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Imaging the in vivo fate of human T cells following transplantation in immunoincompetent mice - Implications for clinical cell therapy trials
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
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2013 (English)In: Transplant Immunology, ISSN 0966-3274, E-ISSN 1878-5492, Vol. 29, no 1-4, 105-108 p.Article in journal (Refereed) Published
Abstract [en]

Many forms of adoptive T cell therapy are on the verge of being translated to the clinic. To gain further insight in their immunomodulating functions and to optimize future clinical trials it is essential to develop techniques to study their homing capacity. CD4+ T cells were labeled using [In-111]oxine, and the radioactive uptake was determined in vitro before intravenous injection in immunodeficient mice. In vivo biodistribution of [In-111] oxine-labeled cells or tracer alone was subsequently measured by mu SPECT/CT and organ distribution. CD4+ T cells incorporated [In-111]oxine with higher labeling yield using Ringer-Acetate compared to 0.9% NaCl. Cellular viability after labeling with [In-111]oxine was not compromised using less than 0.4 MBq/million cells. After intravenous infusion CD4+ T cells preferentially homed to the liver (p < 0.01) and spleen (p < 0.05). This study presents a protocol for labeling of T cells by [In-111]oxine with preserved viability and in vivo tracking by SPECT for up to 8 days, which can easily be translated to clinical cell therapy trials. 

Place, publisher, year, edition, pages
2013. Vol. 29, no 1-4, 105-108 p.
Keyword [en]
T cell, In vivo imaging, Cell therapy, SPECT/CT
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-216763DOI: 10.1016/j.trim.2013.09.009ISI: 000329145600018OAI: oai:DiVA.org:uu-216763DiVA: diva2:690790
Available from: 2014-01-24 Created: 2014-01-24 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Preparatory Studies to Introduce Regulatory T Cells in Clinical Transplantation
Open this publication in new window or tab >>Preparatory Studies to Introduce Regulatory T Cells in Clinical Transplantation
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Solid organ transplantation has evolved from being an experimental procedure to a life-saving treatment for patients with end-stage organ failure. The risk of losing a transplant due to acute rejection is very low with the use of modern immunosuppressive protocols and the short-term results are impressive. However, long-term outcomes are suboptimal and transplant recipients are at increased risks for severe complications such as cancers, opportunistic infections and cardiovascular events. The previous struggle to achieve short-term survival has turned into a search for new strategies to improve patient and transplant longevity.

Regulatory T cells (TRegs), a subset of T cells, occur naturally in the immune system and have the capacity to down regulate immune responses. Under normal conditions they maintain self-tolerance and prevent excessive immune activation. Functional TReg defects lead to a massive autoimmune response and are not compatible with life. Preclinical data support that TRegs can be used as a cell therapy to prevent transplant rejection, with the potential to minimize the need for traditional immunosuppression and improve the long-term outcome.

This thesis aims to enhance the translation of TReg cell therapy to clinical organ transplantation. In particular, strategies for isolation and expansion of TRegs from uremic patients awaiting kidney transplantation have been assessed. A non-invasive imaging technique to study T cell products after intravenous administration was developed, for use in future clinical trials. The performance of a novel cell purification technique was investigated to potentially improve the clinical production of TRegs.

The thesis demonstrates that TRegs can be isolated and expanded from uremic patients to display potent suppressive properties in vitro. The mode of isolation and expansion affect the functional characteristics, where cells purified with cytometry based techniques and expanded with mature dendritic cells were the most advantageous. T cells can be labeled using the radioactive tracer [111In]oxine with preserved viability and subsequently followed in vivo with SPECT/CT for more than 1 week after intravenous administration. The use of microfluidic switch technology offers a novel way of purifying TRegs at high speed, purity and viability, under conditions compatible with clinical use.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 80 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 983
Keyword
Transplantation, Tolerance, Cell therapy, Regulatory T cell, In vivo imaging, Cell purification
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-220873 (URN)978-91-554-8907-6 (ISBN)
Public defence
2014-05-10, Sal X, Universitetshuset, Biskopsgatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2014-04-15 Created: 2014-03-21 Last updated: 2014-04-29

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Berglund, DavidKarlsson, MarieKorsgren, OlleEriksson, Olof

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