Keratinocyte growth factor impairs human thymic recovery from lymphopenia
The lymphocyte-depleting antibody alemtuzumab is a highly effective treatment of relapsing-remitting multiple sclerosis (RRMS); however 50% of patients develop novel autoimmunity post-treatment. Most at risk are individuals who reconstitute their T-cell pool by proliferating residual cells, rather t...
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| Published in: | JCI insight Vol. 4; no. 12 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Language: | English |
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American Society for Clinical Investigation
20.06.2019
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| ISSN: | 2379-3708, 2379-3708 |
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| Abstract | The lymphocyte-depleting antibody alemtuzumab is a highly effective treatment of relapsing-remitting multiple sclerosis (RRMS); however 50% of patients develop novel autoimmunity post-treatment. Most at risk are individuals who reconstitute their T-cell pool by proliferating residual cells, rather than producing new T-cells in the thymus; raising the possibility that autoimmunity might be prevented by increasing thymopoiesis. Keratinocyte growth factor (palifermin) promotes thymopoiesis in non-human primates.
Following a dose-tolerability sub-study, individuals with RRMS (duration ≤10 years; expanded disability status scale ≤5·0; with ≥2 relapses in the previous 2 years) were randomised to placebo or 180mcg/kg/day palifermin, given for 3 days immediately prior to and after each cycle of alemtuzumab, with repeat doses at M1 and M3. The interim primary endpoint was naïve CD4+ T-cell count at M6. Exploratory endpoints included: number of recent thymic-emigrants (RTEs) and signal-joint T-cell receptor excision circles (sjTRECs)/mL of blood. The trial primary endpoint was incidence of autoimmunity at M30.
At M6, individuals receiving palifermin had fewer naïve CD4+T-cells (2.229x107/L vs. 7.733x107/L; p=0.007), RTEs (16% vs. 34%) and sjTRECs/mL (1100 vs. 3396), leading to protocol-defined termination of recruitment. No difference was observed in the rate of autoimmunity between the two groupsConclusion: In contrast to animal studies, palifermin reduced thymopoiesis in our patients. These results offer a note of caution to those using palifermin to promote thymopoiesis in other settings, particularly in the oncology/haematology setting where alemtuzumab is often used as part of the conditioning regime.
ClinicalTrials.gov NCT01712945Funding: MRC and Moulton Charitable Foundation. |
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| AbstractList | The lymphocyte-depleting antibody alemtuzumab is a highly effective treatment of relapsing-remitting multiple sclerosis (RRMS); however 50% of patients develop novel autoimmunity post-treatment. Most at risk are individuals who reconstitute their T-cell pool by proliferating residual cells, rather than producing new T-cells in the thymus; raising the possibility that autoimmunity might be prevented by increasing thymopoiesis. Keratinocyte growth factor (palifermin) promotes thymopoiesis in non-human primates.
Following a dose-tolerability sub-study, individuals with RRMS (duration ≤10 years; expanded disability status scale ≤5·0; with ≥2 relapses in the previous 2 years) were randomised to placebo or 180mcg/kg/day palifermin, given for 3 days immediately prior to and after each cycle of alemtuzumab, with repeat doses at M1 and M3. The interim primary endpoint was naïve CD4+ T-cell count at M6. Exploratory endpoints included: number of recent thymic-emigrants (RTEs) and signal-joint T-cell receptor excision circles (sjTRECs)/mL of blood. The trial primary endpoint was incidence of autoimmunity at M30.
At M6, individuals receiving palifermin had fewer naïve CD4+T-cells (2.229x107/L vs. 7.733x107/L; p=0.007), RTEs (16% vs. 34%) and sjTRECs/mL (1100 vs. 3396), leading to protocol-defined termination of recruitment. No difference was observed in the rate of autoimmunity between the two groupsConclusion: In contrast to animal studies, palifermin reduced thymopoiesis in our patients. These results offer a note of caution to those using palifermin to promote thymopoiesis in other settings, particularly in the oncology/haematology setting where alemtuzumab is often used as part of the conditioning regime.
