Gene therapy with regulatory T cells: A beneficial alliance

Biswas, Moanaro; Kumar, Sandeep R. P.; Terhorst, Cox; Herzog, Roland W.

doi:10.3389/fimmu.2018.00554

Cited by 41Virus-based gene therapy researchT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

Gene therapy with regulatory T cells: A beneficial alliance

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Biswas, Moanaro, Kumar, Sandeep R. P., Terhorst, Cox, Herzog, Roland W.·2018·Frontiers in Immunology

DOI 10.3389/fimmu.2018.00554PMC PMC5868074

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Abstract

Gene therapy aims to replace a defective or deficient protein at therapeutic or curative levels. Improved vector designs have enhanced safety, efficacy and delivery, with potential for lasting treatment. However, innate and adaptive immune responses to the viral vector and transgene product remain obstacles to the establishment of therapeutic efficacy. It is widely accepted that endogenous regulatory T cells (Tregs) are critical for tolerance induction to the transgene product and in some cases, the viral vector. There are two basic strategies to harness the suppressive ability of Tregs: in vivo induction of adaptive Tregs specific to the introduced gene product, or concurrent administration of autologous, ex vivo expanded Tregs. The latter may be polyclonal or engineered to direct specificity to the therapeutic antigen. Recent clinical trials have advanced adoptive immunotherapy with Tregs for the treatment of autoimmune disease and in patients receiving cell transplants. Here, we highlight the potential benefit of combining gene therapy with Treg adoptive transfer to achieve sustained transgene expression. Furthermore, techniques to engineer antigen specific Treg cell populations, either through reprograming conventional CD4+ T cells or transferring T cell receptors with known specificity into polyclonal Tregs, are promising in pre-clinical studies. Thus, based upon these observations and the successful use of chimeric [IgG-based] antigen receptors (CARs) in antigen-specific effector T cells, different types of CAR Tregs could be added to the repertoire of inhibitory modalities to suppress immune responses to therapeutic cargos of gene therapy vectors. The diverse approaches to harness the ability of Tregs to suppress unwanted immune responses to gene therapy and their perspectives are reviewed in this article.

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Careful selection of immunosuppressive agents is necessary as Treg play a critical role in regulating immune response to rAAV products, particularly observed in liver and muscle gene transfer.
“This indicates careful selection of immunosuppressive agents is necessary as Treg play a critical role in regulating immune response to rAAV products, particularly observed in liver and muscle gene transfer (97).”
From Immunomodulation in Administration of RAAV: Preclinical and Clinical Adjuvant Pharmacotherapies (2021) · cites this paper as [97]

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Interleukin-12 (IL-12p70) Promotes Induction of Highly Potent Th1-Like CD4+CD25+ T Regulatory Cells That Inhibit Allograft Rejection in Unmodified Recipients
Verma, N. D., Hall, B. M., Plain, K. M., Robinson, C. M., Boyd, R. A., Tran, G. T., Wang, C., Bishop, G. A., & Hodgkinson, S. J. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00190 · Cited by 75 · see citing works
