Mixed chimerism through donor bone marrow transplantation

Pilat, Nina; Hock, Karin; Wekerle, Thomas

doi:10.1097/mot.0b013e32834ee68b

Cited by 29 publications

(12 citation statements)

References 87 publications

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“…Treg cells manufactured with certain homing properties represent a suitable therapy with potential applications in inflammatory bowel disease [99–101], allergy to food antigens [102], and inducing tolerance in bone marrow transplantation as well as solid organ transplantation [102,103]. Homing molecules to the intestine [104] and bone marrow [105] have been well characterized.…”

Section: Discussionmentioning

confidence: 99%

Single and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells

et al. 2017

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Adoptive transfer of CD4+CD25+FOXP3+ regulatory T cells (Treg cells) has been successfully utilized to treat graft versus host disease and represents a promising strategy for the treatment of autoimmune diseases and transplant rejection. The aim of this study was to evaluate the effects of all-trans retinoic acid (atRA) and rapamycin (RAPA) on the number, phenotype, homing markers expression, DNA methylation, and function of induced human Treg cells in short-term cultures. Naive T cells were polyclonally stimulated and cultured for five days in the presence of different combinations of IL-2, TGF-β1, atRA and RAPA. The resulting cells were characterized by the expression of FOXP3, activation, surface and homing markers. Methylation of the Conserved Non-coding Sequence 2 was also evaluated. Functional comparison of the different culture conditions was performed by suppression assays in vitro. Culturing naive human T cells with IL-2/TGFβ1 resulted in the generation of 54.2% of Treg cells (CD4+CD25+FOXP3+) whereas the addition of 100 nM atRA increased the yield of Treg cells to 66% (p = 0.0088). The addition of RAPA did not increase the number of Treg cells in any of these settings. Treg cells generated in the presence of atRA had an increased expression of the β7 integrin to nearly 100% of the generated Treg cells, while RAPA treated cells showed enhanced expression of CXCR4. The differential expression of homing molecules highlights the possibility of inducing Treg cells with differential organ-specific homing properties. Neither atRA nor RAPA had an effect on the highly methylated CNS2 sites, supporting reports that their contribution to the lineage stability of Treg cells is not mediated by methylation changes in this locus. Treg cells generated in the presence of RAPA show the most potent suppression effect on the proliferation of effector cells.

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Section: Discussionmentioning

confidence: 99%

Single and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells

et al. 2017

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“…The term mixed chimerism has been subjected to a widely encompassing definition, ranging from donor hematopoietic stem cell engraftment with stable long-term multilineage contribution, to regimens using donor bone marrow infusion to achieve transient mixed chimerism that may or may not be followed by a state of microchimerism. These various states of chimerism and the relative role they play in the induction and maintenance of tolerance of transplanted tissues have been demonstrated to vary across models and target organs [8]. …”

Section: Introductionmentioning

confidence: 99%

Tolerance Induction Strategies in Vascularized Composite Allotransplantation: Mixed Chimerism and Novel Developments

Leonard

McGrouther

Kurtz

et al. 2012

Clinical and Developmental Immunology

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Since the start of the clinical vascularized composite allotransplantation (VCA) era over a decade ago this field has witnessed significant developments in both basic and translational research. Transplant tolerance, defined as rejection-free acceptance of transplanted organs or tissues without long-term immunosuppression, holds the potential to revolutionize the field of VCA by removing the need for life-long immunosuppression. While tolerance of organ and vascularized composite transplants may be induced in small animal models by a variety of protocols, only mixed-chimerism-based protocols have successfully bridged the gap to preclinical study and to clinical trial in solid organ transplantation to date. In this paper we review the mixed-chimerism approach to tolerance induction, with specific reference to the field of VCA transplantation, and provide an overview of some novel cellular therapies as potential adjuvants to mixed chimerism in the development of tolerance induction protocols for clinical vascularized composite allotransplantation.

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“…Among all these, strategies based on the use of co-stimulation blockade are the most potent at inducing mixed chimerism (6). However, there are few reports on protocols for promoting stable intestinal allograft acceptance.…”

Section: Discussionmentioning

confidence: 99%

“…Establishment of mixed chimerism through transplantation of donor bone marrow into recipients is one of the most promising strategies for inducing transplantation tolerance (5). Most of the chimerism-inducing protocols require the use of co-stimulation blockade agents (6). Recent results from experimental mouse studies based on co-stimulation blockade induction of stable mixed chimerism are encouraging.…”

Section: Introductionmentioning

confidence: 99%

“…Recent results from experimental mouse studies based on co-stimulation blockade induction of stable mixed chimerism are encouraging. However, translation of tolerance protocols from preclinical animal studies to the clinic is still a major challenge due to the lack of clinically available co-stimulation blockers (6). Regulatory T (Treg) cells have long been recognized to play a critical role in self-tolerance, but administration of Treg cells on their own does not induce robust immune tolerance across MHC barriers in immunocompetent hosts (7).…”

Section: Introductionmentioning

confidence: 99%

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Donor-Specific Regulatory T Cells Acquired from Tolerant Mice Bearing Cardiac Allograft Promote Mixed Chimerism and Prolong Intestinal Allograft Survival

et al. 2016

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The induction of donor-specific transplant tolerance has always been a central problem for small bowel transplantation (SBT), which is thought to be the best therapy for end-stage bowel failure. With the development of new tolerance-inducing strategies, mixed chimerism induced by co-stimulation blockade has become most potent for tolerance of allografts, such as skin, kidney, and heart. However, a lack of clinically available co-stimulation blockers has hindered efficient application in humans. Furthermore, unlike those for other types of solid organ transplantation, strategies to induce robust mixed chimerism for intestinal allografts have not been fully developed. To improve current mixed chimerism induction protocols for future clinical application, we developed a new protocol using donor-specific regulatory T (Treg) cells from mice with heart allograft tolerance, immunosuppressive drugs which could be used clinically and low doses of irradiation. Our results demonstrated that donor-specific Treg cells acquired from tolerant mice after in vitro expansion generate stable chimerism and lead to acceptance of intestinal allograft. Increased intragraft Treg cells and clonal deletion contribute to the development of SBT tolerance.

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Mixed chimerism through donor bone marrow transplantation

Cited by 29 publications

References 87 publications

Single and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells

Single and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells

Tolerance Induction Strategies in Vascularized Composite Allotransplantation: Mixed Chimerism and Novel Developments

Donor-Specific Regulatory T Cells Acquired from Tolerant Mice Bearing Cardiac Allograft Promote Mixed Chimerism and Prolong Intestinal Allograft Survival

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