Autologous apoptotic cells preceding transplantation enhance survival in lethal murine graft-versus-host models

Abstract

Key Points• Prophylactic ECP protects against GVHD in a murine BMT model.• ECP provides apoptotic signals that promote tolerance through dendritic cells and Tregs.Acute graft-versus-host disease (GVHD) is induced by alloreactivity of donor T cells toward host antigens presented on antigen-presenting cells (APCs). Apoptotic cells are capable of inducing tolerance by altering APC maturation. Apoptosis can be induced by extracorporeal photopheresis (ECP). We demonstrate that the use of ECP as a prophylaxis prior to conditioning significantly improves survival (P < .0001) after bone marrow transplantation (BMT) by inhibiting the initiation phase of acute GVHD in a murine BMT model. ECP-treated autologous splenocytes resulted in immune tolerance in the host, including reduced dendritic cell activation with decreased nuclear factor-kB engagement, increased regulatory T-cell (Treg) numbers with enhanced expression of cytolytic T lymphocyte-associated antigen 4, potentiating their suppressive function. The protective effect required host production of interleukin-10 and host Tregs. Conventional T cells that entered this tolerant environment experienced reduced proliferation, as well as a reduction of tissue homing and expression of activation markers. The induction of this tolerant state by ECP was obviated by cotreatment with lipopolysaccharide, suggesting that the inflammatory state of the recipient prior to treatment would play a role in potential clinical translation. The use of prophylactic ECP may provide an alternative and safe method for immunosuppression in the bone marrow transplant setting. (Blood.

Bone Marrow Mesenchymal Stromal Cells from Patients with Acute and Chronic Graft-versus-Host Disease Deploy Normal Phenotype, Differentiation Plasticity, and Immune-Suppressive Activity

“…Supporting this concept are data from a murine nonmyeloablative allogeneic bone marrow transplant study that showed that autologous MSCs infusion enhanced long-term engraftment and tolerance [17], whereas infusion of allogeneic MSCs lead graft failure. Data by Florek et al [52] also showed that infusion of apoptotic autologous splenocytes 24 hours before conditioning could delay the onset of GVHD in a murine model. Whether autologous human MSCs for GVHD can induce anergy is unproven; however, it does offer an attractive secondary mechanism by which tolerance may be established and can be tested clinically.…”

Extracorporeal Photopheresis Promotes IL-1β Production

“…In contrast to direct IL-10 inhibition in ECP-treated PBMC, many studies have demonstrated elevated IL-10 either in ECP-untreated DC/ monocytes being cocultured with ECP-exposed cells (12,49,50) or in ECP Tregs, and the requirement for IL-10 was demonstrated in IL-10-deficient mice (10). Furthermore, additional data have suggested that ECP promoted Treg expansion in recipients (51,52). In our view, these results support the hypothesis that ECP may have dual immunomodulatory activity: immunoregulatory activity of ECP-treated apoptotic lymphocytes interacting with ECP-unexposed host cells and possible immunostimulatory activity of directly ECP-exposed monocytes.…”

CD24hiCD27+ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease

“…ECP possibly induces Tregs through incompletely elucidated mechanisms involving the induction of apoptotic cells. 53 Such a role in the induction of Bregs has not been demonstrated to date, although BAFF levels have been linked to the response of cGVHD to ECP. 54 A validation in a higher number of patients would be of interest.…”