Clinical-Grade Expanded Regulatory T Cells Are Enriched with Highly Suppressive Cells Producing IL-10, Granzyme B, and IL-35

Ulbar, Francesca; Villanova, Ida; Giancola, Raffaella; Baldoni, Stefano; Guardalupi, Francesco; Fabi, Bianca; Olioso, P; Capone, Anita; Sola, Rosaria; Ciardelli, Sara; Papa, Beatrice Del; Brattelli, Antonello; Ricciardi, Ilda; Taricani, Stefano; Sabbatinelli, Giulia; Iuliani, Ornella; Passeri, Cecilia; Sportoletti, Paolo; Santarone, Stella; Pierini, Antonio; Calabrese, Giuseppe; Falzetti, Franca; Bonfini, T.; Accorsi, Patrizia; Ruggeri, Loredana; Martelli, Massimo F.; Velardi, Andrea; Ianni, Mauro Di

doi:10.1016/j.bbmt.2020.08.034

Cited by 18 publications

(15 citation statements)

References 42 publications

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“…have used an automated, clinical‐grade protocol to expand Tregs in vitro. 303 The expression levels of IL‐10, GZMB, and IL‐35 of these expanded Tregs were significantly increased, and could protect mice from GVHD. Among them, the subtype of TIM3 + Tregs (Figure 4 ) exhibited a highly immunosuppressive function.…”

Section: Treg Subsets In Transplantationmentioning

confidence: 97%

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Different subpopulations of regulatory T cells in human autoimmune disease, transplantation, and tumor immunity

Jiang

Zhu

Wang

et al. 2022

MedComm

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CD4 + CD25 + regulatory T cells (Tregs), a subpopulation of naturally CD4 + T cells that characteristically express transcription factor Forkhead box P3 (FOXP3), play a pivotal role in the maintenance of immune homeostasis and the prevention of autoimmunity. With the development of biological technology, the understanding of plasticity and stability of Tregs has been further developed. Recent studies have suggested that human Tregs are functionally and phenotypically diverse. The functions and mechanisms of different phenotypes of Tregs in different disease settings, such as tumor microenvironment, autoimmune diseases, and transplantation, have gradually become hot spots of immunology research that arouse extensive attention. Among the complex functions, CD4 + CD25 + FOXP3 + Tregs possess a potent immunosuppressive capacity and can produce various cytokines, such as IL‐2, IL‐10, and TGF‐β, to regulate immune homeostasis. They can alleviate the progression of diseases by resisting inflammatory immune responses, whereas promoting the poor prognosis of diseases by helping cells evade immune surveillance or suppressing effector T cells activity. Therefore, methods for targeting Tregs to regulate their functions in the immune microenvironment, such as depleting them to strengthen tumor immunity or expanding them to treat immunological diseases, need to be developed. Here, we discuss that different subpopulations of Tregs are essential for the development of immunotherapeutic strategies involving Tregs in human diseases.

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Section: Treg Subsets In Transplantationmentioning

confidence: 97%

“…Ulbar et al. have used an automated, clinical‐grade protocol to expand Tregs in vitro 303 . The expression levels of IL‐10, GZMB, and IL‐35 of these expanded Tregs were significantly increased, and could protect mice from GVHD.…”

Section: Treg Subsets In Transplantationmentioning

confidence: 99%

Different subpopulations of regulatory T cells in human autoimmune disease, transplantation, and tumor immunity

Jiang

Zhu

Wang

et al. 2022

MedComm

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“…The thyTreg product obtained exhibits high purity and suppressive capacity, with a stable FOXP3 expression, whose characteristics are maintained under inflammatory conditions. Regarding the number of therapeutic Treg cells obtained, there is a wide variety of product yields, functionality and fold changes depending on the cell source and the protocol employed to isolate and culture Treg ( 3 , 49 , 50 ). Considering the T-cell receptor (TCR) repertoire, both thymic and peripheral Treg have been shown to present very diverse TCR repertoires ( 51 , 52 ).…”

