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Regulatory CD4 + T cells (Treg) are essential for maintaining peripheral tolerance, preventing autoimmune diseases like dermatomyositis, and play a role in the anti-tumor response and prevention of graft versus host disease (graft versus host disease - GVHD) after allogeneic bone marrow transplantation. Using two markers associated with ATP metabolism, CD26 and CD39, and the CD45RA maturation marker, we separated the Treg into 5 distinct subpopulations, each representing a different stage of maturation. Micro-environmental factors dictate this maturation as well as the functions of these different sub-populations. Dermatomyositis is an autoimmune disease primarily affecting the skin and muscle. During this pathology, we observed a phenotypic modification of Treg with a decrease in CD25 expression and an accumulation of CD39+ populations. The study of immune polarization revealed the disappearance of circulating MAIT (mucosal-associated invariant T cells) cells, the existence of a similar lymphocyte profile between the classic form and the amyopathic form and a skin "type I interferon” polarization during anti-MDA5 associated with the presence of interferon kappa. Finally, we were interested in patients presenting with relapsing MDS or AML after allogeneic transplantation treated with azacytidine (AZA), a hypomethylating agent. We were able to show that the Treg phenotype was modified compared to ungrafted individuals, but that it did not differ between relapse and non-relapse. Treatment with AZA appears to have a different dose-dependent effect on Tregs, both in vivo and in vitro, resulting in particular in the acquisition of FOXP3 and CD39., Les cellules T CD4+ régulatrices (Treg) sont essentielles au maintien de la tolérance périphérique, la prévention des maladies auto-immunes comme la DM et jouent un rôle dans la réponse anti-tumorale et la prévention de la maladie du greffon contre l’hôte (graft versus host disease – GVHD), après allogreffe de moelle. Grâce à deux marqueurs associés au métabolisme de l’ATP, le CD26 et le CD39, et au marqueur de maturation CD45RA, nous avons séparé les Treg en 5 sous-populations distinctes, chacune représentant un stade de maturation différent. Les facteurs micro-environnementaux dictent cette maturation ainsi que les fonctions de ces différentes sous-populations. La DM est une maladie auto-immune affectant principalement la peau et le muscle. Au cours de cette pathologie, nous avons observé une modification phénotypique des Treg avec une diminution d’expression du CD25 et une accumulation de populations CD39+. L’étude de la polarisation immunitaire a révélé la disparition des cellules MAIT (mucosal-associated invariant T cells) circulantes, l’existence d’un profil lymphocytaire similaire entre la forme classique et la forme amyopathique et une polarisation cutanée « interféron de type I » importante au cours de la forme avec anticorps anti-MDA5 en lien avec la présence d’interféron kappa. Enfin, nous nous sommes intéressés à des patients présentant un SMD ou une LAM en rechute après allogreffe traités par azacytidine (AZA), un agent hypométhylant. Nous avons pu montrer que le phénotype des Treg était modifié par rapport à des individus non greffés mais qu’il ne différait pas entre rechuteurs et non rechuteurs. Le traitement par AZA semble exercer un effet sur les Treg différent en fonction de la dose, à la fois in vivo et in vitro, aboutissant notamment à l’acquisition du FOXP3 et du CD39., (MED - Sciences médicales) -- UCL, 2021

OBJECTIVES: Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that are important for antibacterial immunity and may have regulatory roles. MAIT cells are decreased during SLE. However, their frequencies and phenotype have not been investigated in DM. We studied MAIT cell frequencies and phenotype in DM patients with active and inactive disease (after treatment). METHODS: Peripheral blood flow cytometry analysis of MAIT cells was compared between DM (n = 22), SLE (n = 10), psoriasis (n = 7) and atopic dermatitis (n = 5) patients, and healthy controls (n = 19). RESULTS: A dramatic decrease of circulating MAIT cell frequency was observed in active DM and SLE patients compared with healthy controls and other inflammatory skin diseases [active DM: median = 0.25% (interquartile range 0.19-0.6%), P < 0.0001; active SLE: median = 0.61 (0.55-0.77), P < 0.0001 vs healthy controls: 2.32% (1.18-4.45%)]. MAIT cells from active DM patients had an abnormal phenotype including increased expression of CD25 and cytotoxic T-lymphocyte-associated protein 4 that correlated with their low frequency in the blood. CONCLUSION: In DM, peripheral blood MAIT cells are dramatically reduced and have an activated/exhausted phenotype that may be linked to increased activation-induced cell death., SCOPUS: ar.j, DecretOANoAutActif, info:eu-repo/semantics/published

Dermatomyositis pathophysiology is complex. In recent years, medical research has identified molecules associated with disease activity. Besides providing insights into the driving mechanisms of dermatomyositis, these findings could provide potential biomarkers. Activity markers can be used to monitor disease activity in clinical trials and may also be useful in daily practice. This article reviews molecules that could be used as biomarkers for diagnosis and monitoring dermatomyositis disease activity.

