Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics

Brunstein, Claudio G.; Miller, Jeffrey S.; Cao, Qing; McKenna, David H.; Hippen, Keli L.; Curtsinger, Julie; DeFor, Todd E.; Levine, Bruce L.; June, Carl H.; Rubinstein, Pablo; McGlave, Philip B.; Blazar, Bruce R.; Wagner, John E.

doi:10.1182/blood-2010-07-293795

Cited by 925 publications

(908 citation statements)

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“…A greater incidence of acute GvHD occurs following double unit cord blood transplantation. Ex vivo expanded T regulatory cells may decrease occurrence of this adverse event [13,36]. The main obstacle in the use of cord blood transplants in adults has been the risk for graft failure and delayed hematopoietic recovery.…”

Section: Cord Blood Banking Protocols and Standardsmentioning

confidence: 99%

“…), bone marrow failures, inherited metabolic disorders, immunological defects and other genetic diseases [1][2][3][4][5][6][7][8][9][10][11][12]. Double umbilical cord blood grafts, that use cord blood units from two donors, mitigate cell dose limitations for larger children and adults with malignant disorders [12][13][14]. There is a continual need for suitable donors for one third of all patients in need of bone marrow transplants in which no available human leukocyte antigen (HLA) matched donors are found [15].…”

Section: Introductionmentioning

confidence: 99%

“…added potential of decreased chronic graft versus host disease (GvHD) compared with bone marrow and peripheral blood progenitor cell donors [13,16,17].…”

Section: Introductionmentioning

confidence: 99%

“…The results, to date, are encouraging and appear at least comparable to bone marrow or peripheral blood progenitor cells as the donor source for transplants [12,13]. Later, Rubenstein and others were the first to establish an unrelated cord blood bank from voluntary donors and then used the blood units from the bank for unrelated cord blood transplantation [19][20][21].…”

Section: Introductionmentioning

confidence: 99%

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Umbilical cord blood banking: an update

Butler

Menitove²

2011

J Assist Reprod Genet

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Background Umbilical cord blood is a potential vast source of primitive hematopoietic stem and progenitor cells available for clinical application to reconstitute the hematopoietic system and/or restore immunological function in affected individuals requiring treatment. Cord blood can be used as an alternative source for bone marrow transplantation and its use is developing into a new field of treatment for pediatric and adult patients presenting with hematological disorders, immunological defects and specific genetic diseases. Discussion More than 25,000 allogeneic cord blood transplantations have been performed worldwide since the first cord blood transplantation in 1988. There are two banking options for storing umbilical cord blood [private (family) and public]. Cord blood stored in private banks are used for either autologous or allogeneic transplants for the infant donor or related family members but private cord blood banks are not searchable or available to the public. More than 780,000 cord blood units are stored in over 130 private cord blood banks, worldwide, and over 400,000 units in more than 100 quality controlled public cord blood banks.Conclusions Researchers continue to evaluate the usefulness of cord blood cells in treating human diseases or disorders for purposes other than hematological disorders including heart disease, strokes, brain or spinal cord injuries and cancer. This review summarizes the status of umbilical cord blood banking, its history and current and potential use in the treatment of human disease.

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Section: Cord Blood Banking Protocols and Standardsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…added potential of decreased chronic graft versus host disease (GvHD) compared with bone marrow and peripheral blood progenitor cell donors [13,16,17].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Umbilical cord blood banking: an update

Butler

Menitove²

2011

J Assist Reprod Genet

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“…Recent studies have shown the therapeutic potential of Tregs given as cellular immunotherapy to control unwanted immune responses such as autoimmune diabetes mellitus (3)(4)(5) or graftversus-host disease (6)(7)(8). Data from transplantation models using animals have also shown the efficacy of Tregs in controlling the alloreactive immune response, thereby preventing or delaying allograft rejection.…”

mentioning

confidence: 99%

Allogeneic Mature Human Dendritic Cells Generate Superior Alloreactive Regulatory T Cells in the Presence of IL-15

