ObjectiveRegulatory T cells (Tregs) prevent autoimmunity and control inflammation. Consequently, any autoimmune or inflammatory disease reveals a Treg insufficiency. As low-dose interleukin-2 (ld-IL2) expands and activates Tregs, it has a broad therapeutic potential.AimWe aimed to assess this potential and select diseases for further clinical development by cross-investigating the effects of ld-IL2 in a single clinical trial treating patients with 1 of 11 autoimmune diseases.MethodsWe performed a prospective, open-label, phase I–IIa study in 46 patients with a mild to moderate form of either rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Behcet’s disease, granulomatosis with polyangiitis, Takayasu’s disease, Crohn’s disease, ulcerative colitis, autoimmune hepatitis and sclerosing cholangitis. They all received ld-IL2 (1 million IU/day) for 5 days, followed by fortnightly injections for 6 months. Patients were evaluated by deep immunomonitoring and clinical evaluation.Resultsld-IL2 was well tolerated whatever the disease and the concomitant treatments. Thorough supervised and unsupervised immunomonitoring demonstrated specific Treg expansion and activation in all patients, without effector T cell activation. Indication of potential clinical efficacy was observed.ConclusionThe dose of IL-2 and treatment scheme used selectively activate and expand Tregs and are safe across different diseases and concomitant treatments. This and preliminary indications of clinical efficacy should licence the launch of phase II efficacy trial of ld-IL2 in various autoimmune and inflammatory diseases.Trial registration numberNCT01988506.
Most autoimmune diseases (AID) are linked to an imbalance between autoreactive effector T cells (Teffs) and regulatory T cells (Tregs). While blocking Teffs with immunosuppression has long been the only therapeutic option, activating/expanding Tregs may achieve the same objective without the toxicity of immunosuppression. We showed that low-dose interleukin-2 (ld-IL-2) safely expands/activates Tregs in patients with AID, such HCV-induced vasculitis and Type 1 Diabetes (T1D). Here we analyzed the kinetics and dose-relationship of IL-2 effects on immune responses in T1D patients. Ld-IL-2 therapy induced a dose-dependent increase in CD4(+)Foxp3(+) and CD8(+)Foxp3(+) Treg numbers and proportions, the duration of which was markedly dose-dependent. Tregs expressed enhanced levels of activation markers, including CD25, GITR, CTLA-4 and basal pSTAT5, and retained a 20-fold higher sensitivity to IL-2 than Teff and NK cells. Plasma levels of regulatory cytokines were increased in a dose-dependent manner, while cytokines linked to Teff and Th17 inflammatory cells were mostly unchanged. Global transcriptome analyses showed a dose-dependent decrease in immune response signatures. At the highest dose, Teff responses against beta-cell antigens were suppressed in all 4 patients tested. These results inform of broader changes induced by ld-IL-2 beyond direct effects on Tregs, and relevant for further development of ld-IL-2 for therapy and prevention of T1D, and other autoimmune and inflammatory diseases.
In addition to CD4+ regulatory T cells (Tregs), CD8+ suppressor T cells are emerging as an important subset of regulatory T cells. Diverse populations of CD8+ T cells with suppressive activities have been described. Among them, a small population of CD8+CD25+FOXP3+ T cells is found both in mice and humans. In contrast to thymic-derived CD4+CD25+FOXP3+ Tregs, their origin and their role in the pathophysiology of autoimmune diseases (AIDs) are less understood. We report here the number, phenotype, and function of CD8+ Tregs cells in mice and humans, at the steady state and in response to low-dose interleukin-2 (IL-2). CD8+ Tregs represent approximately 0.4 and 0.1% of peripheral blood T cells in healthy humans and mice, respectively. In mice, their frequencies are quite similar in lymph nodes (LNs) and the spleen, but two to threefold higher in Peyer patches and mesenteric LNs. CD8+ Tregs express low levels of CD127. CD8+ Tregs express more activation or proliferation markers such as CTLA-4, ICOS, and Ki-67 than other CD8+ T cells. In vitro, they suppress effector T cell proliferation as well as or even better than CD4+ Tregs. Owing to constitutive expression of CD25, CD8+ Tregs are 20- to 40-fold more sensitive to in vitro IL-2 stimulation than CD8+ effector T cells, but 2–4 times less than CD4+ Tregs. Nevertheless, low-dose IL-2 dramatically expands and activates CD8+ Tregs even more than CD4+ Tregs, in mice and humans. Further studies are warranted to fully appreciate the clinical relevance of CD8+ Tregs in AIDs and the efficacy of IL-2 treatment.