Synergy between rapamycin and FLT3 ligand enhances plasmacytoid dendritic cell-dependent induction of CD4+CD25+FoxP3+ Treg
Biswas, M., Sarkar, D., Kumar, S. R. P., Nayak, S., Rogers, G. L., Markusic, D. M., Liao, G., Terhorst, C., & Herzog, R. W. (2015) · Blood · doi:10.1182/blood-2014-09-599266 · Cited by 70 · see citing works
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Gene therapy for immune tolerance induction in hemophilia with inhibitors
Arruda, V. R., & Samelson-Jones, B. J. (2016) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.13331 · Cited by 69 · see citing works
In Vitro Expansion Improves In Vivo Regulation by CD4+CD25+ Regulatory T Cells
Chai, J., Coe, D., Chen, D., Simpson, E., Dyson, J., & Scott, D. M. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.2.858 · Cited by 67 · see citing works
CD4+FOXP3+ regulatory T cells confer long-term regulation of factor VIII–specific immune responses in plasmid-mediated gene therapy–treated hemophilia mice
Miao, C. H., Harmeling, B. R., Ziegler, S. F., Yen, B. C., Torgerson, T. R., Chen, L., Yau, R. J., Peng, B., Thompson, A. R., Ochs, H. D., et al. (2009) · Blood · doi:10.1182/blood-2009-06-228155 · Cited by 67 · see citing works
Insulin B chain 9–23 gene transfer to hepatocytes protects from type 1 diabetes by inducing Ag-specific FoxP3 + T regs
Akbarpour, M., Goudy, K., Cantore, A., Russo, F., Sanvito, F., Naldini, L., Annoni, A., & Roncarolo, M. G. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aaa3032 · Cited by 66 · see citing works
Prophylactic immune tolerance induced by changing the ratio of antigen-specific effector to regulatory T cells
NAYAK, S., CAO, O., HOFFMAN, B. E., COOPER, M., ZHOU, S., ATKINSON, M. A., & HERZOG, R. W. (2009) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2009.03548.x · Cited by 66 · see citing works
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Oral Tolerance Induction in Hemophilia B Dogs Fed with Transplastomic Lettuce
Herzog, R. W., Nichols, T. C., Su, J., Zhang, B., Sherman, A., Merricks, E. P., Raymer, R. A., Perrin, G. Q., Häger, M., Wiinberg, B., et al. (2017) · Molecular Therapy · doi:10.1016/j.ymthe.2016.11.009 · Cited by 65 · see citing works
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Transient Immunomodulation Allows Repeated Injections of AAV1 and Correction of Muscular Dystrophy in Multiple Muscles
Lorain, S., Gross, D.-A., Goyenvalle, A., Danos, O., Davoust, J., & Garcia, L. (2008) · Molecular Therapy · doi:10.1038/sj.mt.6300377 · Cited by 62 · see citing works
Ex Vivo Expanded Autologous Polyclonal Regulatory T Cells Suppress Inhibitor Formation in Hemophilia
Sarkar, D., Biswas, M., Liao, G., Seay, H. R., Perrin, G. Q., Markusic, D. M., Hoffman, B. E., Brusko, T. M., Terhorst, C., & Herzog, R. W. (2014) · Molecular Therapy - Methods & Clinical Development · doi:10.1038/mtm.2014.30 · Cited by 62 · see citing works
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A Novel Platform for Immune Tolerance Induction in Hemophilia A Mice
Merlin, S., Cannizzo, E. S., Borroni, E., Bruscaggin, V., Schinco, P., Tulalamba, W., Chuah, M., Arruda, V. R., VandenDriessche, T., Prat, M., et al. (2017) · Molecular Therapy · doi:10.1016/j.ymthe.2017.04.029 · Cited by 60 · see citing works
Complexity of immune responses to AAV transgene products – Example of factor IX
Herzog, R. W. (2019) · Cellular Immunology · doi:10.1016/j.cellimm.2017.05.006 · Cited by 60 · see citing works
