Tolerogenic APC suppress both Th1 and Th2 types of immune response-mediated pathogenesis in disease models

Abstract

Rationale TGFβ2-treated antigen-pulsed (tolerogenic) antigen presenting cells (APC) generate T regulatory (Tr) cells that mediate tolerance. The mechanisms of tolerogenic APC to suppress immune mediated pathology in the lung were explored. Methods Tolerogenic APC (5×10 5/mouse) were transferred (retro orbital) into pre-sensitized mice in either OVA-induced mouse asthma model (a Th2-mediated disease model) or Hapten Immune Pulmonary Interstitial Fibrosis (HIPIF) model (a Th1-mediated autoimmune fibrosis model). Airway hyperresponsiveness (AHR) was measured after methacholine (200 mg/ml) challenge using whole body Plethysmography, and mucus production in the airway was visualized by Periodic acid-Schiff staining. Fibrosis was detected by Masson's Trichrome staining specific for collagen and hydroxyproline assay. The effect of Tr cells was detected after they were transferred into another set of pre-sensitized mice in the HIPIF model. Results In OVA-asthma model, tolerogenic APC treatment reduced AHR, mucus production, and cytokine (IL-4, IL-5, and IL-13, but not IFNγ) production in the asthma mice. In HIPIF model, tolerogenic APC blocked the development of immune mediated fibrosis in the HIPIF lung. Enriched splenic CD8 + T cells from the tolerogenic APC-treated HIPIF mice suppressed the development of immune-mediated fibrosis in the second set of HIPIF mice. Conclusion Adoptively transferred tolerogenic APC block Th2-mediated pathogenesis in the OVA-asthma model and Th1-mediated autoimmune response in the HIPIF model. The suppression of the immune response in the lung of pre-sensitized mice by transferring tolerogenic APC is mediated through the generation of CD8 + Tr cells. Mechanisms of tolerance by tolerogenic APC may lead to potential therapy for immune mediated diseases.