Application of Allogeneic Bone Marrow Cells in View of Residual Alloreactivity: Sirolimus but Not Cyclosporine Evolves Tolerogenic Properties

Abstract

BackgroundApplication of bone marrow cells (BMC) is a promising strategy for tolerance induction, but usually requires strong depletion of the host immune system. This study evaluates the ability of immunosuppressants to evolve tolerogenic properties of BMC in view of residual alloreactivity.MethodsThe rat model used a major histocompatibility complex (MHC) class II disparate bone marrow transplantation (BMT) setting (LEW.1AR1 (RT1auu) → LEW.1AR2 (RT1aau)). Heart grafts (LEW.1WR1 (RT1uua)) were disparate for the complete MHC to recipients and for MHC class I to BMC donors. Limited conditioning was performed by total body irradiation of 6 Gy. Cyclosporine (CsA) or Sirolimus (Srl) were administered for 14 or 28 days. Transplantation of heart grafts (HTx) was performed at day 16 or at day 100 after BMT. Chimerism and changes in the T cell pool were detected by flow cytometry.ResultsMixed chimeras accepted HTx indefinitely, although the composition of the regenerated T cell pool was not changed to a basically donor MHC class II haplotype. Non-chimeric animals rejected HTx spontaneously. BMC recipients, who received HTx during T cell recovery at day 16, accepted HTx only after pre-treatment with Srl, although chimerism was lost. CsA pre-treatment led to accelerated HTx rejection as did isolated application of BMC.ConclusionSrl evolves tolerogenic properties of allogeneic BMC to achieve indefinite acceptance of partly MHC disparate HTx despite residual alloreactivity and in particular loss of chimerism.

The importance of MHC class II in allogeneic bone marrow transplantation and chimerism-based solid organ tolerance in a rat model

“…However, the transplantation of donor-derived antigen-presenting cells such as B cells, monocytes or dendritic cells expressing MHC class II and the migration of donor-derived lineages upon engraftment, especially in lymphoid tissues such as the thymus as has been shown by our previous work, could significantly alter the induction of stable chimerism by promoting tolerance through presentation of allogeneic donor antigens, as suggested by others in the past [1,8,13].…”

“…Previous studies have concluded that a lack of recipient antigen presentation through MHC class II disparate donor dendritic cells significantly impairs induction of regulatory T cells and therefore promotes initiation of chronic GvHD [35]. Although, the induction of regulatory T cells was not of primary interest in the current study, results from our previous work with a MHC class II disparate heart transplantation rat model indicated that Sirolimus exerted tolerogenic properties, most likely by increasing the fraction of CD4 + CD25 + regulatory T cells after irradiation [8,36].…”

“…Since cytoreductive conditioning of the bone marrow recipient, by total body irradiation (TBI) or immunosuppressive regimens, is necessary to create an environment for competing donor-derived hematopoietic stem cells, we have investigated the efficacy of different conditioning strategies in experimental rat models in the past [7][8][9].…”