Abstract
Establishing mixed chimerism is a promising approach for inducing donor-specific transplant tolerance. The establishment and maintenance of mixed chimerism may enable long-term engraftment of organ transplants while minimizing the use of immunosuppressants. Several protocols for inducing mixed chimerism have been reported; however, the exact mechanism underlying the development of immune tolerance remains to be elucidated. Therefore, understanding the kinetics of engraftment during early post-transplant period may provide insight into establishing long-term mixed chimerism and permanent transplant tolerance. In this study, we intentionally induced allogeneic mixed chimerism using a nonmyeloablative regimen by host natural killer (NK) cell depletion and T cell-depleted bone marrow (BM) grafts in a major histocompatibility complex (MHC)-mismatched murine model and analyzed the kinetics of donor (C57BL/6) and recipient (BALB/c) engraftment in the weeks following transplantation. Donor BM cells were well engrafted and stabilized without graft-versus-host disease (GVHD) as early as one week post-bone marrow transplantation (BMT). Donor-derived thymic T cells were reconstituted four weeks after BMT; however, the emergence of newly developed T cells was more obvious at the periphery as early as two weeks after BMT. Also, the emergence and changes in ratio of recipient- and donor-derived NKT cells and antigen presenting cells (APCs) including dendritic cells (DCs) and B cells were noted after BMT. Here, we report a longitudinal analysis of the development of donor- and recipient-originated hematopoietic cells in various lymphatic tissues of intentionally induced mixed chimerism mouse model during early post-transplant period. Through the understanding of immune reconstitution at early time points after nonmyeloablative BMT, we suggest guidelines on intentionally inducing durable mixed chimerism.
Highlights
Solid organ transplantation has improved the survival in patients with end-stage organ diseases
Lack of donor cell rejection following partial irradiation of the recipient First, we depleted the natural killer (NK) cells from the recipients and T cells from the donor bone marrow (BM) prior to bone marrow stem cell transplantation (BMT) to prevent both host vs. graft rejection and graft vs. host rejection while inducing stable mixed chimerism
The overall exterior, body weight, and feces of the recipient mice were monitored every day after BMT as markers of graft-versus-host disease (GVHD)
Summary
Solid organ transplantation has improved the survival in patients with end-stage organ diseases. The clinical success of organ transplantation has been mainly dependent on the use of long-term immunosuppressants. Allogeneic bone marrow stem cell transplantation (BMT) is a promising approach for the treatment of non-hematological diseases; high-dose chemoradiotherapy as a preparatory regimen for BMT is associated with incidence of acute graft-versus-host disease (GVHD) and substantial transplant-related toxicity. Despite the therapeutic potential of BMT, the associated risks have limited its broad application. For these reasons, many investigators have focused on developing conditioning strategies that enable the stable engraftment of allogeneic BM without causing severe immunosuppression in recipients [1,2]. The establishment of mixed chimerism by nonmyeloablative BMT is an attractive concept to induce long-term organ allograft tolerance
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