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Plant-based oral tolerance to hemophilia therapy employs a complex immune regulatory response including LAP+CD4+ T cells
Wang, X., Su, J., Sherman, A., Rogers, G. L., Liao, G., Hoffman, B. E., Leong, K. W., Terhorst, C., Daniell, H., & Herzog, R. W. (2015) · Blood · doi:10.1182/blood-2014-08-597070 · Cited by 59 · see citing works
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Liver gene therapy by lentiviral vectors reverses anti‐factor IX pre‐existing immunity in haemophilic mice
Annoni, A., Cantore, A., Valle, P. D., Goudy, K., Akbarpour, M., Russo, F., Bartolaccini, S., D’Angelo, A., Roncarolo, M. G., & Naldini, L. (2013) · EMBO Molecular Medicine · doi:10.1002/emmm.201302857 · Cited by 59 · see citing works
Impact of Humoral Immune Response on Distribution and Efficacy of Recombinant Adeno-Associated Virus-Derived Acid α-Glucosidase in a Model of Glycogen Storage Disease Type II
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The Skeletal Muscle Environment and Its Role in Immunity and Tolerance to AAV Vector-Mediated Gene Transfer
Boisgérault, F., & Mingozzi, F. (2015) · Current Gene Therapy · doi:10.2174/1566523215666150630121750 · Cited by 54 · see citing works
Resistance to regulatory T cell-mediated suppression in rheumatoid arthritis can be bypassed by ectopic foxp3 expression in pathogenic synovial T cells
Beavis, P. A., Gregory, B., Green, P. A., Cribbs, A. P., Kennedy, A., Amjadi, P., Palfreeman, A. C., Feldmann, M., & Brennan, F. M. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1112722108 · Cited by 53 · see citing works
Enhanced selection of FoxP3 + T-regulatory cells protects CTLA-4-deficient mice from CNS autoimmune disease
Verhagen, J., Gabryšová, L., Minaee, S., Sabatos, C. A., Anderson, G., Sharpe, A. H., & Wraith, D. C. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0803186106 · Cited by 50 · see citing works
Gene Therapy for “Bubble Boy” Disease
Hoggatt, J. (2016) · Cell · doi:10.1016/j.cell.2016.06.049 · Cited by 50 · see citing works
A TLR and Non-TLR Mediated Innate Response to Lentiviruses Restricts Hepatocyte Entry and Can be Ameliorated by Pharmacological Blockade
Agudo, J., Ruzo, A., Kitur, K., Sachidanandam, R., Blander, J. M., & Brown, B. D. (2012) · Molecular Therapy · doi:10.1038/mt.2012.150 · Cited by 48 · see citing works
Phase I/II Trial of Diaphragm Delivery of Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase (rAAV1-CMV- GAA ) Gene Vector in Patients with Pompe Disease
Byrne, B. J., Smith, B. K., Mah, C. S., Lawson, L. A., Islam, S., Corti, M., Martin, D., Dobija, N., Irwin, M. V., Conlon, T. J., et al. (2014) · Human Gene Therapy Clinical Development · doi:10.1089/humc.2014.2514 · Cited by 45 · see citing works
β-Thalassemia Treatment Succeeds, With a Caveat
Kaiser, J. (2009) · Science · doi:10.1126/science.326.5959.1468-b · Cited by 45 · see citing works
CD4+ CD25+ regulatory T cells inhibit immune-mediated transgene rejection
Gross, D.-A., Leboeuf, M., Gjata, B., Danos, O., & Davoust, J. (2003) · Blood · doi:10.1182/blood-2003-05-1454 · Cited by 45 · see citing works
Generation of donor-specific Tr1 cells to be used after kidney transplantation and definition of the timing of their in vivo infusion in the presence of immunosuppression
Mfarrej, B. G., Tresoldi, E., Stabilini, A., Paganelli, A., Caldara, R., Secchi, A., & Battaglia, M. (2017) · Journal of Translational Medicine · doi:10.1186/s12967-017-1133-8 · Cited by 41 · see citing works
