Long-Term Survival of Composite Hemiface/Mandible/Tongue Allografts Correlates With Multilineage Chimerism Development in the Lymphoid and Myeloid Compartments of Recipients

Külahçi, Yalçın; Klimczak, Aleksandra; Madajka, Maria; Altuntaş, Selman Hakkı; Siemionow, Maria

doi:10.1097/tp.0b013e3181f28bb0

Cited by 28 publications

(17 citation statements)

References 42 publications

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“…Recently, it has been proposed that VBMT may be superior to bone marrow cell transplantation for the establishment of chimerism and the induction of tolerance. Several studies have suggested that femoral, sternal, mandibular elements within the allograft may serve as a substantial source of bone marrow cells, resulting in the development of donor-specific chimerism [11], [21], [22].…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that vascularized bone marrow transplantation (VBMT) may be superior to conventional bone marrow cell transplantation for the induction of tolerance. This phenomenon is thought to be associated with the bone components, which serve as a vascularized method of delivering donor-origin stem and progenitor cells [10], [11]. However, the exact mechanism remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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Role of Donor-Specific Regulatory T Cells in Long-Term Acceptance of Rat Hind Limb Allograft

Wang¹,

Zheng²,

Wang³

et al. 2012

PLoS ONE

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BackgroundVascularized bone marrow transplantation (VBMT) is widely accepted as an efficient means of establishing chimerism and inducing tolerance. However, the mechanism underlying is poorly understood. Recently, regulatory T cells (Tregs) have been shown to play an important role in regulating immune responses to allogeneic antigens. In this study, we explored the role of Tregs in the induction of tolerance in an allogeneic hind limb transplantation model.Methodology/Principal FindingsForty-eight Lewis rats were divided into 6 groups. They received isografts and allografts from Brown-Norway hind limbs. Recipients in groups 1 and 2 received isografts and those in the other groups received allografts. The bone components of donor limbs were kept intact in groups 1, 3, and 5 but removed before transplantation into groups 2, 4, and 6. Tapered cyclosporin A (CsA) was administered to recipients in groups 5 and 6 after transplantation. During the 100-day observation period, all isografts survived, but the allografts in groups 3 and 4 were rejected within 8 to 12 days. CsA-treated intact allografts survived rejection-free for more than 100 days, and CsA-treated allografts lacking bone elements were rejected within 2 months. Stable peripheral chimerism and myeloid chimerism were observed in group 5. Declining peripheral chimerism and a lack of myeloid chimerism were observed in group 6. Donor-specific Tregs were exclusively detected in both peripheral blood and in the spleens of long-term recipient rats in group 5, with an increased FoxP3 mRNA expression in the allografts. This was further demonstrated to be responsible for donor-specific hyporeactivity by in vitro one-way mixed lymphocyte reaction (MLR).Conclusion/SignificanceBone components in the allogeneic hind limbs can induce myeloid chimerism and donor-specific Tregs may be essential to tolerance induction. The bone-removal hind limb model may be a suitable counterpart to the induction of tolerance in the study of limb transplantation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of Donor-Specific Regulatory T Cells in Long-Term Acceptance of Rat Hind Limb Allograft

Wang¹,

Zheng²,

Wang³

et al. 2012

PLoS ONE

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“…Monotherapy protocol with CsA has been applied in many experimental VCA models including models with a single component of allograft (skin) and in more complex models such as limb and face allografts [9–23]. …”

Section: Monotherapy Protocol With Calcineurin Inhibitors For Chimmentioning

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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“…Indeed, infusion of BM-derived cells from HDODs, as an adjuvant therapy, can induce specific immunological tolerance of the transplanted organ (25)(26)(27). Thus, Cirocco et al (28) observed that renal recipients had significantly lower rates of chronic rejection and higher graft survival compared with equivalent non-infused controls.…”

Section: Discussionmentioning

confidence: 95%

Bone Marrow of Multiorgan Donors Underutilized

Baumert

Kawa²,

Kotowski³

et al. 2012

Transplantation

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Long-Term Survival of Composite Hemiface/Mandible/Tongue Allografts Correlates With Multilineage Chimerism Development in the Lymphoid and Myeloid Compartments of Recipients

Abstract: We introduced a new multitissue model of composite hemiface/mandible/tongue allograft containing lymphoid and vascularized BM components. Long-term allograft survival correlated with development and maintenance of donor-specific chimerism in lymphoid organs and BM compartment.

Cited by 28 publications

References 42 publications

Role of Donor-Specific Regulatory T Cells in Long-Term Acceptance of Rat Hind Limb Allograft

Role of Donor-Specific Regulatory T Cells in Long-Term Acceptance of Rat Hind Limb Allograft

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

Bone Marrow of Multiorgan Donors Underutilized

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