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Photopheresis Efficacy in the Treatment of Rheumatoid Arthritis

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Photopheresis Efficacy in the Treatment of Rheumatoid Arthritis Coppard et al. J Transl Med (2019) 17:312 https://doi.org/10.1186/s12967-019-2066-1 Journal of Translational Medicine RESEARCH Open Access Photopheresis efcacy in the treatment of rheumatoid arthritis: a pre-clinical proof of concept Céline Coppard1,2, Francis Bonnefoy3, Dalil Hannani1,2,4 , Françoise Gabert1,2, Olivier Manches1,2 , Joel Plumas1,2, Sylvain Perruche3 and Laurence Chaperot1,2* Abstract Background: Despite major advances in rheumatoid arthritis outcome, not all patients achieve remission, and there is still an unmet need for new therapeutic approaches. This study aimed at evaluating in a pre-clinical murine model the efcacy of extracorporeal photopheresis (ECP) in the treatment of rheumatoid arthritis, and to provide a relevant study model for dissecting ECP mechanism of action in autoimmune diseases. Methods: DBA/1 mice were immunized by subcutaneous injection of bovine collagen type II, in order to initiate the development of collagen-induced arthritis (CIA). Arthritic mice received 3 ECP treatments every other day, with psoralen UVA-treated (PUVA) spleen cells obtained from arthritic mice. Arthritis score was measured, and immune cell subsets+ were monitored. Results: ECP-treated mice recovered from arthritis as evidenced by a decreasing arthritic score over time. Signifcant decrease in the frequency of Th17 cells in the spleen of treated mice was observed. Interestingly, while PUVA-treated spleen cells from healthy mouse had no efect, PUVA-treated arthritic mouse derived-spleen cells were able to induce control of arthritis development. Conclusions: Our results demonstrate that ECP can control arthritis in CIA-mice, and clarifes ECP mechanisms of action, showing ECP efcacy and Th17 decrease only when arthritogenic T cells are contained within the treated sam- ple. These data represent a pre-clinical proof of concept supporting the use of ECP in the treatment of RA in Human. Keywords: Collagen-induced arthritis, Extracorporeal photopheresis, Preclinical study, Autoimmunity Background Caucasian individuals in western countries. During the Among autoimmune diseases, rheumatoid arthritis (RA) course of RA, immune cells infltrate the synovial sublin- [1] is a complex common autoimmune disease respon- ing, half of them being CD4+ memory T cells, and it has sible for progressive disabilities due to synovial infam- been shown that autoreactive T cell frequency is corre- mation, bone and cartilage destruction associated with lated with disease activity [2]. Type 1 helper T (T1) cells systemic disorders. Rheumatoid arthritis development have long been considered as crucial in RA development, involves environmental factors that trigger the disease in but accumulating evidence support a major role for T17 individuals with a predisposing genotype, such as some cells in RA pathogenesis. Despite major advances in HLA DRβ polymorphisms, and it afects 0.5 to 1% of rheumatoid arthritis outcome, not all patients achieve remission, and there is still an unmet need for new thera- peutic approaches [3]. *Correspondence: [email protected] Few clinical trials have assessed the therapeutic efect 2 Etablissement Français du Sang Auvergne-Rhône-Alpes, Research and Development Lab, 29 Av Maquis du Grésivaudan, 38701 La Tronche, of extracorporeal photopheresis (ECP) in rheumatoid France arthritis. In 1991, 7 patients with RA were treated by ECP, Full list of author information is available at the end of the article and interesting clinical improvements were reported for © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Coppard et al. J Transl Med (2019) 17:312 Page 2 of 10 4 of them [4]. clinical improvements were reported in 2015061815254659. Tese animal experiments comply 1993 for seven ECP-treated RA-patients [5], and in 1996, with the ARRIVE guidelines [13]. Some of the experi- for 12 patients with psoriatic arthritis [6]. Despite these ments have been performed at the UMR1098 animal encouraging results (overall clinical improvement for facility (agreement #C25-056-7; Besançon, France) under approximately 50% of patients [7]), the clinical use of ECP #02831 project number authorization. for RA and autoimmune diseases treatment remains rare. Indeed, ECP is a cell therapy mostly applied to treat graft versus host diseases, transplant rejection and cutaneous Induction of collagen‑induced arthritis T cell lymphomas. Te therapeutic process is based on DBA/1 mice were immunized by subcutaneous injection extraction of mononuclear cells by apheresis, followed by at the tail base with 100 µl of emulsion of bovine