ACAID–like human dendritic cells suppress a Th2 response in a chimera asthma model

Abstract

Abstract: : Purpose: ACAID–like tolerogenic APC (TGF–beta–2 treated, antigen pulsed) suppress the Th2 response in mouse OVA–asthma model. Here we tested 1) if human dendritic cells (Hu–DC) were modulated by exposure to TGF–beta–2 and antigen, and 2) if such ACAID–like tolerogenic DC were able to alter the course of an ongoing Th2 immune response in a human–SCID mouse asthma model. Methods: The chimera asthma model was established by transferring (intratracheal, i.t. 10⁷/mouse) human PBMC to SCID mice prior to antigen sensitization (intraperitoneal, i.p.) and challenge (i.t.). The dose of TGF–beta–2 was titrated to ensure the increased production of IL–10 in tolerogenic Hu–DC. Tolerogenic Hu–DC were transferred (i.v. 5 x 10⁵/mouse) to pre–sensitized chimera mice seven days prior to antigen (Timothy grass extract) challenge (i.t.). The number of human T cells in the experimental lungs was measured by flow cytometry analyses, and the Th2 cytokine IL–4 mRNA level was measured by RT–PCR. Results: The lungs of the chimera mice showed an increase in the number of human T cells and an increase in the human IL–4 mRNA after Timothy grass extract sensitization (i.p.) and pulmonary challenge (i.t.). The lung draining lymph nodes (LDLN) of the chimera asthma mice that were treated with tolerogenic Hu–DC (100 pg/ml TGF–beta–2 treated, Timothy grass extract pulsed) showed reduced human IL–4 mRNA compared to the LDLN of the chimera asthma mice that were untreated or treated with Hu–DC pulsed with Timothy grass extract only. Conclusions: ACAID mechanisms previously shown to modulate APC function toward tolerance in the mouse are effective in modulating Hu–DC. ACAID–like tolerogenic Hu–DC suppress the Th2 response in the chimera asthma model. The ability of ACAID inducing mechanisms to modulate Hu–DC raises the possibility for the development of novel therapy for immune mediated diseases in the human.

Keywords: ACAID • immune tolerance/privilege • immunomodulation/immunoregulation