returned to pre-treatment levels several months later the therapy end. Conclusions (4): This review suggests that orthodontic treatment with removable appliances induces changes to oral microflora, but these alterations might not be permanent

Inflammation converts human mesoangioblasts into targets of alloreactive immune responses:implications for allogeneic cell therapy of DMD

Stem cell therapy is a promising approach to regenerate healthy tissues starting from a limited amount of self-renewing cells. Immunological rejection of cell therapy products might represent a major limitation. In this study, we investigated the immunological functional profile of mesoangioblasts, vessel-associated myogenic stem cells, currently tested in a phase 1–2a trial, active in our Institute, for the treatment of Duchenne muscular dystrophy. We report that in resting conditions, human mesoangioblasts are poorly immunogenic, inefficient in promoting the expansion of alloreactive T cells and intrinsically resistant to T-cell killing. However, upon exposure to interferon-γ or differentiation into myotubes, mesoangioblasts acquire the ability to promote the expansion of alloreactive T cells and acquire sensitivity to T-cell killing. Resistance of mesoangioblasts to T-cell killing is largely due to the expression of the intracellular serine protease inhibitor-9 and represents a relevant mechanism of stem cell immune evasion

A longitudinal analysis of humoral, T cellular response and influencing factors in a cohort of healthcare workers: Implications for personalized SARS-CoV-2 vaccination strategies

IntroductionSARS-CoV-2 mRNA vaccinations elicit both virus-specific humoral and T-cell responses, but a complex interplay of different influencing factors, such as natural immunity, gender, and age, guarantees host protection. The present study aims to assess the immune dynamics of humoral, T-cell response, and influencing factors to stratify individual immunization status up to 10 months after Comirnaty-vaccine administration. MethodsTo this aim, we longitudinally evaluated the magnitude and kinetics of both humoral and T-cell responses by serological tests and enzyme-linked immunospot assay at 5 time points. Furthermore, we compared the course over time of the two branches of adaptive immunity to establish an eventual correlation between adaptive responses. Lastly, we evaluated putative influencing factors collected by an anonymized survey administered to all participants through multiparametric analysis. Among 984 healthcare workers evaluated for humoral immunity, 107 individuals were further analyzed to describe SARS-CoV-2-specific T-cell responses. Participants were divided into 4 age groups: <40 and >= 40 years for men, <48 and >= 48 years for women. Furthermore, results were segregated according to SARS-CoV-2-specific serostatus at baseline. ResultsThe disaggregated evaluation of humoral responses highlighted antibody levels decreased in older subjects. The humoral responses were higher in females than in males (p=0.002) and previously virus-exposed subjects compared to naive subjects (p<0.001). The vaccination induced a robust SARS-CoV-2 specific T-cell response at early time points in seronegative subjects compared to baseline levels (p<0.0001). However, a contraction was observed 6 months after vaccination in this group (p<0.01). On the other hand, the pre-existing specific T-cell response detected in natural seropositive individuals was longer-lasting than the response of the seronegative subjects, decreasing only 10 months after vaccination. Our data suggest that T-cell reactiveness is poorly impacted by sex and age. Of note, SARS-CoV-2-specific T-cell response was not correlated to the humoral response at any time point. DiscussionThese findings suggest prospects for rescheduling vaccination strategies by considering individual immunization status, personal characteristics, and the appropriate laboratory tests to portray immunity against SARS-CoV-2 accurately. Deepening our knowledge about T and B cell dynamics might optimize the decision-making process in vaccination campaigns, tailoring it to each specific immune response