Mechanisms of donor-specific transfusion tolerance: preemptive induction of clonal T-cell exhaustion via indirect presentation

Abstract

Induction of transplantation tolerance to alloantigens without general immunosuppression remains an enduring challenge. Injecting a donor-specific transfusion (DST) of spleen cells together with blocking ␣CD154 antibody prior to graft transplantation is an effective way to induce long-lived graft acceptance. Using a novel T-cell receptor (TCR) transgenic (Tg) model of CD4 ؉ T-cell-mediated rejection, this study sheds new insights into the cellular basis for enhanced graft survival induced by DST and ␣CD154. The study shows that DST and ␣CD154 induce an early, robust, abortive expansion of the Tg T cells that results in profound anergy. This is contrasted with the more delayed, regional, productive response elicited by an allogeneic graft. Studies show that the induction of tolerance to the allograft induced by DST is mediated by indirect presentation by host antigen-presenting cells. Based on these observations, we conclude that DST and ␣CD154 preemptively tolerize the alloreactive T-cell compartment to prohibit subsequent responses to the immunogenic allograft.

OX40/OX40L Costimulation Affects Induction of Foxp3+ Regulatory T Cells in Part by Expanding Memory T Cells In Vivo

“…ϩ TCR-transgenic mice were provided by Dr. R. Noelle (Dartmouth University Medical School, Lebanon, NH) (27). Both TEa mice and OT II mice were crossed with our foxp3gfp mice.…”

Peripheral deletion of mature alloreactive B cells induced by costimulation blockade

“…It has been proposed that such treatment impairs the maturation of host antigen-presenting cells, generates tolerogenic dendritic cells, promotes T cell anergy (12) and deletion (13), and induces regulatory T cells (14,15). Graft survival can be further enhanced by donor-specific transfusion (DST) (16), and in the presence of anti-CD154, the infused DST is presented by host antigen-presenting cells in a tolerogenic manner, resulting in T cell anergy and regulation (17). Blocking CD154-CD40 interaction also prevents the T-dependent humoral responses (18).…”

Cell-Based Therapies in the Prevention of Solid Organ Transplant Rejection

“…Brouard and Soulillou and colleagues demonstrated that infusion of splenocytes without additional immunosuppression leads to long-term survival of cardiac allografts through expansion of Treg and that transfer of long-term survivor splenic T cells to new allograft recipients transfers long-term allograft survival in an Ag-specific manner (Lair et al, 2007). Importantly, in the Quezada study, the injected living donor splenocytes did not directly interact with CD4 + T cells (Quezada et al, 2003). This finding suggests that living splenocytes upon i.v.…”

“…DST in transplantation of solid organ allografts: Quezada et al (2003) showed that DST significantly prolongs skin allograft survival through peripheral deletion of indirect pathway CD4 + T cells and increased numbers of regulatory T cells (Treg). Brouard and Soulillou and colleagues demonstrated that infusion of splenocytes without additional immunosuppression leads to long-term survival of cardiac allografts through expansion of Treg and that transfer of long-term survivor splenic T cells to new allograft recipients transfers long-term allograft survival in an Ag-specific manner (Lair et al, 2007).…”