ClinicalTrials.gov NCT01712945Funding: MRC and Moulton Charitable Foundation. The lymphocyte-depleting antibody alemtuzumab is a highly effective treatment of relapsing-remitting multiple sclerosis (RRMS); however 50% of patients develop novel autoimmunity post-treatment. Most at risk are individuals who reconstitute their T-cell pool by proliferating residual cells, rather than producing new T-cells in the thymus; raising the possibility that autoimmunity might be prevented by increasing thymopoiesis. Keratinocyte growth factor (palifermin) promotes thymopoiesis in non-human primates.BACKGROUNDThe lymphocyte-depleting antibody alemtuzumab is a highly effective treatment of relapsing-remitting multiple sclerosis (RRMS); however 50% of patients develop novel autoimmunity post-treatment. Most at risk are individuals who reconstitute their T-cell pool by proliferating residual cells, rather than producing new T-cells in the thymus; raising the possibility that autoimmunity might be prevented by increasing thymopoiesis. Keratinocyte growth factor (palifermin) promotes thymopoiesis in non-human primates.Following a dose-tolerability sub-study, individuals with RRMS (duration ≤10 years; expanded disability status scale ≤5·0; with ≥2 relapses in the previous 2 years) were randomised to placebo or 180mcg/kg/day palifermin, given for 3 days immediately prior to and after each cycle of alemtuzumab, with repeat doses at M1 and M3. The interim primary endpoint was naïve CD4+ T-cell count at M6. Exploratory endpoints included: number of recent thymic-emigrants (RTEs) and signal-joint T-cell receptor excision circles (sjTRECs)/mL of blood. The trial primary endpoint was incidence of autoimmunity at M30.METHODSFollowing a dose-tolerability sub-study, individuals with RRMS (duration ≤10 years; expanded disability status scale ≤5·0; with ≥2 relapses in the previous 2 years) were randomised to placebo or 180mcg/kg/day palifermin, given for 3 days immediately prior to and after each cycle of alemtuzumab, with repeat doses at M1 and M3. The interim primary endpoint was naïve CD4+ T-cell count at M6. Exploratory endpoints included: number of recent thymic-emigrants (RTEs) and signal-joint T-cell receptor excision circles (sjTRECs)/mL of blood. The trial primary endpoint was incidence of autoimmunity at M30.At M6, individuals receiving palifermin had fewer naïve CD4+T-cells (2.229x107/L vs. 7.733x107/L; p=0.007), RTEs (16% vs. 34%) and sjTRECs/mL (1100 vs. 3396), leading to protocol-defined termination of recruitment. No difference was observed in the rate of autoimmunity between the two groupsConclusion: In contrast to animal studies, palifermin reduced thymopoiesis in our patients. These results offer a note of caution to those using palifermin to promote thymopoiesis in other settings, particularly in the oncology/haematology setting where alemtuzumab is often used as part of the conditioning regime.FINDINGSAt M6, individuals receiving palifermin had fewer naïve CD4+T-cells (2.229x107/L vs. 7.733x107/L; p=0.007), RTEs (16% vs. 34%) and sjTRECs/mL (1100 vs. 3396), leading to protocol-defined termination of recruitment. No difference was observed in the rate of autoimmunity between the two groupsConclusion: In contrast to animal studies, palifermin reduced thymopoiesis in our patients. These results offer a note of caution to those using palifermin to promote thymopoiesis in other settings, particularly in the oncology/haematology setting where alemtuzumab is often used as part of the conditioning regime.ClinicalTrials.gov NCT01712945Funding: MRC and Moulton Charitable Foundation.TRIAL REGISTRATIONClinicalTrials.gov NCT01712945Funding: MRC and Moulton Charitable Foundation. Keratinocyte growth factor impairs T cell recovery in patients with relapsing-remitting multiple sclerosis receiving treatment with the lymphocyte-depleting monoclonal antibody alemtuzumab. |
| Author | Douek, Daniel C. Jones, Joanne L. Handel, Adam E. Sadler, Timothy J. Jayne, David Holländer, Georg Needham, Edward Isaacs, John D. Kousin-Ezewu, Onajite Brown, J. William L. Seggewiss-Bernhardt, Ruth Dawson, Sarah Howlett, Sarah Deadman, Mary Davies, Jessica Coles, Alasdair J. Mullay, Harpreet Kaur Jarvis, Lorna May, Karen Thompson, Sara A.J. Rainbow, Daniel Maio, Stefano Azzopardi, Laura Rota, Ioanna Babar, Judith Georgieva, Zoya G. |