colla- treatment of cells with 8-methoxy-psoralen (8-MOP) and gen type II (200 mg/ml dissolved in 0.5 M of acetic acid, exposure to ultraviolet A light. Tis procedure results in MD Bioscience) and Complete Freund adjuvant (4 mg of crosslinking of DNA pyrimidine bases in all treated cells, Mycobacterium tuberculosis toxin in 1 ml of incomplete leading to their apoptosis. Te cells are then reinfused to Freund adjuvant, Sigma-Aldrich), 50 µl in each side of the patients. Depending on the disease, ECP is thought the tail. Arthritis developed at days 21–28 after collagen to trigger an immunomodulation either leading to immu- immunization. Te health status of the animals was care- nization (in CTCL context) or immunosuppression (in fully monitored, by daily observation of animal behav- GVHD or transplant rejection) [8–10]. ior and external physical appearance. Animals were also Te American council on ECP has recently published weighed every day. Te protocol dictated that mice losing a consensus report, describing ECP as a bidirectional more than 20% of start weight at any time would be sacri- therapy, able to induce both immunizing and toler- fced, however this did not occur. No unexpected adverse izing efects [11]. ECP seems to be a safe and efcient event occurred. Arthritis severity was measured by visual treatment for diseases that are associated to T cell dys- evaluation of the paws. Each paw was scale of 0–4, where regulations, leading to specifc long-lasting immuno- 0 = normal paw, 1 = swelling in one digit, 2 = swelling suppression, making it attractive to treat autoimmune of one or more digit or mild swelling of the entire paw, diseases [12]. Te central role of T cells in RA pathogen- 3 = moderate erythema and swelling of the entire paw, esis, with circulating autoreactive T cells is a strong argu- and 4 = erythema and severe swelling involving the entire ment to propose ECP as a therapy for this disease. Te paw (Fig. 1a). Te clinical score for each mouse was lack of randomized clinical trials and the poor under- the result of the sum of the four paws (maximum score standing of ECP mechanism of action clearly hinder ECP 16). Food and water were placed directly in the cage for development in the context of autoimmune diseases. In animals with a score higher than 8, to compensate for order to evaluate the potential efcacy of ECP in arthritis, their mobility impairment. To take into account dis- we used a well characterized mouse model of collagen- ease heterogeneity at the time of treatment, mice were induced arthritis, extensively used for modeling human stratifed according to arthritis score and split into the RA. In this paper, we show that ECP is efcient in revers- diferent treatments groups (n = 5 mice per group). Te ing arthritis, by decreasing T17 cells. Tese data repre- sample size was calculated on the basis of pilot experi- sent a pre-clinical proof of concept, rationalizing the use ments, indicating that in untreated animals the mean of ECP in the treatment of RA, and provide a relevant arthritis score at day 40 post-collagen injection was 9.6 study model for dissecting ECP mechanism of action in (SD = 0.88). Power calculations indicated that for a mean autoimmune diseases. diference in arthritis score of 2 points to be detected with 90% power at this time point with a one-sided sig- Materials and methods nifcance level of 5%, 5 mice in each treated group were Mice required (calculation made with R software, epi R pack- Six- to eight-week-old male DBA/1 mice were obtained age). Te average and standard deviation of clinical scores from Janvier Labs (Le Genest-Saint-Isle, France), housed were similar for each group in each experiment (n = 5). at the University of Grenoble animal core facility PHTA To standardize the monitoring of the therapeutic efect (Plateforme de Haute Technologie Animale, agreement of ECP on arthritis development, we calculated for each #C 38516 10 006 delivered by Direction Départementale mouse and each day a relative CIA score, by subtracting de la Protection des Personnes de l’Isère), in individu- the value of CIA score at the beginning of the treatment ally ventilated cages (5 mice per cage) and fed ad libitum to the measured CIA score. Hence, on day 0, when the a standard diet and fltered water. All experiments were frst injection was performed, all mice have a relative CIA approved by the local ethic committee as well as French score of zero. Arthritis score was measured every day, ministry of Research and Innovation, under the number: and the relative arthritis score was calculated. If arthritis Coppard et al. J Transl Med (2019) 17:312 Page 3 of 10 a 2 2 3 4 b Fig. 1 Typical clinical pattern of collagen-induced arthritis in male DBA/1 mice.
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