Aims/hypothesis Low-dose IL-2 (ld-IL2) selectively activates and expands regulatory T cells (Tregs) and thus has the potential to skew the regulatory/effector T (Treg/Teff) cell balance towards improved regulation. We investigated which low doses of IL-2 would more effectively and safely activate Tregs during a 1 year treatment in children with recently diagnosed type 1 diabetes. Methods Dose Finding Study of IL-2 at Ultra-low Dose in Children With Recently Diagnosed Type 1 Diabetes (DF-IL2-Child) was a multicentre, double-blinded, placebo-controlled, dose-finding Phase I/II clinical trial conducted in four centres at university hospitals in France: 24 children (7-14 years old) with type 1 diabetes diagnosed within the previous 3 months were randomly assigned 1:1:1:1 to treatment by a centralised randomisation system, leading to a 7/5/6/6 patient distribution of placebo or IL-2 at doses of 0.125, 0.250 or 0.500 million international units (MIU)/m 2 , given daily for a 5 day course and then fortnightly for 1 year. A study number was attributed to patients by an investigator unaware of the randomisation list and all participants as well as investigators and staff involved in the study conduct and analyses were blinded to treatments. The primary outcome was change in Tregs, expressed as a percentage of CD4 + T cells at day 5. It pre-specified that a ≥60% increase in Tregs from baseline would identify Treg high responders. Results There were no serious adverse events. Non-serious adverse events (NSAEs) were transient and mild to moderate. In treated patients vs placebo, the commonest NSAE was injection site reaction (37.9% vs 3.4%), whereas other NSAEs were at the Michelle Rosenzwajg and Randa Salet contributed equally to this study.
IntroductionAutoimmune and autoinflammatory diseases (AIDs) represent a socioeconomic burden as the second cause of chronic illness in Western countries. In this context, the TRANSIMMUNOM clinical protocol is designed to revisit the nosology of AIDs by combining basic, clinical and information sciences. Based on classical and systems biology analyses, it aims to uncover important phenotypes that cut across diagnostic groups so as to discover biomarkers and identify novel therapeutic targets.Methods and analysisTRANSIMMUNOM is an observational clinical protocol that aims to cross-phenotype a set of 19 AIDs, six related control diseases and healthy volunteers. We assembled a multidisciplinary cohort management team tasked with (1) selecting informative biological (routine and omics type) and clinical parameters to be captured, (2) standardising the sample collection and shipment circuit, (3) selecting omics technologies and benchmarking omics data providers, (4) designing and implementing a multidisease electronic case report form and an omics database and (5) implementing supervised and unsupervised data analyses.Ethics and disseminationThe study was approved by the institutional review board of Pitié-Salpêtrière Hospital (ethics committee Ile-De-France 48–15) and done in accordance with the Declaration of Helsinki and good clinical practice. Written informed consent is obtained from all participants before enrolment in the study. TRANSIMMUNOM’s project website provides information about the protocol (https://www.transimmunom.fr/en/) including experimental set-up and tool developments. Results will be disseminated during annual scientific committees appraising the project progresses and at national and international scientific conferences.DiscussionSystems biology approaches are increasingly implemented in human pathophysiology research. The TRANSIMMUNOM study applies such approach to the pathophysiology of AIDs. We believe that this translational systems immunology approach has the potential to provide breakthrough discoveries for better understanding and treatment of AIDs.Trial registration numberNCT02466217; Pre-results.