Immunomodulation for inhibitors in hemophilia A: the important role of Treg cells
Miao, C. H. (2010) · Expert Review of Hematology · doi:10.1586/ehm.10.33 · Cited by 40 · see citing works
Prevention and Reversal of Antibody Responses Against Factor IX in Gene Therapy for Hemophilia B
Nayak, S., Sarkar, D., Perrin, G. Q., Moghimi, B., Hoffman, B. E., Zhou, S., Byrne, B. J., & Herzog, R. W. (2011) · Frontiers in Microbiology · doi:10.3389/fmicb.2011.00244 · Cited by 40 · see citing works
Self-citation
Characterization of Adeno-Associated Viral Vector-Mediated Human Factor VIII Gene Therapy in Hemophilia A Mice
Greig, J. A., Wang, Q., Reicherter, A. L., Chen, S., Hanlon, A. L., Tipper, C. H., Clark, K. R., Wadsworth, S. C., Wang, L., & Wilson, J. M. (2017) · Human Gene Therapy · doi:10.1089/hum.2016.128 · Cited by 40 · see citing works
Translational Data from Adeno-Associated Virus-Mediated Gene Therapy of Hemophilia B in Dogs
Nichols, T. C., Whitford, M. H., Arruda, V. R., Stedman, H. H., Kay, M. A., & High, K. A. (2015) · Human Gene Therapy Clinical Development · doi:10.1089/humc.2014.153 · Cited by 36 · see citing works
Antigen-Specific Regulatory T Cells and Low Dose of IL-2 in Treatment of Type 1 Diabetes
Pham, M. N., von Herrath, M. G., & Vela, J. L. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00651 · Cited by 34 · see citing works
Specific Immunosuppression with Inducible Foxp3-Transduced Polyclonal T cells
Andersen, K. G., Butcher, T., & Betz, A. G. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060276 · Cited by 29 · see citing works
Generation of Human Alloantigen-Specific Regulatory T Cells under Good Manufacturing Practice-Compliant Conditions for Cell Therapy
Chera, M., Hamel, Y., Baillou, C., Touil, S., Guillot‐Delost, M., Charlotte, F., Kossir, L., Simonin, G., Maury, S., Cohen, J. L., et al. (2014) · Cell Transplantation · doi:10.3727/096368914x683566 · Cited by 28 · see citing works
Generation of Donor-specific T Regulatory Type 1 Cells From Patients on Dialysis for Cell Therapy After Kidney Transplantation
Petrelli, A., Tresoldi, E., Mfarrej, B. G., Paganelli, A., Spotti, D., Caldara, R., Secchi, A., & Battaglia, M. (2015) · Transplantation · doi:10.1097/tp.0000000000000751 · Cited by 24 · see citing works
Oral-tolerization Prevents Immune Responses and Improves Transgene Persistence Following Gene Transfer Mediated by Adeno-associated Viral Vector
Hardet, R., Chevalier, B., Dupaty, L., Naïmi, Y., Riou, G., Drouot, L., Jean, L., Salvetti, A., Boyer, O., & Adriouch, S. (2015) · Molecular Therapy · doi:10.1038/mt.2015.146 · Cited by 20 · see citing works
A Cure For Hemophilia: the Promise Becomes a Reality
Herzog, R. W. (2016) · Molecular Therapy · doi:10.1038/mt.2016.169 · Cited by 15 · see citing works
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Differential Phenotypic and Genotypic Characteristics of qnrS1 -Harboring Plasmids Carried by Hospital and Community Commensal Enterobacteria
Vien, L. T. M., AbuOun, M., Morrison, V., Thomson, N. R., Campbell, J. I., Woodward, M. J., Châu, N. V. V., Farrar, J., Schultsz, C., & Baker, S. G. (2011) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01200-10 · Cited by 12 · see citing works
Treg adoptive therapy: is more better?
Parmar, S., & Shpall, E. J. (2016) · Blood · doi:10.1182/blood-2015-12-682492 · Cited by 12 · see citing works
Development of citrullinated-vimentin-specific CAR for targeting Tregs to treat autoimmune rheumatoid arthritis.
