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Background: Immunosuppression is a major risk factor for the development of visceral leishmaniasis (VL). The number of patients receiving immunosuppressant drugs such as TNF antagonist (anti-TNF) and methotrexate (MTX) is increasing. In these patients, VL is more severe, their response to treatment poorer, and they are at higher risk of relapse, a consequence (largely) of the poor and inappropriate immune response they develop. Objectives: To examine the effect of immunosuppressive treatment on the host immune response and thus gain insight into the reduced efficacy of pentavalent antimonials in these patients. Experiments were performed using BALB/c mice immunosuppressed with anti-TNF or MTX, infected with Leishmania infantum promastigotes, and then treated with Glucantime® at clinical doses. Results: Immunosuppression with both agents impeded parasite elimination from the spleen and bone marrow. Low pro-inflammatory cytokine production by CD4+ and CD8+ T cells was detected, along with an increase in PD-1 and IL-10 expression by B and T cells in the immunosuppressed groups after treatment. Conclusion: The immunosuppressed mice were unable to develop specific cellular immunity to the parasite, perhaps explaining the greater risk of VL relapse seen in pharmacologically immunosuppressed human patients. [ABSTRACT FROM AUTHOR]

BackgroundImmunosuppression is a major risk factor for the development of visceral leishmaniasis (VL). The number of patients receiving immunosuppressant drugs such as TNF antagonist (anti-TNF) and methotrexate (MTX) is increasing. In these patients, VL is more severe, their response to treatment poorer, and they are at higher risk of relapse, a consequence (largely) of the poor and inappropriate immune response they develop.ObjectivesTo examine the effect of immunosuppressive treatment on the host immune response and thus gain insight into the reduced efficacy of pentavalent antimonials in these patients. Experiments were performed using BALB/c mice immunosuppressed with anti-TNF or MTX, infected with Leishmania infantum promastigotes, and then treated with Glucantime® at clinical doses.ResultsImmunosuppression with both agents impeded parasite elimination from the spleen and bone marrow. Low pro-inflammatory cytokine production by CD4+ and CD8+ T cells was detected, along with an increase in PD-1 and IL-10 expression by B and T cells in the immunosuppressed groups after treatment.ConclusionThe immunosuppressed mice were unable to develop specific cellular immunity to the parasite, perhaps explaining the greater risk of VL relapse seen in pharmacologically immunosuppressed human patients.

CD4+ T-cell activation through recognition of Human Leukocyte Antigen II (HLAII)-presented peptides is a key step in the development of unwanted immune response against biotherapeutics, such as the generation of anti-drug antibodies (ADA). Therefore, the identification of HLAII-presented peptides derived from biotherapeutics is a crucial part of immunogenicity risk assessment and mitigation strategies during drug development. To date, numerous CD4+ T-cell epitopes have been identified by HLAII immunopeptidomics in antibody-based biotherapeutics using either their native or aggregated form. Antibody-target immune complexes have been detected in patients with ADA and are thought to play a role in ADA development by enhancing the presentation of CD4+ T-cell epitopes at the surface of antigen presenting cells (APCs). The aim of this study was to investigate the effect of biotherapeutic antibody-target immune complexes on the HLAII peptide presentation of biotherapeutics in human primary monocyte-derived dendritic cells (DCs). The trimeric tumor necrosis factor (TNF) and its biotherapeutic antagonists infliximab (INFL), adalimumab (ADAL), and a single armed Fab' were used as a model system. The HLAII immunopeptidome of DCs loaded with antagonists or their immune complexes with TNF was analyzed by trapped ion mobility time-of-flight mass spectrometry (timsTOF MS) leading to the identification of ~ 12,000 unique HLAII-associated peptides per preparation. Anti-TNF sequences were detected at a median of 0.3% of the total immunopeptidome, against a majority background of peptides from endogenous and media-derived proteins. TNF antagonist presentation spanned the variable and constant regions in a widespread manner in both light and heavy chains, consistent with previously discovered HLAII peptides. This investigation extends the collection of observed HLAII peptides from anti-TNF biotherapeutics to include sequences that at least partially span the complementary determining regions (CDRs), such as the LCDR1 for both INFL and ADAL. Although antagonist presentation varied significantly across donors, peptides from both bivalent antagonists INFL-and ADAL were more highly presented relative to the Fab'. While TNF immune complexes did not alter overall HLAII presentation, a moderate increase in presentation of a subset of peptide clusters was observed in the case of INFL-TNF, which included HCDR2, HCDR3 and LCDR2 sequences. [ABSTRACT FROM AUTHOR]