The project was funded by the LabEx Transimmunom (grant no. ANR-11-IDEX-0004-02) and European Research Council Advanced Grant TRiPoD (322856) to D.K. G.C. was supported by the Acad emie Nationale de M edecine. Disclosure of potential conflict of interest: M. Rosenzwajg and D. Klatzmann are inventors in a patent application related to the therapeutic use of ld-IL2 for treating autoimmune-related or inflammatory disorders, which belongs to their academic institutions and has been licensed to ILTOO pharma. G. Churlaud, M. Rosenzwajg, and D. Klatzmann hold shares in ILTOO pharma. The rest of the authors declare that they have no relevant conflicts of interest.
BackgroundSystemic sclerosis (SSc) is a chronic autoimmune disease, with impaired immune response, increased fibrosis, and endothelial dysfunction. (1,2) Regulatory T cells (Tregs), which are essential to prevent autoimmunity, showed a decreased frequency and impaired function during SSc. (3,4) Low-dose interleukin-2 (ld-IL2) can expand and activate Tregs, but there are no data in SSc.ObjectivesWe aimed to assess the in vivo biological efficacy of ld-IL2 on Tregs and its safety in patients with SSc.MethodsWe performed an interventional prospective, open-label phase I-IIa study in nine patients with SSc without severe organ involvement (eight patients with limited cutaneous subtype). This trial is a part of the TRANSREG study. All patients received 1 Million International Units (MIU)/day of IL-2 for five days, followed by fortnightly injections for 6 months. The primary endpoint was the change in the relative Tregs blood concentration identified as CD25hiCD127lo/−Foxp3+cells frequencies on day 8 among TCD4+ cells compared with baseline. Laboratory and clinical evaluations (modified Rodnan skin score (mRSS), Clinical Global Impression (CGI) activity and severity scale) were performed between day 8 and month 18.ResultsAt day 8, the primary endpoint was reached with a 1.8(± 0.5) fold increase of Tregs levels among TCD4+lymphocytes (p= 0.008). Changes in concentration of effector T cells (Teffs) and BCD19+cells were not statistically significant at day 8 and during maintenance period until month 6.Patients’ clinical assessments were stable throughout the follow-up with no modification on mRSS CGI activity and severity scale. Ld-IL2 was well tolerated, and no serious adverse events occurred.ConclusionLd-IL2 at a dosage of 1 MIU/day for five consecutive days selectively activates and expands Tregs in SSc. Safety data were very encouraging. Phase II efficacy trials are needed to validate therapeutic potential of ld-IL2.References[1]Allanore Y, Simms R, Distler O, Trojanowska M, Pope J, Denton CP, et al. Systemic sclerosis. Nat Rev Dis Primer. 23 avr 2015;1:15002.[2]Denton CP, Khanna D. Systemic sclerosis. Lancet Lond Engl. 7 oct 2017;390(10103):1685‑99.[3]Frantz C, Auffray C, Avouac J, Allanore Y. Regulatory T Cells in Systemic Sclerosis. Front Immunol. 2018;9:2356.[4]Antiga E, Quaglino P, Bellandi S, Volpi W, Del Bianco E, Comessatti A, et al. Regulatory T cells in the skin lesions and blood of patients with systemic sclerosis and morphoea. Br J Dermatol. mai 2010;162(5):1056‑63.Table: Lymphocyte subpopulations analysisDay 1Day 8Treg cellscells/mm3% Among CD4+46.1 ± 15.5121 ± 7.4*6.3 ± 1.410.7 ±.8*Lymphocytescells/mm31307 ± 4581819 ± 14*Treg cells/Teff cells% Among CD4+4.6 ± 1.28.1 ± 1.9*CD3+T cellscells/mm31039 ± 4431463 ± 407*CD4+T cellscells/mm3782 ± 3531108 ± 369*CD8+T cellscells/mm3281 ± 156358 ± 150CD19+B cellscells/mm3159 ± 89140 ± 71CD3-CD56±NK cellscells/mm384.8 ± 36.7178 ± 66.5***Data are represented as mean ± sd. Changes between baseline and day 8 were analyzed using by ANOVA for ranked data considering factor time *p<0.05; **p<0.01; ***p<0.001.Figure 1.TRANSREG study designAcknowledgements:NIL.Disclosure of InterestsFrançois BARDE: None declared, Roberta Lorenzon: None declared, Sebastien RIVIERE: None declared, Patrice cacoub Shareholder of: ILTOO Pharma, Michelle Rosenzwajg Shareholder of: ILTOO Pharma, Carlotta CACCIATORE: None declared, Anne Daguenel-Nguyen: None declared, olivier fain: None declared, David Klatzmann Shareholder of: ILTOO Pharma, Arsene Mekinian: None declared.