Invited speaker - Award for best poster with a short oral presentation, info:eu-repo/semantics/nonPublished

CD4+ T cells are critical regulators of immune responses, but their functional role in human breast cancer is relatively unknown. The goal of this study was to produce an image of CD4+ T cells infiltrating breast tumors using limited ex vivo manipulation to better understand the in vivo differences associated with patient prognosis. We performed comprehensive molecular profiling of infiltrating CD4+ T cells isolated from untreated invasive primary tumors and found that the infiltrating T cell subpopulations included follicular helper T (Tfh) cells, which have not previously been found in solid tumors, as well as Th1, Th2, and Th17 effector memory cells and Tregs. T cell signaling pathway alterations included a mixture of activation and suppression characterized by restricted cytokine/chemokine production, which inversely paralleled lymphoid infiltration levels and could be reproduced in activated donor CD4+ T cells treated with primary tumor supernatant. A comparison of extensively versus minimally infiltrated tumors showed that CXCL13-producing CD4+ Tfh cells distinguish extensive immune infiltrates, principally located in tertiary lymphoid structure germinal centers. An 8-gene Tfh signature, signifying organized antitumor immunity, robustly predicted survival or preoperative response to chemotherapy. Our identification of CD4+ Tfh cells in breast cancer suggests that they are an important immune element whose presence in the tumor is a prognostic factor., JOURNAL ARTICLE, SCOPUS: ar.j, info:eu-repo/semantics/published

Objective: To evaluate the effect in mice with arthritis of active anti-tumour necrosis factor (TNF)α immunotherapy based on a keyhole limpet haemocyanin-human TNFα heterocomplex (hTNFα kinoid or TNFK) adjuvanted in incomplete Freund adjuvant. Immunotherapy was evaluated also with methotrexate. Methods: Human TNFα-transgenic mice received TNFK with or without methotrexate. Follow-up ranged from 6 weeks (short term) to 17 weeks (long term). Arthritis was evaluated clinically and histologically. Monitoring included titration of anti-hTNFα antibodies by ELISA and neutralisation assay. Results: Vaccination with TNFK was associated with rapid-onset, long-lasting protection. Long-term results showed significantly milder arthritis in vaccinated animals than in control animals at the peak of the disease. Vaccination was followed by resolution of the clinical evidence of arthritis, contrasting with severe progressive arthritis in the control group. Histological improvements with decreased inflammation and destruction were noted in all immunised groups, even after the shortest follow-up (6 weeks). High titres of neutralising anti-hTNFα antibodies were detected as early as the fifth week post immunisation and persisted over time. Methotrexate given concomitantly with the vaccine did not influence either the effect on arthritis or the anti-hTNFα antibody titres. Conclusion: Anti-cytokine induction of autoimmune protection against chronic hTNFα overproduction is an efficient alternative to TNFα blockade in experimental arthritis and can be achieved using a TNFK vaccine., SCOPUS: ar.j, info:eu-repo/semantics/published

Anti-Tat therapeutic vaccination has been clinically investigated by different groups [1-4], given that 1) extracellular Tat protein induces T cell apoptosis and cellular immune suppression, 2) epidemiological data showed that LTNP exhibit high level of serum anti-Tat Ab, negatively correlated with p24 antigenemia, 3) in Tat immunized macaques, viremia decreased following SHIV challenge. Anti-Tat therapeutic vaccination using Tat Toxoid adjuvanted either with Seppic [1,2] or with alum or DcChol (Aventis Pasteur) proved to be safe. A prospective structured treatment interruption study (STI) monitored according to EU guidelines was conducted at Hospital St-Pierre, Brussels (Pr. N. Clumeck) on 31 vaccinees who received a DcChol adjuvanted Tat Toxoid (n = 12), a DcChol placebo (n = 8) or non adjuvanted Tat toxoid (n = 11). The 2 year study follow-up showed that vaccinees developing high titer of Abs neutralizing Tat bioactivity prolonged HAART-interruption., info:eu-repo/semantics/published, Oral presentation. From 2006 International Meeting of The Institute of Human VirologyBaltimore, USA. 17–21 November, 2006

Current therapeutic vaccine trials in major chronic diseases including AIDS, cancer, allergy and autoimmunity, target antigenic pathogens but not the pathogenic stromal cytokines which can be major sources of histopathologic processes. Considering that the limited efficacy of these vaccines has been ascribed to local pathogen-induced cytokine dysfunction, we propose to antagonize pathogenic cytokine(s) by high affinity neutralizing auto-Abs triggered by specific anti-cytokine vaccines. As anticipated by theoretical considerations, animal experiments and initial clinical trials showed that anti-cytokine immunization was safe, well tolerated and triggered transient high titers Abs neutralizing pathogenic cytokines but, in contrast to conventional vaccines, no relevant cellular response was observed. Advantages of active versus passive anti-cytokine Ab therapy, particularly for long-term treatments, as those required in AIDS, cancer, allergy and autoimmunity include greater ease of maintaining high Ab titers, lack of anti-antibody responses and low cost. © 2003 Elsevier Science Ltd. All rights reserved., SCOPUS: re.j, info:eu-repo/semantics/published