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

Abstract

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.

T cell immunomodulation by clinically used allogeneic human cancellous bone fragments: a potential novel immunotherapy tool

“…Based on this, we hypothesised that these CBFs could have an innate immunomodulatory activity partially related to MSC content. In support of this hypothesis, immunosuppressive effects of allogeneic bone grafts have been previously reported in several independent animal studies 15 – 17 . The aim of this study was, therefore, to examine the immunomodulatory capacity of these CBFs without any manipulation or MSC expansion, in co-cultures with allogeneic CD3/CD28-stimulated CD4 T cells.…”

“…As such, these clinically available cellular allografts can be considered as a potential novel immunotherapy tool. As stated, several animal model studies have previously reported the ability of allogenic bone to prevent the rejection of transplanted organs 15 , 17 . In this context, our study demonstrated that clinically used CBFs could provide an ‘immuno-privileged niche’ capable of controlling adaptive immune cell responses in the allogeneic settings.…”

Donor derived hematopoietic stem cell niche transplantation facilitates mixed chimerism mediated donor specific tolerance

“…In contrast, VCA without a vascularized bone component, such as VSM, or even VSM combined with low dose donor BMC transfusion (equivalent of femur bone marrow cells), only exhibited transient, lower-level MC in periphery blood, and failed to prevent allograft acute rejection. Similar studies were reported by multiple groups using bone graft transplantation ( 43 , 52 , 53 ) or vascularized bone marrow transplantation ( 33 , 36 , 37 ) to induce hematopoietic chimerism and allograft tolerance.…”

Bone Fragment Co-transplantation Alongside Bone Marrow Aspirate Infusion Protects Kidney Transplant Recipients

“…Although basic research has shown that free bone co-transplantation combined with conventional immunosuppression can induce immunologic tolerance and extend allograft survival (33)(34)(35)(36)(37), in this study tolerance was not achieved and was not the target of therapy. However, regulatory effects of BF-BM on the immune system could still be identified.…”