Anti-CD45RC antibody immunotherapy prevents and treats experimental autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy syndrome
Targeted monoclonal antibody (mAb) therapies show great promise for the treatment of transplant rejection and autoimmune diseases by inducing more specific immunomodulatory effects than broadly immunosuppressive drugs routinely used. We recently described the therapeutic advantage of targeting CD45R...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2022-04-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI156507 |
| _version_ | 1811326456242896896 |
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| author | Marine Besnard Céline Sérazin Jason Ossart Anne Moreau Nadège Vimond Léa Flippe Hanna Sein Grace A. Smith Stefania Pittaluga Elise M.N. Ferré Claire Usal Ignacio Anegon Annamari Ranki Michail S. Lionakis Pärt Peterson Carole Guillonneau |
| author_facet | Marine Besnard Céline Sérazin Jason Ossart Anne Moreau Nadège Vimond Léa Flippe Hanna Sein Grace A. Smith Stefania Pittaluga Elise M.N. Ferré Claire Usal Ignacio Anegon Annamari Ranki Michail S. Lionakis Pärt Peterson Carole Guillonneau |
| author_sort | Marine Besnard |
| collection | DOAJ |
| description | Targeted monoclonal antibody (mAb) therapies show great promise for the treatment of transplant rejection and autoimmune diseases by inducing more specific immunomodulatory effects than broadly immunosuppressive drugs routinely used. We recently described the therapeutic advantage of targeting CD45RC, expressed at high levels by conventional T (Tconv) cells (CD45RChi), their precursors, and terminally differentiated T (TEMRA) cells, but not by regulatory T cells (Tregs; CD45RClo/–). We demonstrated efficacy of anti-CD45RC mAb treatment in transplantation, but its potential has not been examined in autoimmune diseases. Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) is a rare genetic syndrome caused by loss-of-function mutations of autoimmune regulator (AIRE), a key central tolerance mediator, leading to abnormal autoreactive T cell responses and autoantibody production. Herein, we show that, in a rat model of APECED syndrome, anti-CD45RC mAb was effective for both prevention and treatment of autoimmune manifestations and inhibited autoantibody development. Anti-CD45RC mAb intervention depleted CD45RChi T cells, inhibited CD45RChi B cells, and restored the Treg/Tconv cell ratio and the altered Treg transcriptomic profile. In APECED patients, CD45RC was significantly increased in peripheral blood T cells, and lesioned organs from APECED patients were infiltrated by CD45RChi cells. Our observations highlight the potential role for CD45RChi cells in the pathogenesis of experimental and human APECED syndrome and the potential of anti-CD45RC antibody treatment. |
| first_indexed | 2024-04-13T14:50:35Z |
| format | Article |
| id | doaj.art-3354f3a8b337479b98648db65c0555cf |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-04-13T14:50:35Z |
| publishDate | 2022-04-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-3354f3a8b337479b98648db65c0555cf2022-12-22T02:42:37ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-04-011327Anti-CD45RC antibody immunotherapy prevents and treats experimental autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy syndromeMarine BesnardCéline SérazinJason OssartAnne MoreauNadège VimondLéa FlippeHanna SeinGrace A. SmithStefania PittalugaElise M.N. FerréClaire UsalIgnacio AnegonAnnamari RankiMichail S. LionakisPärt PetersonCarole GuillonneauTargeted monoclonal antibody (mAb) therapies show great promise for the treatment of transplant rejection and autoimmune diseases by inducing more specific immunomodulatory effects than broadly immunosuppressive drugs routinely used. We recently described the therapeutic advantage of targeting CD45RC, expressed at high levels by conventional T (Tconv) cells (CD45RChi), their precursors, and terminally differentiated T (TEMRA) cells, but not by regulatory T cells (Tregs; CD45RClo/–). We demonstrated efficacy of anti-CD45RC mAb treatment in transplantation, but its potential has not been examined in autoimmune diseases. Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) is a rare genetic syndrome caused by loss-of-function mutations of autoimmune regulator (AIRE), a key central tolerance mediator, leading to abnormal autoreactive T cell responses and autoantibody production. Herein, we show that, in a rat model of APECED syndrome, anti-CD45RC mAb was effective for both prevention and treatment of autoimmune manifestations and inhibited autoantibody development. Anti-CD45RC mAb intervention depleted CD45RChi T cells, inhibited CD45RChi B cells, and restored the Treg/Tconv cell ratio and the altered Treg transcriptomic profile. In APECED patients, CD45RC was significantly increased in peripheral blood T cells, and lesioned organs from APECED patients were infiltrated by CD45RChi cells. Our observations highlight the potential role for CD45RChi cells in the pathogenesis of experimental and human APECED syndrome and the potential of anti-CD45RC antibody treatment.https://doi.org/10.1172/JCI156507AutoimmunityTherapeutics |
| spellingShingle | Marine Besnard Céline Sérazin Jason Ossart Anne Moreau Nadège Vimond Léa Flippe Hanna Sein Grace A. Smith Stefania Pittaluga Elise M.N. Ferré Claire Usal Ignacio Anegon Annamari Ranki Michail S. Lionakis Pärt Peterson Carole Guillonneau Anti-CD45RC antibody immunotherapy prevents and treats experimental autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy syndrome The Journal of Clinical Investigation Autoimmunity Therapeutics |
| title | Anti-CD45RC antibody immunotherapy prevents and treats experimental autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy syndrome |
| title_full | Anti-CD45RC antibody immunotherapy prevents and treats experimental autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy syndrome |
| title_fullStr | Anti-CD45RC antibody immunotherapy prevents and treats experimental autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy syndrome |
| title_full_unstemmed | Anti-CD45RC antibody immunotherapy prevents and treats experimental autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy syndrome |
| title_short | Anti-CD45RC antibody immunotherapy prevents and treats experimental autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy syndrome |
| title_sort | anti cd45rc antibody immunotherapy prevents and treats experimental autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome |
| topic | Autoimmunity Therapeutics |
| url | https://doi.org/10.1172/JCI156507 |
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