Adherent dendritic cells expressing high levels of interleukin‐10 and low levels of interleukin‐12 induce antigen‐specific tolerance to experimental autoimmune encephalomyelitis

Abstract

SUMMARYWe have previously shown that tolerance can be induced against acute experimental autoimmune encephalomyelitis (EAE) in Lewis rats by bone marrow-derived dendritic cells (DC) that have been pulsed in vitro with encephalitogenic myelin basic protein peptide 68±86 (MBP 68±86), and injected subcutaneously into healthy rats prior to immunization with MBP 68±86 plus complete Freund's adjuvant. To elucidate better the properties of tolerogenic DC, we here compared plastic-adherent DC with¯oating, non-adherent DC, which were cultured for 7 days in the presence of granulocyte± macrophage colony-stimulating factor plus interleukin-4 (IL-4). Adherent DC expressed high levels of IL-10 mRNA and protein, and low levels of IL-12 mRNA and showed high expression of CD54 compared with¯oating DC. Proliferation, nitrite concentration and capacity for antigen presentation were lower in adherent DC than in¯oating DC. There were no differences between adherent and¯oating DC regarding expression of CD11c, OX62, major histocompatibility complex class II, CD80, or CD86. Most importantly, we observed that adherent DC induced tolerance to EAE in vivo when injected subcutaneously into Lewis rats prior to immunization, while¯oating DC did not. Adherent DC-mediated tolerance to EAE was associated with augmented proliferation, nitric oxide production and frequency of apoptotic cells as well as with up-regulation of transforming growth factor-b (TGF-b) -expressing cells in T-cell areas of lymph nodes. Tolerance induction by adherent DC seems to be related to a nitric oxide±apoptosis pathway and to upregulation of TGF-b-expressing cells.

Binding and Transfer of Human Immunodeficiency Virus by DC-SIGN+Cells in Human Rectal Mucosa

“…In the gut, IL-10 is crucial for the development of T R 1 regulatory T cells, which prevent colitis (19), probably via interaction with tolerogenic DCs generated in the presence of IL-10 (48). Although IL-10 treatment of in vitro MDDCs is known to give rise to DCs with a tolerogenic phenotype (9,57) (Fig. 6), we have provided in vivo correlative data suggesting that IL-10 may also favor the development of tolerogenic DCs in the gut.…”

Resistance to experimental autoimmune encephalomyelitis development in Lewis rats from a conventional animal facility

“…However, differently form what was expected, animals form Botucatu colony submitted to EAE induction produced no IL-10 in response to myelin and even produced less IL-10 after ConA stimulation. We cannot, however, exclude other possibilities as production of this cytokine by other kind of cells as dendritic cells or by cells that migrated to the CNS as has been demonstrated in EAE (Jander et al 1998, Yang et al 2000. Additionally, the contribution of other cytokines as TGF-β that is described as an important endogenous mechanism to limit the extension of inflammation cannot be ruled out (Tanuma et al 1997).…”

Simultaneous Induction of CD4 T Cell Tolerance and CD8 T Cell Immunity by Semimature Dendritic Cells

“…As experiments with semimature DC from IL-10 Ϫ/Ϫ mice showed, DC do not have to produce IL-10 themselves to excert tolerogenic capacity (14). This is in contrast to IL-10-producing DC protecting from EAE (32,33) or inducing mucosal tolerance (11) in other studies. Similar to immature human DC (34,35) the mechanism of MOG-tolerance induction by semimature DC was revealed to be dependent on IL-10-producing regulatory T cells (14), a mechanism that has been demonstrated to act also through bystander suppression (36,37).…”