CD4+ T-cell activation through recognition of Human Leukocyte Antigen II (HLAII)-presented peptides is a key step in the development of unwanted immune response against biotherapeutics, such as the generation of anti-drug antibodies (ADA). Therefore, the identification of HLAII-presented peptides derived from biotherapeutics is a crucial part of immunogenicity risk assessment and mitigation strategies during drug development. To date, numerous CD4+ T-cell epitopes have been identified by HLAII immunopeptidomics in antibody-based biotherapeutics using either their native or aggregated form. Antibody-target immune complexes have been detected in patients with ADA and are thought to play a role in ADA development by enhancing the presentation of CD4+ T-cell epitopes at the surface of antigen presenting cells (APCs). The aim of this study was to investigate the effect of biotherapeutic antibody-target immune complexes on the HLAII peptide presentation of biotherapeutics in human primary monocyte-derived dendritic cells (DCs). The trimeric tumor necrosis factor (TNF) and its biotherapeutic antagonists infliximab (INFL), adalimumab (ADAL), and a single armed Fab’ were used as a model system. The HLAII immunopeptidome of DCs loaded with antagonists or their immune complexes with TNF was analyzed by trapped ion mobility time-of-flight mass spectrometry (timsTOF MS) leading to the identification of ~ 12,000 unique HLAII-associated peptides per preparation. Anti-TNF sequences were detected at a median of 0.3% of the total immunopeptidome, against a majority background of peptides from endogenous and media-derived proteins. TNF antagonist presentation spanned the variable and constant regions in a widespread manner in both light and heavy chains, consistent with previously discovered HLAII peptides. This investigation extends the collection of observed HLAII peptides from anti-TNF biotherapeutics to include sequences that at least partially span the complementary determining regions (CDRs), such as the LCDR1 for both INFL and ADAL. Although antagonist presentation varied significantly across donors, peptides from both bivalent antagonists INFL and ADAL were more highly presented relative to the Fab’. While TNF immune complexes did not alter overall HLAII presentation, a moderate increase in presentation of a subset of peptide clusters was observed in the case of INFL-TNF, which included HCDR2, HCDR3 and LCDR2 sequences.

PurposeThis study is aimed to assess the efficacy of adalimumab in alleviating peripheral vascular leakage in pediatric chronic anterior uveitis patients, along with its ability to improve best-corrected visual acuity (BCVA) and inflammation parameters, its efficacy in reducing topical glucocorticosteroids (GCs) and systemic immunomodulatory therapy (IMT), and its safety profile.MethodsA self-controlled study of pediatric chronic anterior uveitis patients who presented with peripheral retinal vascular leakage on ultra-widefield fluorescein fundus angiography and underwent adalimumab treatment was conducted. The primary outcome was the extent of retinal vascular leakage at the 3- and 6-month follow-up visits. Secondary outcomes included BCVA, inflammation parameters (fresh keratic precipitates, anterior chamber cell, and vitreous cell grades), frequency of topical glucocorticosteroid eye drops, IMT load, and adverse effects at the 3- and 6-month follow-up visits.ResultsTwenty patients with a mean age of 9.30 ± 3.26 years old were included. The mean follow-up period was 9.0 ± 3.0 months, with all patients followed up for at least 6 months. At the 3- and 6-month follow-ups, the peripheral vascular leakage score decreased significantly (2.87, 95% CI (2.14, 3.60), p < 0.001 for 3 months, 2.75, 95% CI (1.76, 3.73), p < 0.001 for 6 months). Alongside BCVA (p = 0.013 for 3 months, p = 0.005 for 6 months) was improved significantly, inflammatory parameters represented by fresh keratic precipitates, anterior chamber cell, and vitreous cell grades were improved significantly (p < 0.001, p < 0.001, for all parameters) and topical GC usage was significantly reduced (p < 0.001, p < 0.001) at 3 and 6 months. There was also a statistically significant reduction in systemic IMT load at 6 months (p < 0.001). Adverse events in the observation period included local redness around the injection site and mild upper respiratory symptoms.ConclusionAdalimumab could effectively alleviate peripheral vascular leakage in pediatric patients with chronic anterior uveitis. It could also be helpful in improving BCVA and inflammation parameters and decreasing topical glucocorticosteroid eye drops and systemic IMT. Adalimumab is generally safe for pediatric uveitis.

Introduction: Cardiac sarcoidosis (CS) is a life-threatening disease in which clear recommendations are lacking. We report a case series of CS successfully treated by tumor necrosis factor (TNF)α antagonists.Methods: We conducted a single-center retrospective study of our patients with CS treated by TNFα antagonists.Results: Four cases (4/84, 4.7%) were found in our database. Mean age was 40 years (range 34–53 years), and all were Caucasian men. Mean follow-up was 54.75 months (range 25–115 months). All patients received corticosteroid therapy (CT) and immunosuppressive therapy (IT). TNFα antagonists (infliximab or adalimumab) were started after the first or second CS relapse under CT and IT. One patient experienced relapse under TNFα antagonists (isolated decreased left ventricular ejection) and responded to a shorter interval of TNFα antagonist infusion. CT was discontinued in three patients treated with TNFα antagonists without relapse or major cardiac events during follow-up. No serious adverse event occurred in our case series, possibly due to dose sparing and frequent arrest of CT.Conclusion: TNFα antagonists were effective in refractory and/or relapsing CS treated by corticosteroids and/or immunosuppressive agents, without serious adverse events, and should be considered earlier in CS treatment scheme.