Raffin, C., Zhou, Y., Piccoli, L., Lanzavecchia, A., Sadelain, M., & Bluestone, J. A. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.196.supp.210.19 · Cited by 11 · see citing works
Targeting FVIII-Specific B Cells Using BAR-Transduced Regulatory T Cells
Zhang, A.-H., Yoon, J. H., Kim, Y. C., & Scott, D. W. (2016) · Blood · doi:10.1182/blood.v128.22.329.329 · Cited by 10 · see citing works
A self‐deletion lentiviral vector to reduce the risk of replication‐competent virus formation
Fang, Y., Gong, X., Xu, M., Zeng, F., & Zhang, J. (2013) · The Journal of Gene Medicine · doi:10.1002/jgm.2700 · Cited by 8 · see citing works
Hepatic gene therapy using lentiviral vectors: Has safety been established?
Dismuke, D. J., & Samulski, J. R. (2013) · Hepatology · doi:10.1002/hep.26460 · Cited by 6 · see citing works
Tilt balance towards regulation: evolving new strategy for treatment of hemophilia inhibitors
Miao, C. H. (2011) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2011.04391.x · Cited by 4 · see citing works
Translational Data from AAV-Mediated Gene Therapy of Hemophilia B in Dogs
Nichols, T. C., Whitford, M. H., Arruda, V. R., Stedman, H. H., Kay, M. A., & High, K. A. (2014) · Human Gene Therapy Clinical Development · doi:10.1089/hum.2014.153 · Cited by 4 · see citing works

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Adeno-associated virus vector as a platform for gene therapy delivery
Wang, D., Tai, P. W. L., & Gao, G. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0012-9 · Cited by 2,444 · see citing works
Chimeric Antigen Receptor (CAR) Treg: A Promising Approach to Inducing Immunological Tolerance
Zhang, Q., Lu, W., Liang, C.-L., Chen, Y., Liu, H., Qiu, F., & Dai, Z. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02359 · Cited by 168 · see citing works
CAR-T Regulatory (CAR-Treg) Cells: Engineering and Applications
Arjomandnejad, M., Kopec, A. L., & Keeler, A. M. (2022) · Biomedicines · doi:10.3390/biomedicines10020287 · Cited by 151 · see citing works
Durability of transgene expression after rAAV gene therapy
Muhuri, M., Lévy, D., Schulz, M., McCarty, D. M., & Gao, G. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.03.004 · Cited by 148 · see citing works
Toward an optimized process for clinical manufacturing of CAR-treg cell therapy
Fritsche, E., Volk, H.-D., Reinke, P., & Abou-El-Enein, M. (2020) · Trends in Biotechnology · doi:10.1016/j.tibtech.2019.12.009 · Cited by 97 · see citing works
Exploring modified chitosan-based gene delivery technologies for therapeutic advancements
Gholap, A. D., Kapare, H. S., Pagar, S., Kamandar, P. A., Bhowmik, D. D., Vishwakarma, N., Raikwar, S., Garkal, A., Mehta, T. A., Rojekar, S. V., et al. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.129581 · Cited by 67 · see citing works
Cas9-directed immune tolerance in humans—a model to evaluate regulatory T cells in gene therapy?
Wagner, D. L., Peter, L., & Schmueck-Henneresse, M. (2021) · Gene Therapy · doi:10.1038/s41434-021-00232-2 · Cited by 63 · see citing works
Immunomodulation in Administration of RAAV: Preclinical and Clinical Adjuvant Pharmacotherapies
Chu, W. S., & Ng, J. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.658038 · Cited by 59 · see citing works
Rheumatology 4.0: big data, wearables and diagnosis by computer
Burmester, G. R. (2018) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2017-212888 · Cited by 53 · see citing works
Regulatory CAR-T cells in autoimmune diseases: Progress and current challenges
Riët, T., & Chmielewski, M. M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.934343 · Cited by 54 · see citing works
Delivery of genome editing tools: A promising strategy for HPV-related cervical malignancy therapy
Aghamiri, S., Talaei, S., Roshanzamiri, S., Zandsalimi, F., Fazeli, E., Aliyu, M., Avarvand, O. K., Ebrahimi, Z., Keshavarz‐Fathi, M., & Ghanbarian, H. (2020) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2020.1747429 · Cited by 36 · see citing works
Immune modulation via T regulatory cell enhancement: Disease‐modifying therapies for autoimmunity and their potential for chronic allergic and inflammatory diseases—An EAACI position paper of the Task Force on Immunopharmacology (TIPCO)
Roth‐Walter, F., Adcock, I. M., Benito‐Villalvilla, C., Bianchini, R., Bjermer, L. H., Boyman, O., Caramori, G., Cari, L., Chung, K. F., Diamant, Z., et al. (2020) · Allergy · doi:10.1111/all.14478 · Cited by 38 · see citing works
Progress in Translational Regulatory T Cell Therapies for Type 1 Diabetes and Islet Transplantation.
