Immunophenotype associated with high sustained antibody titers against enzyme replacement therapy in infantile-onset Pompe disease
IntroductionThe efficacy of enzyme replacement therapy (ERT) with alglucosidase alfa for infantile-onset Pompe disease (IOPD) is limited in some patients due to the development of high and sustained antibody titers (HSAT; ≥12,800).MethodsWe carried out detailed immunophenotyping of IOPD patients (n=...
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Frontiers Media S.A.
2024-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1301912/full |
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| author | Ankit K. Desai P. Brian Smith P. Brian Smith John S. Yi Amy S. Rosenberg Trevor D. Burt Trevor D. Burt Priya S. Kishnani |
| author_facet | Ankit K. Desai P. Brian Smith P. Brian Smith John S. Yi Amy S. Rosenberg Trevor D. Burt Trevor D. Burt Priya S. Kishnani |
| author_sort | Ankit K. Desai |
| collection | DOAJ |
| description | IntroductionThe efficacy of enzyme replacement therapy (ERT) with alglucosidase alfa for infantile-onset Pompe disease (IOPD) is limited in some patients due to the development of high and sustained antibody titers (HSAT; ≥12,800).MethodsWe carried out detailed immunophenotyping of IOPD patients (n=40), including analysis of circulating cell populations by flow cytometry and plasma cytokines by multiplex array, to determine whether patients with HSAT have unique immunological characteristics compared to those with low titers (LT; <12,800).ResultsCompared to patients with LT, patients who develop HSAT were skewed toward a type 2 immune profile, with an increased frequency of Th2 cells that was positively correlated with levels of Th2 (IL-4, IL-5, IL-13) and pro-inflammatory (IL-6, TNF-α, MIP-1α, MIP-1β) cytokines. B cells were increased in HSAT patients with a decreased fraction of unswitched memory B cells. Plasma GM-CSF concentrations were lower on average in HSAT patients, while CXCL11 was elevated. Finally, using principal components analysis, we derived an HSAT Signature Score that successfully stratified patients according to their antibody titers.DiscussionThe immune profiles revealed in this study not only identify potential biomarkers of patients that developed HSAT but also provide insights into the pathophysiology of HSAT that will ultimately lead to improved immunotherapy strategies. |
| first_indexed | 2024-03-08T17:06:24Z |
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| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-08T17:06:24Z |
| publishDate | 2024-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-ec2469dc10d54eddb7249c22c74a90792024-01-04T05:11:05ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-01-011410.3389/fimmu.2023.13019121301912Immunophenotype associated with high sustained antibody titers against enzyme replacement therapy in infantile-onset Pompe diseaseAnkit K. Desai0P. Brian Smith1P. Brian Smith2John S. Yi3Amy S. Rosenberg4Trevor D. Burt5Trevor D. Burt6Priya S. Kishnani7Division of Medical Genetics, Department of Pediatrics, Duke University Health System, Durham, NC, United StatesDivision of Neonatology, Department of Pediatrics, Duke University School of Medicine, Durham, NC, United StatesDuke Clinical Research Institute, Durham, NC, United StatesDivision of Surgical Sciences, Department of Surgery, Duke University School of Medicine, Durham, NC, United StatesEpiVax, Inc., Providence, RI, United StatesDivision of Neonatology, Department of Pediatrics, Duke University School of Medicine, Durham, NC, United StatesChildren’s Health and Discovery Initiative, Duke University School of Medicine, Durham, NC, United StatesDivision of Medical Genetics, Department of Pediatrics, Duke University Health System, Durham, NC, United StatesIntroductionThe efficacy of enzyme replacement therapy (ERT) with alglucosidase alfa for infantile-onset Pompe disease (IOPD) is limited in some patients due to the development of high and sustained antibody titers (HSAT; ≥12,800).MethodsWe carried out detailed immunophenotyping of IOPD patients (n=40), including analysis of circulating cell populations by flow cytometry and plasma cytokines by multiplex array, to determine whether patients with HSAT have unique immunological characteristics compared to those with low titers (LT; <12,800).ResultsCompared to patients with LT, patients who develop HSAT were skewed toward a type 2 immune profile, with an increased frequency of Th2 cells that was positively correlated with levels of Th2 (IL-4, IL-5, IL-13) and pro-inflammatory (IL-6, TNF-α, MIP-1α, MIP-1β) cytokines. B cells were increased in HSAT patients with a decreased fraction of unswitched memory B cells. Plasma GM-CSF concentrations were lower on average in HSAT patients, while CXCL11 was elevated. Finally, using principal components analysis, we derived an HSAT Signature Score that successfully stratified patients according to their antibody titers.DiscussionThe immune profiles revealed in this study not only identify potential biomarkers of patients that developed HSAT but also provide insights into the pathophysiology of HSAT that will ultimately lead to improved immunotherapy strategies.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1301912/fullinfantile-onset Pompe diseaseimmunophenotypinganti-drug antibodiesimmune profilingimmune activationenzyme replacement therapy |
| spellingShingle | Ankit K. Desai P. Brian Smith P. Brian Smith John S. Yi Amy S. Rosenberg Trevor D. Burt Trevor D. Burt Priya S. Kishnani Immunophenotype associated with high sustained antibody titers against enzyme replacement therapy in infantile-onset Pompe disease Frontiers in Immunology infantile-onset Pompe disease immunophenotyping anti-drug antibodies immune profiling immune activation enzyme replacement therapy |
| title | Immunophenotype associated with high sustained antibody titers against enzyme replacement therapy in infantile-onset Pompe disease |
| title_full | Immunophenotype associated with high sustained antibody titers against enzyme replacement therapy in infantile-onset Pompe disease |
| title_fullStr | Immunophenotype associated with high sustained antibody titers against enzyme replacement therapy in infantile-onset Pompe disease |
| title_full_unstemmed | Immunophenotype associated with high sustained antibody titers against enzyme replacement therapy in infantile-onset Pompe disease |
| title_short | Immunophenotype associated with high sustained antibody titers against enzyme replacement therapy in infantile-onset Pompe disease |
| title_sort | immunophenotype associated with high sustained antibody titers against enzyme replacement therapy in infantile onset pompe disease |
| topic | infantile-onset Pompe disease immunophenotyping anti-drug antibodies immune profiling immune activation enzyme replacement therapy |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1301912/full |
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