Transfer of gene-corrected T cells corrects humoral and cytotoxic defects in patients with X-linked lymphoproliferative disease - 04/07/18
Abstract |
Background |
X-linked lymphoproliferative disease 1 arises from mutations in the SH2D1A gene encoding SLAM-associated protein (SAP), an adaptor protein expressed in T, natural killer (NK), and NKT cells. Defects lead to abnormalities of T-cell and NK cell cytotoxicity and T cell–dependent humoral function. Clinical manifestations include hemophagocytic lymphohistiocytosis, lymphoma, and dysgammaglobulinemia. Curative treatment is limited to hematopoietic stem cell transplantation, with outcomes reliant on a good donor match.
Objectives |
Because most symptoms arise from defective T-cell function, we investigated whether transfer of SAP gene–corrected T cells could reconstitute known effector cell defects.
Methods |
CD3+ lymphocytes from Sap-deficient mice were transduced with a gammaretroviral vector encoding human SAP cDNA before transfer into sublethally irradiated Sap-deficient recipients. After immunization with the T-dependent antigen 4-hydroxy-3-nitrophenylacetly chicken gammaglobulin (NP-CGG), recovery of humoral function was evaluated through germinal center formation and antigen-specific responses. To efficiently transduce CD3+ cells from patients, we generated an equivalent lentiviral SAP vector. Functional recovery was demonstrated by using in vitro cytotoxicity and T follicular helper cell function assays alongside tumor clearance in an in vivo lymphoblastoid cell line lymphoma xenograft model.
Results |
In Sap-deficient mice 20% to 40% engraftment of gene-modified T cells led to significant recovery of germinal center formation and NP-specific antibody responses. Gene-corrected T cells from patients demonstrated improved cytotoxicity and T follicular helper cell function in vitro. Adoptive transfer of gene-corrected cytotoxic T lymphocytes from patients reduced tumor burden to a level comparable with that seen in healthy donor cytotoxic T lymphocytes in an in vivo lymphoma model.
Conclusions |
These data demonstrate that autologous T-cell gene therapy corrects SAP-dependent defects and might offer an alternative therapeutic option for patients with X-linked lymphoproliferative disease 1.
Le texte complet de cet article est disponible en PDF.Key words : X-linked lymphoproliferative disease, T-cell gene therapy, follicular helper T cells, T-cell cytotoxicity
Abbreviations used : BV, CTL, HLH, HSCT, HVS, LCL, MOI, NK, NP-CGG, PD-1, PE, SAP, TFH, XLP
Plan
| Supported by Action Medical Research and Bloodwise. C.B. is in receipt of a Wellcome Trust Early Postdoctoral Training Fellowship. A.J.T. is in receipt of a Wellcome Trust Principal Research Fellowship (104807/Z/14/Z); B.H. is also supported on this fellowship. H.B.G. is supported by the Great Ormond Street Children's Charity. This research was supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. |
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| Disclosure of potential conflict of interest: B. Houghton and his institution received grant money from the Leukaemia Lymphoma Research Charity. A. J. Thrasher and H. B. Gaspar are board members, received money for consultancy unrelated to this project from, and have stock options with Orchard Therapeutics. A. J. Thrasher is a board member and received money for consultancy unrelated to this project from Torus and Rocket Pharmaceuticals and has stock options in Torus. C. Booth received money for consultancy unrelated to this project from Novimmune and received payment for the development of educational presentations unrelated to this project from Springer. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 142 - N° 1
P. 235 - juillet 2018 Retour au numéro
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