Marfil-Garza, B., Hefler, J., de León, M. B., Pawlick, R., Dadheech, N., & Shapiro, A. M. J. (2020) · Endocrine reviews · doi:10.1210/endrev/bnaa028 · Cited by 27 · see citing works
Regulatory T Cells, a Viable Target Against Airway Allergic Inflammatory Responses in Asthma
Zhang, J., Zou, Y., Chen, L., Xu, Q., Wang, Y., Xie, M., Liu, X., Zhao, J., & Wang, C. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.902318 · Cited by 34 · see citing works
Regulatory T cells targeting a pathogenic MHC class II: Insulin peptide epitope postpone spontaneous autoimmune diabetes
Obarorakpor, N., Patel, D., Boyarov, R., Amarsaikhan, N., Cepeda, J. R., Eastes, D., Robertson, S., Johnson, T. S., Yang, K., Tang, Q., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1207108 · Cited by 34 · see citing works
Transgene distribution and immune response after ultrasound delivery of rAAV9 and PHP.B to the brain in a mouse model of amyloidosis
Kofoed, R. H., Heinen, S., Silburt, J., Dubey, S., Dibia, C. L., Maes, M. S., Simpson, E. M., Hynynen, K., & Aubert, I. (2021) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2021.10.001 · Cited by 28 · see citing works
Scientific and Regulatory Policy Committee Points to Consider: Nonclinical Research and Development of In Vivo Gene Therapy Products, Emphasizing Adeno-Associated Virus Vectors
Hutt, J. A., Assaf, B. T., Bolon, B. N., Cavagnaro, J. A., Galbreath, E. J., Grubor, B., Kattenhorn, L. M., Romeike, A., & Whiteley, L. O. (2021) · Toxicologic Pathology · doi:10.1177/01926233211041962 · Cited by 27 · see citing works
Immune tolerance against infused FVIII in hemophilia A is mediated by PD-L1+ Tregs
Becker-Gotot, J., Meissner, M., Kotov, V., Jurado-Mestre, B., Maione, A., Pannek, A., Albert, T., Flores, C., Schildberg, F. A., Gleeson, P. A., et al. (2022) · Journal of Clinical Investigation · doi:10.1172/jci159925 · Cited by 27 · see citing works
Reprogrammed CD4+ T Cells That Express FoxP3+ Control Inhibitory Antibody Formation in Hemophilia A Mice
Herzog, R. W., Kuteyeva, V., Saboungi, R., Terhorst, C., & Biswas, M. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00274 · Cited by 24 · see citing works
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Gene editing for inflammatory disorders
Ewart, D. T., Peterson, E. J., & Steer, C. J. (2018) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2018-213454 · Cited by 24 · see citing works
Neutralizing Antibodies: Role in Immune Response and Viral Vector Based Gene Therapy
Tsaregorodtseva, T. S., Gubaidullina, A. A., Kayumova, B. R., Shaimardanova, A. A., Issa, S. S., Solovyeva, V. V., Sufianov, A. A., Суфианова, Г. З., & Rizvanov, A. A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26115224 · Cited by 19 · see citing works
Tolerance induction in hemophilia: innovation and accomplishments
Sherman, A., Biswas, M., & Herzog, R. W. (2018) · Current Opinion in Hematology · doi:10.1097/moh.0000000000000446 · Cited by 17 · see citing works
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FSHD Therapeutic Strategies: What Will It Take to Get to Clinic?
