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

Abstract

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.

Donor Recipient Chimeric Cells Induce Chimerism and Extend Survival of Vascularized Composite Allografts

“…The DRCC therapy was tested with and without a 7-day non-myeloablative IS protocol of anti-αβTCR/CsA. The rationale for selection and duration of the IS protocol was based on our previous studies assessing the 7-day IS protocol in rat limb, face and groin flap VCA models (Demir et al 2005 ; Hivelin et al 2016 ; Ozer et al 2004 ; Siemionow and Klimczak 2013 ; Siemionow et al 2002b , 2003 ), which confirmed its efficacy in extending VCA survival and supporting chimerism induction.…”

“…However, in the clinical scenario transplantation of VCA including substantial bone component to induce tolerance is technically demanding and not always possible thus, different experimental models of VBMT were proposed as an alternative methods for tolerance induction (Gordon et al 2007 ; Klimczak et al 2006 ; Siemionow et al 2008 ). Our study assessing development of chimerism in VBMT model under 7 day anti-αβTCR/CsA showed a gradual chimerism decline reaching 1% at 100 days PT which was associated with the gradual development of fibrosis within the donor’s bone (Klimczak et al 2006 ; Siemionow and Klimczak 2013 ). Thus, intraosseous delivery of cell therapy to the BM niche as performed in the current study may overcome this hurdle since it will lead to more effective engraftment of cells allowing for maintenance of the long-term chimerism.…”

“…Interestingly, in vascularized BMT model 100% allograft survival was achieved up to 100 days PT under 7-day anti-αβTCR/CsA IS protocol (Siemionow et al 2008 ) and transplantation of VCA combined with vascularized bone component significantly extended allograft survival (125 days) compared to 50% reduction of survival in VCA transplant without bone component despite application of the same IS protocol (Ozmen et al 2006a ). The higher survival rates observed in the VCA models containing vascularized bone component validate previous reports on the immunomodulatory role of BMCs supporting development of donor-derived chimerism and tolerance in VCA transplants (Siemionow and Klimczak 2013 ; Siemionow et al 2003 , 2008 ).…”

Delivery of Rapamycin Using In Situ Forming Implants Promotes Immunoregulation and Vascularized Composite Allograft Survival

“…Aside from the development of innovative drug delivery systems for site-specific immunosuppression, the possibility to induce immunoregulatory mechanisms to modulate the host immune response to the engraftment (e.g. by promoting chimerism and/or expansion of regulatory cells) has been investigated as a potential solution for minimizing immunosuppression-related complications in VCA 28,29 . In this study we argue that these two strategies may be combined.…”

Vascularized bone transplant chimerism mediated by vascular endothelial growth factor

“…Donor‐specific tolerance is another method with strong potential to facilitate clinical allotransplantation. Siemionow et al studied the induction of tolerance extensively in vascularized composite allotransplants using various animal models with promising results with improved allotransplants survival.…”