Recent Progress in Tolerance Induction through Mixed Chimerism

Pree, Ines; Pilat, Nina; Wekerle, Thomas

doi:10.1159/000104740

Cited by 21 publications

(18 citation statements)

References 224 publications

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“…At first myeloablative recipient conditioning was used (Ildstad and Sachs 1984), which has been extensively modified so that substantially milder regimens have since become available (Pree et al 2007). Mixed chimerism was found to be preferable over full chimerism as it reduces the risk of graft versus host disease (GVHD) and is associated with superior immunocompetence (Singer et al 1981;Sykes et al 1988).…”

Section: Mixed Chimerismmentioning

confidence: 99%

Cell-Based Therapy in Allergy

Baranyi

Gattringer

Valenta

et al. 2011

Vaccines Against Allergies

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IgE-mediated allergy is an immunological disorder occurring in response to otherwise harmless environmental antigens (i.e., allergens). Development of effective therapeutic or preventive approaches inducing robust tolerance toward allergens remains an unmet goal. Several experimental tolerance approaches have been described. The therapeutic use of regulatory T cells (Tregs) and the establishment of molecular chimerism are two cell-based strategies that are of particular interest. Treg therapy is close to clinical application, but its efficacy remains to be fully defined. Recent proof-of-concept studies demonstrated that transplantation of syngeneic hematopoietic stem cells modified in vitro to express a major allergen leads to molecular chimerism and robust allergen-specific tolerance. Here we review cell-based tolerance strategies in allergy, discussing their potentials and limitations.

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Section: Mixed Chimerismmentioning

confidence: 99%

Cell-Based Therapy in Allergy

Baranyi

Gattringer

Valenta

et al. 2011

Vaccines Against Allergies

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“…Extensive research on tolerance induction performed during the last two decades has proven that development of donor-specific chimerism may accompany induction of tolerance in VCA; however, the role of chimerism in tolerance induction is still debatable [5–7]. …”

Section: Introductionmentioning

confidence: 99%

Chimerism-Based Experimental Models for Tolerance Induction in Vascularized Composite Allografts: Cleveland Clinic Research Experience

Siemionow

Klimczak

2013

Clinical and Developmental Immunology

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The preclinical experimental models of vascularized composite allografts (VCAs) have been rapidly developed for the assessment of immunomodulatory protocols for clinical application. Recently, researchers have focused on immunomodulatory protocols which overcome the immunologic barrier between the allogeneic donor and recipient and may lead to tolerance induction. In order to test the feasibility of chimerism induction, experimental VCAs have been performed in different models including rodents, large animals, and nonhuman primates. These models differ in the complexity of transplanted tissue and in their responses to immunomodulatory protocols. In most applications, VCA contains multiple-tissue components; however, each individual component of CTA possesses unique immunologic characteristics that ultimately contribute to the chimerism induction and successful outcome of the VCA. Heterogenic character and complexity of tissue components in different VCA models determine the quality and robustness of donor-specific chimerism. As introduced in experimental studies, variable immunomodulatory options have been studied to achieve tolerance to VCA in rodents and large animal models allowing for widespread application in clinic. In this paper, based on our own experience, we have analyzed the current knowledge of tolerance-inducing strategies via chimerism induction in VCA experimental models in the context of immunomodulatory protocols and VCA complexity and their relevance and applicability to clinical practice.

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“…One approach to transplantation, which essentially has been the "Holy Grail" of the field, is the induction of immunological tolerance, which effectively would coax the recipient immune system into accepting the allograft as "self." Unfortunately, to date the only reproducible means of inducing tolerance clinically involves the creation of a state of hematopoietic stem cell (HSC) chimerism (7)(8)(9). This approach, however, is not practical due to the high morbidity and mortality associated with recipient preconditioning before the HSC transplantation.…”

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confidence: 99%

Free Bone Graft Attenuates Acute Rejection and in Combination with Cyclosporin A Leads to Indefinite Cardiac Allograft Survival

Wang

Ge²,

Arp³

et al. 2009

The Journal of Immunology

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We report on a novel approach aimed at preventing acute vascular rejection (AVR), one of the major unresolved hurdles of clinical transplantation. In a C3H-to-BALB/c heterotopic heart transplant model, we demonstrate that free bone transplantation combined with cyclosporin A suppresses antidonor Ab responses, induces indefinite cardiac allograft survival (>100 days), and preserves graft architecture. In contrast, untreated- or cyclosporin A alone-treated recipients rejected their cardiac grafts on days 7.7 ± 0.6 and 15.5 ± 1.1, respectively, with graft histology indicative of AVR. Splenic dendritic cells from nonrejecting recipients expressed low levels of MHC II, CD40, and CD86, reduced ability to stimulate donor cell proliferation, and augmented IL-10 production of responding T cells in vitro. Adoptive transfer of dendritic cells from long-term surviving recipients 1 day before cardiac grafting was able to confer hyporesponsiveness to naive BALB/c recipients of cardiac allografts. To determine whether graft survival was associated with hematopoietic or stromal elements of the transplanted free bone, we administered isolated bone marrow mononuclear cells or free bone that was irradiated to deplete hematopoietic elements. Although bone marrow mononuclear cells had no effect on cardiac graft survival, irradiated free bone transplantation was capable of prolonging graft survival. Most interestingly, the prolongation effect was Ag nonspecific, because third party irradiated bone graft was also effective. Due to the fact that current immunosuppressive approaches are clinically ineffective at preventing AVR, this study provides promise for further investigations of BM components as a means of addressing a currently unmet medical need.

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Recent Progress in Tolerance Induction through Mixed Chimerism

Cited by 21 publications

References 224 publications

Cell-Based Therapy in Allergy

Cell-Based Therapy in Allergy

Chimerism-Based Experimental Models for Tolerance Induction in Vascularized Composite Allografts: Cleveland Clinic Research Experience

Free Bone Graft Attenuates Acute Rejection and in Combination with Cyclosporin A Leads to Indefinite Cardiac Allograft Survival

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