Himeda, C. L., & Jones, P. L. (2022) · Journal of Personalized Medicine · doi:10.3390/jpm12060865 · Cited by 15 · see citing works
Preclinical Development and Characterization of Novel Adeno-Associated Viral Vectors for the Treatment of Lipoprotein Lipase Deficiency
Mehta, N., Gilbert, R., Chahal, P. S., Moreno, M., Nassoury, N., Coulombe, N., Lytvyn, V., Mercier, M., Fatehi, D., Lin, W., et al. (2023) · Human Gene Therapy · doi:10.1089/hum.2023.075 · Cited by 15 · see citing works
Controlled WASp activity regulates the proliferative response for Treg cell differentiation in the thymus
Vasconcelos‐Fontes, L., Vieira, R. C., He, M., Ferreira‐Reis, R., Jurberg, A. D., Mendes‐da‐Cruz, D. A., Andersson, J., Cotta-de-Almeida, V., & Westerberg, L. S. (2024) · European Journal of Immunology · doi:10.1002/eji.202350450 · Cited by 4 · see citing works
Development of a novel vector for siRNA delivery based on arginine‐modified polyvinylamine
Lin, M., Lin, A., Huang, S., Liu, T., Ke, F., Qiu, D., Lin, X., & Luo, D. (2022) · Polymer International · doi:10.1002/pi.6386 · Cited by 4 · see citing works
CD 4+ CD 25− LAG 3+ regulatory T cells in humoral immunity
Inoue, M., Okamura, T., Komai, T., Yamamoto, K., & Fujio, K. (2019) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12498 · Cited by 4 · see citing works
Enhancing AAV9-UFμDys1 Gene Therapy Efficacy Through Immunosuppression in Mice with Pre-Existing Immunity and Enabling Redosing Strategies for Duchenne Muscular Dystrophy
Saha, M., Bhake, R., Meyers, C., Coleman, K. E., Trivedi, P. D., Gallman, M., Biswas, M., Herzog, R. W., Byrne, B. J., & Corti, M. (2025) · Human Gene Therapy · doi:10.1177/10430342251385586 · Cited by 3 · see citing works
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Innovative Therapies and Strategies for Rheumatoid Arthritis
Gupta, K. R., Kathoke, P., Thombre, K. R., & Umekar, M. J. (2025) · Current Rheumatology Reviews · doi:10.2174/0115733971340845250120054856 · Cited by 3 · see citing works
Glucose metabolism in CD4 and CD8 T cells
Masson, J. J. R., & Palmer, C. S. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-849886-6.00016-1 · Cited by 2 · see citing works
The immune response is a prerequisite for the development of CD4+Foxp3+ regulatory T cells in transplantation.
Ma, P., Yang, X. C., Dong, R., Ming, L., Tang, H., Liu, X., Zhang, S., & Zheng, P. (2018) · Europe PMC (PubMed Central) · Cited by 2 · see citing works
The role of miRNAs in the development of Super-Tregs as a potential therapy for neurodegenerative diseases
Mukherjee, K., & Bhattacharyya, S. N. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1708031 · Cited by 1 · see citing works
Regulatory T cells as a potential treatment for autoimmune inflammatory rheumatic and musculoskeletal diseases
Chikanza, I. C., Mnkandla-Khumalo, C. S. N., & Sakkas, L. I. (2026) · Clinical Rheumatology · doi:10.1007/s10067-026-08069-z · Cited by 1 · see citing works
The future of TCR-Treg therapies is renewables
Peh, C. R., Nguyen‐Dumont, T., Ting, Y. T., & Ooi, J. D. (2026) · Autoimmunity Reviews · doi:10.1016/j.autrev.2026.104139 · Cited by 1 · see citing works
Immune Responses to Adeno-Associated Virus-Mediated CRISPR Therapy
Keeler, A. M. (2021) · Human Gene Therapy · doi:10.1089/hum.2021.29193.amk · Cited by 1 · see citing works
Faculty Opinions recommendation of Adeno-associated virus vector as a platform for gene therapy delivery.
