Prolongation of Heart Allograft Survival by Immature Dendritic Cells Generated from Recipient Type Bone Marrow Progenitors

Abstract

Recent studies suggest that particular dendritic cells (DC) subpopulations may be tolerogenic. To test the capacity of different DC subpopulations to modulate allograft rejection, we generated two distinct populations of rat bone marrow-derived DCs (BMDC) with low doses of GM-CSF and IL-4. The non-adherent population (nBMDC), which are the 'classical' DCs was able to stimulate naïve allogeneic T cells and could be induced to completely mature using various stimuli. In contrast, the adherent population (aBMDC), which displayed an immature phenotype, was unable to stimulate T cells and was more resistant to maturation. We found that syngeneic aBMDCs, injected one day before transplantation, induced significant prolongation of heart allograft survival and decreased anti-donor humoral and cellular responses. Similarly, syngeneic aBMDCs inhibited T-cell responses to KLH in the spleen but not in lymph node in a KLH immunization model without graft. This effect was not antigen specific and could be reversed using an inhibitor of inducible nitric oxide synthase. This compartmentalized inhibition could be in part explained by the fact that the majority of syngeneic adherent cells administered intravenously were found in the spleen with some of them reaching the T-cell areas. These data suggest that syngeneic aBMDCs can modulate immune responses.

T Regulatory Cells Control Numbers of NK Cells and CD8α+ Immature Dendritic Cells in the Lymph Node Paracortex

“…However, in the absence of infection, LN iDCs are important for induction and maintenance of T cell tolerance to peripheral Ags (36,58,59). Supporting this view, selective depletion of iDCs (and a reciprocal increase in the number of mature DCs) is a hallmark of a classical human autoimmune disease: systemic lupus erythematosus (60, 61).…”

The Innate Immune System in Allograft Rejection and Tolerance

“…Recent studies have used immature donor DCs with the addition of costimulation blockade, revealing a synergistic effect in promoting long-term allograft survival (65). Interestingly, recipient-derived immature DCs also prolong allograft survival by a mechanism that is not donor specific and depends in part on the production of NO (66).…”

Tolerogenic Dendritic Cells for Therapy of Immune-Mediated Inflammatory Diseases

“…It has been shown that graft rejection can be modulated by using non-modified, donor iDCs alone prior to transplantation (Fu, Li et al 1996;Lu, Li et al 1997). In addition, DC differentiation in the presence of GM-CSF and IL-4 at lower concentrations, results in generation of "semi-differentiated" adherent DCs with lower stimulatory capacity than their fully differentiated counterparts (Peche, Trinite et al 2005). In this manner, such adherent DCs administered just one day prior to transplantation induced significant prolongation of heart allograft survival and suppressed anti-donor humoral and cellular immune responses (Peche, Trinite et al 2005).…”