Litjens

Boer

Zuijderwijk

et al. 2015

The Journal of Immunology

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Expansion of Ag-specific naturally occurring regulatory T cells (nTregs) is required to obtain sufficient numbers of cells for cellular immunotherapy. In this study, different allogeneic stimuli were studied for their capacity to generate functional alloantigen-specific nTregs. A highly enriched nTreg fraction (CD4+CD25brightCD127− T cells) was alloantigen-specific expanded using HLA-mismatched immature, mature monocyte-derived dendritic cells (moDCs), or PBMCs. The allogeneic mature moDC-expanded nTregs were fully characterized by analysis of the demethylation status within the Treg-specific demethylation region of the FOXP3 gene and the expression of both protein and mRNA of FOXP3, HELIOS, CTLA4, and cytokines. In addition, the Ag-specific suppressive capacity of these expanded nTregs was tested. Allogeneic mature moDCs and skin-derived DCs were superior in inducing nTreg expansion compared with immature moDCs or PBMCs in an HLA-DR– and CD80/CD86-dependent way. Remarkably, the presence of exogenous IL-15 without IL-2 could facilitate optimal mature moDC-induced nTreg expansion. Allogeneic mature moDC-expanded nTregs were at low ratios (<1:320), potent suppressors of alloantigen-induced proliferation without significant suppression of completely HLA-mismatched, Ag-induced proliferation. Mature moDC-expanded nTregs were highly demethylated at the Treg-specific demethylation region within the FOXP3 gene and highly expressed of FOXP3, HELIOS, and CTLA4. A minority of the expanded nTregs produced IL-10, IL-2, IFN-γ, and TNF-α, but few IL-17–producing nTregs were found. Next-generation sequencing of mRNA of moDC-expanded nTregs revealed a strong induction of Treg-associated mRNAs. Human allogeneic mature moDCs are highly efficient stimulator cells, in the presence of exogenous IL-15, for expansion of stable alloantigen-specific nTregs with superior suppressive function.

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Immunological Tolerance: Therapeutic Induction

Mair¹,

Reynolds²,

Anderton³

2013

Encyclopedia of Life Sciences

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When the natural mechanisms of immune tolerance break down, autoimmune or allergic disease can result. There is considerable experimental evidence that the ultimate response to antigen, full immunity or tolerance, is dependent on the activation status of the antigen‐presenting dendritic cells, with those in steady state inducing tolerance. Current therapeutic options either deplete immune cell populations, interfere with immune cell trafficking to the tissues or inhibit inflammatory cytokine function or lymphocyte signalling. Although these treatments can be effective for certain diseases, they carry with them significant adverse effects and it is unlikely that they induce true, long‐lived immune tolerance. Cellular therapies using either tolerogenic dendritic cells or regulatory T cells may be able to achieve this. Alternatively, administration of antigen in tolerogenic form can provide the most specific therapy, with the least risk of adversely affecting normal immune function against infection or neoplasia. Key Concepts: Peripheral tolerance mechanisms consist of lymphocyte apoptosis, anergy and regulation. Current therapeutic options for the clinic can be effective, but in general are nonspecific and may not provide long‐term tolerance. Dendritic cell (DC) activation status determines the type of immune response. Activated DC provokes immunity whereas steady‐state DC promotes tolerance. ‘Tolerogenic’ DC can be administered to give protection from autoimmune disease, allergy and graft rejection as shown in animal models, and are being tested for clinical application. Administration of antigen in tolerogenic form (without adjuvant) also provides protection from disease in animal models; however, clinical translation is proving challenging. Transfer of antigen‐specific regulatory T cells (Treg) can also protect against disease, and can be curative in some models. Translation of cellular therapies (using DC or Treg) or tolerogenic antigen will require a fuller understanding of the critical autoantigens/epitopes that drive autoimmune pathology.

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Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics

Cited by 925 publications

References 41 publications

Umbilical cord blood banking: an update

Umbilical cord blood banking: an update

Allogeneic Mature Human Dendritic Cells Generate Superior Alloreactive Regulatory T Cells in the Presence of IL-15

Immunological Tolerance: Therapeutic Induction

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