Fehlings, M. G. (2020) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.734958350.793573257
Caractérisation phénotypique et fonctionnelle des lymphocytes T régulateurs dans la polyarthrite rhumatoïde
Ahmadi, Y. E. (2020) · doi:10.70675/cd8f08aezd8ecz4711zb43czd35ef03dfd1b
Les cellules souches mésenchymateuses dérivées du tissu adipeux dans le traitement de la polyarthrite rhumatoïde : approches in vitro et in vivo
Sayegh, S. (2019) · doi:10.70675/8121e62fz9318z43f3z81c5zfebc88df751c
Regulatory T cells in autoimmune diseases: biological mechanisms, clinical translation, and translational challenges
Li, J., Pang, J., Wu, P., Wang, E., Zheng, S. J., 阮庆国, & Liu, R. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1881360
Clinical immunogenicity in rAAV gene therapy: Insights and implications
Gulve, N., Bego, M. G., Gandhi, H., Khan, Z., Tong, O., Katebifar, S., & Rajadhyaksha, M. (2026) · Molecular Therapy Advances · doi:10.1016/j.omta.2026.201848
Targeting the Th17/Treg axis: from immunological insights to therapeutic avenues in atherosclerosis
Qin, Z., Chen, S., Lyu, Z., Zhou, F., Liu, L., Ai, Q., & Zeng, Z. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1923083

Emerging Role of Regulatory T Cells in Gene Transfer
Cao, O., Furlan-Freguia, C., Arruda, V. R., & Herzog, R. W. (2007) · Current Gene Therapy · doi:10.2174/156652307782151506 · Cited by 26 · see citing works
Self-citation
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Sato, Y. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1762753 · Cited by 2 · see citing works
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Authors: Biswas, M., Kumar, S. R. P., Terhorst, C., & Herzog, R. W.
Affiliations: University of Florida (US)
Beth Israel Deaconess Medical Center (US)
Corresponding author: Biswas, Moanaro
ORCID: Biswas, Moanaro
Kumar, Sandeep R. P.
Terhorst, Cox
Herzog, Roland W.
Venue: Frontiers in Immunology
Publisher: Frontiers Media SA
Published: 2018-03-19
Volume: 9
Pages: 554-554
ISSN: 1664-3224 (ISSN-L)
DOI: 10.3389/fimmu.2018.00554
PMC: PMC5868074
OpenAlex: W2792287345
Cited by: 41
References: 184
Citations by year: 2026: 6 · 2025: 3 · 2024: 2 · 2023: 2 · 2022: 7 · 2021: 5 · 2020: 6 · 2019: 5 · 2018: 5
FWCI: 0.72
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
Locations: Frontiers in Immunology (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Institutes of Health
National Heart, Lung, and Blood Institute (HL-097088, HL131093, R01HL097088, R01HL131093)
National Institute of Allergy and Infectious Diseases (R01AI051390)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords: gene therapy, regulatory T cells, adoptive Treg transfer, ex vivo Treg expansion, CAR-Tregs, chimeric antigen receptor, immunosuppression, sustained transgene expression, autoimmune disease, cell transplantation
MeSH terms: Animals, Antigen-Presenting Cells, Autoimmune Diseases, Genetic Vectors, Humans, Genetic Therapy, Lentivirus, Models, Immunological, Transgenes, T-Lymphocytes, Regulatory

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Gene therapy with regulatory T cells: A beneficial alliance

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