First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127− T regulatory cells

Trzonkowski, Piotr; Bieniaszewska, Maria; Juścińska, Jolanta; Dobyszuk, Anita; Krzystyniak, Adam; Marek, Natalia; Myśliwska, Jolanta; Hellmann, Andrzej

doi:10.1016/j.clim.2009.06.001

Cited by 584 publications

(505 citation statements)

References 16 publications

Supporting

Mentioning

492

Contrasting

Unclassified

Order By: Relevance

“…Innate and adaptive immune responses can be controlled by Treg cells, thereby offering new therapeutic options after organ transplantation [2][3][4][5][6]. CD4 + CD25 high FOXP3 + Treg cells have been shown to be of major importance in allospecific tolerance in animal models and to influence donor-specific immune responses in transplant patients [7][8][9][10]. After allogeneic hematopoietic stem cell transplantation, polyspecific Treg cells can prevent GVH disease without influencing * These authors contributed equally to this work.…”

Section: Introductionmentioning

confidence: 99%

Isolation of human antigen‐specific regulatory T cells with high suppressive function

et al. 2014

View full text Add to dashboard Cite

Adoptive transfer of regulatory T (Treg) cells could be an alternative to chronic immunosuppression for prevention of allogeneic graft rejection. While polyspecific Treg cells can prevent immune responses under lymphopenic conditions, Ag-specific Treg cells are needed to treat autoimmunity and graft rejection. Yet, reliable markers for Ag-specific Treg cells are missing. We report that latency-associated peptide (LAP) and glycoprotein A repetitions predominant (GARP) can identify human Ag-specific Treg cells. In addition,we show that the depletion of CD154 + cells from LAP + or GARP + Treg cells increases the Treg-cell purity to over 90%, as assessed by epigenetic analysis. These Ag-specific Treg cells can be isolated magnetically and might contribute to the development of GMP-based protocols. In addition, Ag-specific Treg cells are functionally far superior to CD4 + CD25 high or CD4 + CD25 high CD127 low Treg cells in vitro and in preventing strong alloreactions in humanized mice. They could, therefore, have a high therapeutic potential for the control of alloimmune, autoimmune, and allergic immune responses in patients.Keywords: Antigen-specific r CD154 r GARP r LAP r Regulatory T (Treg) cells Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionIn organ transplantation, acute rejection can be prevented by a combination of nonspecific immunosuppressive drugs and immunomodulatory induction therapies, yet chronic rejection and chronic graft dysfunction remain a clinical problem [1]. In addition, chronic nonspecific immunosuppression causes renal dysfunction and predisposes patients to infections and increased Correspondence: Dr. Elmar Jaeckel e-mail: Jaeckel.Elmar@mh-hannover.de risk of malignancies [1]. Innate and adaptive immune responses can be controlled by Treg cells, thereby offering new therapeutic options after organ transplantation [2][3][4][5][6]. CD4 + CD25 high FOXP3 + Treg cells have been shown to be of major importance in allospecific tolerance in animal models and to influence donor-specific immune responses in transplant patients [7][8][9][10]. After allogeneic hematopoietic stem cell transplantation, polyspecific Treg cells can prevent GVH disease without influencing * These authors contributed equally to this work.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 2592-2602 Cellular immune response 2593 graft-versus-leukemia responses [11,12]. Therefore, polyspecific CD4 + CD25 high cells are currently being evaluated after stem cell transplantation [13]. However, under nonlymphopenic conditions as seen in patients with autoimmune diseases or in patients after organ transplantation, polyspecific Treg cells have so far been largely ineffective in controlling immune responses [5,14,15] [24], and CD137 (4-1BB) [25] were described as Treg-cell activation markers after polyspecific Treg-cell activation.In this manuscript, we demonstrated for the first time that LAP and GARP can be use...

show abstract

Section: Introductionmentioning

confidence: 99%

Isolation of human antigen‐specific regulatory T cells with high suppressive function

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Functional Tregs from healthy individuals can now be selected and expanded polyclonally in vitro under good manufacturing practice (GMP) conditions (4,9,10). Thus, clinical cell therapy with Tregs is a realistic possibility.…”

Section: Introductionmentioning

confidence: 99%

Comparison of Regulatory T Cells in Hemodialysis Patients and Healthy Controls

Afzali

Edozie

Fazekasova

et al. 2013

Clinical Journal of the American Society of Nephrology

View full text Add to dashboard Cite

SummaryBackground and objectives Cell-based therapy with natural (CD4 + CD25 hi CD127 lo ) regulatory T cells to induce transplant tolerance is now technically feasible. However, regulatory T cells from hemodialysis patients awaiting transplantation may be functionally/numerically defective. Human regulatory T cells are also heterogeneous, and some are able to convert to proinflammatory Th17 cells. This study addresses the suitability of regulatory T cells from hemodialysis patients for cell-based therapy in preparation for the first clinical trials in renal transplant recipients (the ONE Study).Design, setting, participants, & measurements Healthy controls and age-and sex-matched hemodialysis patients without recent illness/autoimmune disease on established, complication-free hemodialysis for a minimum of 6 months were recruited. Circulating regulatory T cells were studied by flow cytometry to compare the regulatory T cell subpopulations. Regulatory T cells from members of each group were compared for suppressive function and plasticity (IL-17-producing capacity) before and after in vitro expansion with and without Rapamycin, using standard assays.Results Both groups had similar total regulatory T cells and subpopulations I and III. In each subpopulation, regulatory T cells expressed similar levels of the function-associated markers CD27, CD39, HLA-DR, and FOXP3. Hemodialysis regulatory T cells were less suppressive, expanded poorly compared with healthy control regulatory T cells, and produced IL-17 in the absence of Rapamycin. However, Rapamycin efficiently expanded hemodialysis regulatory T cells to a functional and stable cell product.Conclusions Rapamycin-based expansion protocols should enable clinical trials of cell-based immunotherapy for the induction of tolerance to renal allografts using hemodialysis regulatory T cells.

show abstract

“…Trzonkowski et al (2009) performed a trial in two patients who were failing standard treatment of GVHD following allogeneic stem cell transplant. Treg were isolated from the stem cell donor and infused back into the recipient.…”

Section: Regulatory T Cellsmentioning

confidence: 99%

Tolerance--Is It Worth It?

Finger

Strom

Matas

2013

Cold Spring Harbor Perspectives in Medicine

View full text Add to dashboard Cite

We are entering an exciting time in the study of immunologic tolerance. Several cellular and molecular strategies have been developed that show promise in nonhuman transplant models and these approaches are just now appearing in clinical trials. Tolerance strategies that prevent immune rejection and obviate the need for immunosuppressive medications (with inherent risk of cancer, infection, and organ toxicity) would improve both graft and patient survival. Each tolerance protocol brings its own set of associated risks. As the results of these trials become available, we must continue to evaluate their successes and failures. The balance of these outcomes will help us answer the question: "Tolerance-Is it worth it?"WHAT IS TOLERANCE?

show abstract

First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127− T regulatory cells

Cited by 584 publications

References 16 publications

Isolation of human antigen‐specific regulatory T cells with high suppressive function

Isolation of human antigen‐specific regulatory T cells with high suppressive function

Comparison of Regulatory T Cells in Hemodialysis Patients and Healthy Controls

Tolerance--Is It Worth It?

Contact Info

Product

Resources

About