Depletion of CD11c+ cells in the CD11c.DTR model drives expansion of unique CD64+ Ly6C+ monocytes that are poised to release TNF-α

Dendritic cells (DCs) play a vital role in innate and adaptive immunities. Inducible depletion of CD11c+ DCs engineered to express a high-affinity diphtheria toxin receptor has been a powerful tool to dissect DC function in vivo. However, despite reports showing that loss of DCs induces transient monocytosis, the monocyte population that emerges and the potential impact of monocytes on studies of DC function have not been investigated. We found that depletion of CD11c+ cells from CD11c.DTR mice induced the expansion of a variant CD64+ Ly6C+ monocyte population in the spleen and blood that was distinct from conventional monocytes. Expansion of CD64+ Ly6C+ monocytes was independent of mobilization from the BM via CCR2 but required the cytokine, G-CSF. Indeed, this population was also expanded upon exposure to exogenous G-CSF in the absence of DC depletion. CD64+ Ly6C+ monocytes were characterized by upregulation of innate signaling apparatus despite the absence of inflammation, and an increased capacity to produce TNF-α following LPS stimulation. Thus, depletion of CD11c+ cells induces expansion of a unique CD64+ Ly6C+ monocyte population poised to synthesize TNF-α. This finding will require consideration in experiments using depletion strategies to test the role of CD11c+ DCs in immunity

Outcome after allogeneic stem cell transplantation with haploidentical versus HLA-matched donors in patients with higher-risk MDS.

peer reviewedAllogeneic hematopoietic stem cell transplantation remains the best curative option for higher-risk myelodysplastic syndrome. The presence of monosomal karyotype and/or complex karyotype abnormalities predicts inferior survival after allo-SCT in MDS patients. Haploidentical allo-SCT has been increasingly used in acute leukemia (AL) and has similar results as using HLA-matched donors, but data on higher-risk MDS is sparse. We compared outcomes in 266 patients with higher-risk MDS after HLA-matched sibling donor (MSD, n = 79), HLA-matched unrelated donor (MUD, n = 139) and HLA haploidentical donor (HID, n = 48) from 2010 to 2019. Median donor age differed between the three groups (p < 0.001). The overall survival was significantly different between the three groups with a better OS observed in the MUD group (p = 0.014). This observation could be explained by a higher progression-free survival with MUD (p = 0.014). The cumulative incidence of grade 2-4 acute GvHD was significantly higher in the HID group (p = 0.051). However, in multivariable analysis, patients transplanted using an HID had comparable mortality to patients transplanted using a MUD (subdistribution hazard ratio [sHR]: 0.58 [0.32-1.07]; p = 0.080) and a MSD ([sHR]: 0.56 [0.28-1.11]; p = 0.094). MUD do not remain a significant positive predictor of survival, suggesting that beyond the donor-recipient HLA matching, the donor age might impact recipient outcome

Activated phosphoinositide 3-kinase δ syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity

Background: Activated phosphoinositide-3-kinase d syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking. Objectives: This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain of-function (GOF) disease; and identify predictors of severity in APDS. Methods: Data was collected from the ESID (European Society for Immunodeficiencies)-APDS registry and was compared with published cohorts of the other IEIs. Results: The analysis of 170 patients with APDS outlines high penetrance and early onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common, particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS. Conclusions: APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEIs is substantial. Some specific features distinguish APDS1 from APDS2. Early onset is a risk factor for severe disease course calling for specific treatment studies in younger patients. (J Allergy Clin Immunol 2023;152:984-96.

Le rôle immunomodulateur dans la réponse allo-immune de cellules hématopoïétiques mobilisées par du G-CSF

