Metabolite and thymocyte development defects in ADA-SCID mice receiving enzyme replacement therapy

Abstract Deficiency of adenosine deaminase (ADA, EC3.5.4.4), a housekeeping enzyme intrinsic to the purine salvage pathway, leads to severe combined immunodeficiency (SCID) both in humans and mice. Lack of ADA results in the intracellular accumulation of toxic metabolites which have effects on T cel...

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Autores principales:	Federico A. Moretti, Giuliana Giardino, Teresa C. H. Attenborough, Athina Soragia Gkazi, Ben K. Margetts, Giancarlo la Marca, Lynette Fairbanks, Tessa Crompton, H. Bobby Gaspar
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f65c7cd9d5074750a94e03ee0d0444ee
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spelling	oai:doaj.org-article:f65c7cd9d5074750a94e03ee0d0444ee2021-12-05T12:14:26ZMetabolite and thymocyte development defects in ADA-SCID mice receiving enzyme replacement therapy10.1038/s41598-021-02572-w2045-2322https://doaj.org/article/f65c7cd9d5074750a94e03ee0d0444ee2021-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-02572-whttps://doaj.org/toc/2045-2322Abstract Deficiency of adenosine deaminase (ADA, EC3.5.4.4), a housekeeping enzyme intrinsic to the purine salvage pathway, leads to severe combined immunodeficiency (SCID) both in humans and mice. Lack of ADA results in the intracellular accumulation of toxic metabolites which have effects on T cell development and function. While untreated ADA-SCID is a fatal disorder, there are different therapeutic options available to restore ADA activity and reconstitute a functioning immune system, including enzyme replacement therapy (ERT). Administration of ERT in the form of pegylated bovine ADA (PEG-ADA) has proved a life-saving though non-curative treatment for ADA-SCID patients. However, in many patients treated with PEG-ADA, there is suboptimal immune recovery with low T and B cell numbers. Here, we show reduced thymus cellularity in ADA-SCID mice despite weekly PEG-ADA treatment. This was associated with lack of effective adenosine (Ado) detoxification in the thymus. We also show that thymocyte development in ADA-deficient thymi is arrested at the DN3-to-DN4 stage transition with thymocytes undergoing dATP-induced apoptosis rather than defective TCRβ rearrangement or β-selection. Our studies demonstrate at a detailed level that exogenous once-a-week enzyme replacement does not fully correct intra-thymic metabolic or immunological abnormalities associated with ADA deficiency.Federico A. MorettiGiuliana GiardinoTeresa C. H. AttenboroughAthina Soragia GkaziBen K. MargettsGiancarlo la MarcaLynette FairbanksTessa CromptonH. Bobby GasparNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Federico A. Moretti Giuliana Giardino Teresa C. H. Attenborough Athina Soragia Gkazi Ben K. Margetts Giancarlo la Marca Lynette Fairbanks Tessa Crompton H. Bobby Gaspar Metabolite and thymocyte development defects in ADA-SCID mice receiving enzyme replacement therapy
description	Abstract Deficiency of adenosine deaminase (ADA, EC3.5.4.4), a housekeeping enzyme intrinsic to the purine salvage pathway, leads to severe combined immunodeficiency (SCID) both in humans and mice. Lack of ADA results in the intracellular accumulation of toxic metabolites which have effects on T cell development and function. While untreated ADA-SCID is a fatal disorder, there are different therapeutic options available to restore ADA activity and reconstitute a functioning immune system, including enzyme replacement therapy (ERT). Administration of ERT in the form of pegylated bovine ADA (PEG-ADA) has proved a life-saving though non-curative treatment for ADA-SCID patients. However, in many patients treated with PEG-ADA, there is suboptimal immune recovery with low T and B cell numbers. Here, we show reduced thymus cellularity in ADA-SCID mice despite weekly PEG-ADA treatment. This was associated with lack of effective adenosine (Ado) detoxification in the thymus. We also show that thymocyte development in ADA-deficient thymi is arrested at the DN3-to-DN4 stage transition with thymocytes undergoing dATP-induced apoptosis rather than defective TCRβ rearrangement or β-selection. Our studies demonstrate at a detailed level that exogenous once-a-week enzyme replacement does not fully correct intra-thymic metabolic or immunological abnormalities associated with ADA deficiency.
format	article
author	Federico A. Moretti Giuliana Giardino Teresa C. H. Attenborough Athina Soragia Gkazi Ben K. Margetts Giancarlo la Marca Lynette Fairbanks Tessa Crompton H. Bobby Gaspar
author_facet	Federico A. Moretti Giuliana Giardino Teresa C. H. Attenborough Athina Soragia Gkazi Ben K. Margetts Giancarlo la Marca Lynette Fairbanks Tessa Crompton H. Bobby Gaspar
author_sort	Federico A. Moretti
title	Metabolite and thymocyte development defects in ADA-SCID mice receiving enzyme replacement therapy
title_short	Metabolite and thymocyte development defects in ADA-SCID mice receiving enzyme replacement therapy
title_full	Metabolite and thymocyte development defects in ADA-SCID mice receiving enzyme replacement therapy
title_fullStr	Metabolite and thymocyte development defects in ADA-SCID mice receiving enzyme replacement therapy
title_full_unstemmed	Metabolite and thymocyte development defects in ADA-SCID mice receiving enzyme replacement therapy
title_sort	metabolite and thymocyte development defects in ada-scid mice receiving enzyme replacement therapy
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f65c7cd9d5074750a94e03ee0d0444ee
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Metabolite and thymocyte development defects in ADA-SCID mice receiving enzyme replacement therapy

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