Background:Regulatory T cells (Tregs) prevent autoimmunity and control inflammation. As low-dose interleukin-2 (ld-IL2) expands and activates Tregs, it has a broad therapeutic potential for any autoimmune or inflammatory disease (AIID). We performed a disease-finding “basket trial” (TRANSREGNCT01988506) in patients affected by one of 11 different AIID and reported the outcome of the first 46 patients (Rosenzwajg et al, ARD 2019).Objectives:Here we analyzed and discussed results from deep immunophenotyping, of 78 patients, to comprehensively study the effect of ld-IL2 on the immune system of patients affected by various AIIDMethods:We performed a prospective, open label, phase I-IIa study in 78 patients with a mild to moderate form of one of 13 selected AIID. All patients received ld-IL2 (1 million IU/day) for 5 days, followed by fortnightly injections for 6 months. Deep immunophenotyping was performed before and after 5 days of ld-IL2.Results:ld-IL2 significantly expands both memory Tregs as well as naïve Tregs, including recent thymic emigrant Tregs. It also activates Tregs as demonstrated by the significantly increased expression of HLA-DR, CD39, CD73, GITR, CTLA-4. Similar results were observed across the different AIID.Conclusion:ld-IL2 “universally” improves Treg fitness across 13 autoimmune and inflammatory disease.References:[1]Rosenzwajg M#, Lorenzon R#, Cacoub P, Pham HP, Pitoiset F, El Soufi K, RIbet C, Bernard C, Aractingi S, Banneville B, Beaugerie L, Berenbaum F, Champey J, Chazouilleres O, Corpechot C, Fautrel B, Mekinian A, Regnier E, Saadoun D, Salem JE, Sellam J, Seksik P, Daguenel-Nguyen A, Doppler V, Mariau J, Vicaut E, Klatzmann D. Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial. Ann Rheum Dis. 2019 Feb;78(2):209-217. doi: 10.1136/annrheumdis-2018-214229. Epub 2018 Nov 24.Disclosure of Interests:Michelle Rosenzwajg: None declared, Roberta Lorenzon: None declared, Patrice cacoub: None declared, Fabien Pitoiset: None declared, Selim Aractingi: None declared, Beatrice Banneville Speakers bureau: Lilly, Novartis, Laurent Beaugerie: None declared, Francis Berenbaum Grant/research support from: TRB Chemedica (through institution), MSD (through institution), Pfizer (through institution), Consultant of: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Bone Therapeutics, Regulaxis, Peptinov, 4P Pharma, Paid instructor for: Sandoz, Speakers bureau: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Sandoz, Julien Champey: None declared, Olivier Chazouilleres: None declared, Christophe Corpechot: None declared, Bruno Fautrel Grant/research support from: AbbVie, Lilly, MSD, Pfizer, Consultant of: AbbVie, Biogen, BMS, Boehringer Ingelheim, Celgene, Lilly, Janssen, Medac MSD France, Nordic Pharma, Novartis, Pfizer, Roche, Sanofi Aventis, SOBI and UCB, Arsene Mekinian: None declared, Elodie Regnier: None declared, david Saadoun: None declared, Joe-Elie Salem: None declared, Jérémie SELLAM: None declared, Philippe Seksik: None declared, David Klatzmann Consultant of: ILTOO Pharma
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