Allogeneic Hematopoietic Stem Cell Transplantation (Allo-HSCT) is the most effective immunotherapy for acute leukemia, due to the development of graft-versus-leukemia (GVL) effect mediated by alloreactive donor T cells. However, donor T cells specific for recipient alloantigens are also responsible for graft-versus-host disease (GVHD), a life-threatening complication that frequently occurs after allo-HSCT. The administration of Granulocyte colony stimulating factor (G-CSF) is routinely performed to collect Peripheral Blood Stem Cells (PBSC) from healthy donors for allo-HSCT. Few studies identified that G-CSF can induce myeloid suppressive cells in mice (CD11b+ Gr1+) with no human counterpart. We demonstrated in our study that G-CSF can induce a new population named CD34+Monocyte. The cumulative incidence of acute grade II to IV GVHD following allo-HSCT was lower in patients receiving grafts containing CD34+ monocyte frequencies above 12% of the CD34+ population. In mice, we demonstrated that G-CSF mobilized a highly conserved CD34+ monocyte population. CD34+Monocytes require T cell-mediated IFN-γ to produce Nitric Oxide that inhibits T cell activation and proliferation. In vivo, we report that CD34+ monocyte-derived NO regulates the alloreactive response by inducing T cell apoptosis and subsequently, the induction of regulatory T cells. In fact, uptake of apoptotic T cells by macrophages triggers them to produce high levels of TGF-β that drives the expansion of Tregs and induces immune tolerance. Such tolerogenic monocytes could represent a good candidate for the development of novel immunoregulatory and therapeutic cellular therapies.L’allogreffe de cellules souches hématopoïétiques (CSH) reste à l’heure actuelle la seule thérapie curative de nombreuses hémopathies malignes. Les lymphocytes T (LT) du donneur constituent une immunothérapie contre les cellules de la leucémie (ou lymphome) appelé effet « GVL » pour « Graft versus Leukemia ». Malheureusement cet effet est intimement lié à la maladie du greffon contre l’hôte appelée « GVH » pour « Graft versus Host » (destruction des cellules saines du receveur par les LT du donneur). L’allogreffe de CSH est de plus en plus souvent réalisées avec des greffons mobilisés par du G-CSF. Quelques publications identifient des cellules immunosuppressives avec un phénotype peu précis CD11b+ Gr1+ induites par le G-CSF pouvant regrouper plusieurs sous-types cellulaires et sans trouver de contre-partie humaine ou avec un mécanisme d’action peu clair. Nous avons démontré que le G-CSF mobilise chez l’homme, dans la fraction CD34+ du greffon, une population monocytaire. Lorsqu’elle représente plus de 12% des CD34+, les receveurs ont une incidence moindre de la GVH aiguë. Cette même population est phénotypiquement et fonctionnellement conservée chez la souris. En réponse à l’IFN-γ relargué par les LT allogéniques, elle produit de l’Oxyde Nitrique capable d’induire l’apoptose de ces LT in vitro. In vivo, nous avons pu décortiquer (chez la souris uniquement) les mécanismes de régulation de la GVH aiguë. Les LT apoptotiques phagocytés par les macrophages capables alors de devenir tolérogènes en produisant du TGF-β et ainsi d’induire des LT régulateurs. Dans le modèle murin d’allogreffe de CSH, le transfert adoptif de cette population purifiée protège le receveur de la GVH aiguë. Nous pensons que si cette population peut être cultivée et expandue ex vivo, elle pourrait être une thérapie cellulaire préventive contre la GVH

Adenovirus-specific T-lymphocyte efficacy in the presence of methylprednisolone: An in vitro study

International audienceVirus-specific T-cell (VST) infusion becomes a promising alternative treatment for refractory viral infections after hematopoietic stem cell transplantation (HSCT). However, VSTs are often infused during an immunosuppressive treatment course, especially corticosteroids, which are a first-line curative treatment of graft-versus-host disease (GVHD). We were interested in whether corticosteroids could affect adenovirus (ADV)-VST functions. After interferon (IFN)-γ based immunomagnetic selection, ADV-VSTs were in vitro expanded according to three different culture conditions: without methylprednisolone (MP; n = 7), with a final concentration of MP 1 µg/mL (n = 7) or MP 2 µg/mL (n = 7) during 28 ± 11 days. Efficacy and alloreactivity of expanded ADV-VSTs was controlled in vitro. MP transitorily inhibited ADV-VST early expansion. No impairment of specific IFN-γ secretion capacity and cytotoxicity of ADV-VSTs was observed in the presence of MP. However, specific proliferation and alloreactivity of ADV-VSTs were decreased in the presence of MP. Altogether, these results and the preliminary encouraging clinical experiences of co-administration of MP 1 mg/kg and ADV-VSTs will contribute to safe and efficient use of anti-viral immunotherapy

Update on Actinomucor elegans , a mucormycete infrequently detected in human specimens: how combined microbiological tools contribute efficiently to a more accurate medical care

International audienceActinomucor elegans is a fungus belonging to mucormycetes and is still probably underdiagnosed due to misidentification. Based on a recent first case of Actinomucor elegans sinusitis in Europe, in an immunocompromised patient under voriconazole treatment, this paper aims to summarize knowledge about A. elegans mucormycoses. Even if the diagnosis of mucormycosis was made using traditional mycology techniques, precise identification of the fungus could only be achieved using molecular tools. In this observation, the galactomannan dosage was positive until the introduction of treatment and surgical debridement. The patient experienced no relapse after one year. By reviewing the four previous A. elegans reported cases and describing the mycological characteristics of this species, we highlight the need to use a combination of tools to improve the diagnostic strategy in such rare and life-threatening clinical situations

Letermovir for Secondary Prophylaxis of Cytomegalovirus Infection and Disease after Allogeneic Hematopoietic Cell Transplantation: Results from the French Compassionate Program

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