| AuthorAffiliation | 7 Department of Hematology/Oncology, Soziastiftung Bamberg, Bamberg, Germany 2 Nuffield Department of Clinical Neurosciences and 8 National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA 9 Institute of Cellular Medicine, Newcastle University, and Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom 6 University Hospital of Würzburg, Würzburg, Germany 5 Medical Research Council (MRC) Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, United Kingdom 3 Department of Paediatrics, University of Oxford, Oxford, United Kingdom 1 Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom 4 Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom |
| AuthorAffiliation_xml | – name: 3 Department of Paediatrics, University of Oxford, Oxford, United Kingdom – name: 9 Institute of Cellular Medicine, Newcastle University, and Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom – name: 4 Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom – name: 1 Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom – name: 6 University Hospital of Würzburg, Würzburg, Germany – name: 7 Department of Hematology/Oncology, Soziastiftung Bamberg, Bamberg, Germany – name: 8 National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA – name: 2 Nuffield Department of Clinical Neurosciences and – name: 5 Medical Research Council (MRC) Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, United Kingdom |
| Author_xml | – sequence: 1 givenname: Alasdair J. orcidid: 0000-0003-4738-0760 surname: Coles fullname: Coles, Alasdair J. – sequence: 2 givenname: Laura orcidid: 0000-0002-1252-8828 surname: Azzopardi fullname: Azzopardi, Laura – sequence: 3 givenname: Onajite surname: Kousin-Ezewu fullname: Kousin-Ezewu, Onajite – sequence: 4 givenname: Harpreet Kaur surname: Mullay fullname: Mullay, Harpreet Kaur – sequence: 5 givenname: Sara A.J. surname: Thompson fullname: Thompson, Sara A.J. – sequence: 6 givenname: Lorna orcidid: 0000-0002-5760-0125 surname: Jarvis fullname: Jarvis, Lorna – sequence: 7 givenname: Jessica orcidid: 0000-0002-8888-1441 surname: Davies fullname: Davies, Jessica – sequence: 8 givenname: Sarah surname: Howlett fullname: Howlett, Sarah – sequence: 9 givenname: Daniel orcidid: 0000-0003-4931-3289 surname: Rainbow fullname: Rainbow, Daniel – sequence: 10 givenname: Judith surname: Babar fullname: Babar, Judith – sequence: 11 givenname: Timothy J. surname: Sadler fullname: Sadler, Timothy J. – sequence: 12 givenname: J. William L. surname: Brown fullname: Brown, J. William L. – sequence: 13 givenname: Edward surname: Needham fullname: Needham, Edward – sequence: 14 givenname: Karen surname: May fullname: May, Karen – sequence: 15 givenname: Zoya G. orcidid: 0000-0002-9531-8884 surname: Georgieva fullname: Georgieva, Zoya G. – sequence: 16 givenname: Adam E. orcidid: 0000-0001-8385-6346 surname: Handel fullname: Handel, Adam E. – sequence: 17 givenname: Stefano orcidid: 0000-0001-9518-6466 surname: Maio fullname: Maio, Stefano – sequence: 18 givenname: Mary surname: Deadman fullname: Deadman, Mary – sequence: 19 givenname: Ioanna surname: Rota fullname: Rota, Ioanna – sequence: 20 givenname: Georg surname: Holländer fullname: Holländer, Georg – sequence: 21 givenname: Sarah surname: Dawson fullname: Dawson, Sarah – sequence: 22 givenname: David surname: Jayne fullname: Jayne, David – sequence: 23 givenname: Ruth surname: Seggewiss-Bernhardt fullname: Seggewiss-Bernhardt, Ruth – sequence: 24 givenname: Daniel C. surname: Douek fullname: Douek, Daniel C. – sequence: 25 givenname: John D. orcidid: 0000-0002-6103-7056 surname: Isaacs fullname: Isaacs, John D. – sequence: 26 givenname: Joanne L. orcidid: 0000-0003-4974-1371 surname: Jones fullname: Jones, Joanne L. |
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| Keywords | T cell development Immunology Autoimmune diseases T cells Therapeutics |
| Language | English |
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| Snippet | The lymphocyte-depleting antibody alemtuzumab is a highly effective treatment of relapsing-remitting multiple sclerosis (RRMS); however 50% of patients develop... Keratinocyte growth factor impairs T cell recovery in patients with relapsing-remitting multiple sclerosis receiving treatment with the lymphocyte-depleting... |
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| SubjectTerms | Adolescent Adult Animals CD4-Positive T-Lymphocytes - immunology CD52 Antigen - metabolism Clinical Medicine Disease Models, Animal Female Fibroblast Growth Factor 7 - pharmacology Fibroblast Growth Factor 7 - therapeutic use Humans Lymphopenia - drug therapy Male Mice Middle Aged Multiple Sclerosis, Relapsing-Remitting - immunology Young Adult |
| Title | Keratinocyte growth factor impairs human thymic recovery from lymphopenia |
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