Section: Discussionmentioning

confidence: 99%

A Novel GMP Protocol to Produce High-Quality Treg Cells From the Pediatric Thymic Tissue to Be Employed as Cellular Therapy

et al. 2022

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Due to their suppressive capacity, the adoptive transfer of regulatory T cells (Treg) has acquired a growing interest in controlling exacerbated inflammatory responses. Limited Treg recovery and reduced quality remain the main obstacles in most current protocols where differentiated Treg are obtained from adult peripheral blood. An alternate Treg source is umbilical cord blood, a promising source of Treg cells due to the higher frequency of naïve Treg and lower frequency of memory T cells present in the fetus’ blood. However, the Treg number isolated from cord blood remains limiting. Human thymuses routinely discarded during pediatric cardiac surgeries to access the retrosternal operative field has been recently proposed as a novel source of Treg for cellular therapy. This strategy overcomes the main limitations of current Treg sources, allowing the obtention of very high numbers of undifferentiated Treg. We have developed a novel good manufacturing practice (GMP) protocol to obtain large Treg amounts, with very high purity and suppressive capacity, from the pediatric thymus (named hereafter thyTreg). The total amount of thyTreg obtained at the end of the procedure, after a short-term culture of 7 days, reach an average of 1,757 x106 (range 50 x 106 – 13,649 x 106) cells from a single thymus. The thyTreg product obtained with our protocol shows very high viability (mean 93.25%; range 83.35% – 97.97%), very high purity (mean 92.89%; range 70.10% – 98.41% of CD25+FOXP3+ cells), stability under proinflammatory conditions and a very high suppressive capacity (inhibiting in more than 75% the proliferation of activated CD4+ and CD8+ T cells in vitro at a thyTreg:responder cells ratio of 1:1). Our thyTreg product has been approved by the Spanish Drug Agency (AEMPS) to be administered as cell therapy. We are recruiting patients in the first-in-human phase I/II clinical trial worldwide that evaluates the safety, feasibility, and efficacy of autologous thyTreg administration in children undergoing heart transplantation (NCT04924491). The high quality and amount of thyTreg and the differential features of the final product obtained with our protocol allow preparing hundreds of doses from a single thymus with improved therapeutic properties, which can be cryopreserved and could open the possibility of an “off-the-shelf” allogeneic use in another individual.

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“…Albeit patients received a mean of 1.1 ± 0.6 × 10 6 haploidentical CD3 + /kg BW, GvHD incidences were comparable to a historical control group with fully T-cell depleted grafts. In order to increase transplantable cell numbers and to be compliant with current regulation, a GMP-compatible manufacturing process was developed, in which isolated T reg were expanded with IL-2 and rapamycin ( 232 ). After 14 days of expansion, a 9.6 fold expansion was achieved with good suppressive function of the final T reg product.…”

Section: Immune Reconstitution and Graft-vs-leukaemia Effectmentioning

confidence: 99%

Immune Reconstitution After Allogeneic Haematopoietic Cell Transplantation: From Observational Studies to Targeted Interventions

Yanir

Schulz²,

Lawitschka

et al. 2022

Front. Pediatr.

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Immune reconstitution (IR) after allogeneic haematopoietic cell transplantation (HCT) represents a central determinant of the clinical post-transplant course, since the majority of transplant-related outcome parameters such as graft-vs.-host disease (GvHD), infectious complications, and relapse are related to the velocity, quantity and quality of immune cell recovery. Younger age at transplant has been identified as the most important positive prognostic factor for favourable IR post-transplant and, indeed, accelerated immune cell recovery in children is most likely the pivotal contributing factor to lower incidences of GvHD and infectious complications in paediatric allogeneic HCT. Although our knowledge about the mechanisms of IR has significantly increased over the recent years, strategies to influence IR are just evolving. In this review, we will discuss different patterns of IR during various time points post-transplant and their impact on outcome. Besides IR patterns and cellular phenotypes, recovery of antigen-specific immune cells, for example virus-specific T cells, has recently gained increasing interest, as certain threshold levels of antigen-specific T cells seem to confer protection against severe viral disease courses. In contrast, the association between IR and a possible graft-vs. leukaemia effect is less well-understood. Finally, we will present current concepts of how to improve IR and how this could change transplant procedures in the near future.

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Clinical-Grade Expanded Regulatory T Cells Are Enriched with Highly Suppressive Cells Producing IL-10, Granzyme B, and IL-35

Cited by 18 publications

References 42 publications

Different subpopulations of regulatory T cells in human autoimmune disease, transplantation, and tumor immunity

Different subpopulations of regulatory T cells in human autoimmune disease, transplantation, and tumor immunity

A Novel GMP Protocol to Produce High-Quality Treg Cells From the Pediatric Thymic Tissue to Be Employed as Cellular Therapy

Immune Reconstitution After Allogeneic Haematopoietic Cell Transplantation: From Observational Studies to Targeted Interventions

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