Role of Macrophage Tissue Factor in the Development of the Delayed Hypersensitivity Reaction in Monkey Skin

Delayed-type hypersensitivity (DTH) reaction is a cell-mediated immune response, characterized by fibrin deposition. To determine whether macrophage tissue factor (TF), an initiator of blood coagulation, was associated with the DTH reaction, TF expression on macrophages and resulting fibrin deposition at the site of DTH, induced in Bacille-Calmette-Guerin (BCG)-sensitized Japanese monkeys with intradermal administration of pure protein derivative of tuberculin (PPD), were examined immunohistochemically using monoclonal antibodies (MoAbs) against TF and fibrin. Most mononuclear cells, but not polymorphonuclear cells, in DTH reaction sites were TF-positive and were identified as macrophages by double-immunostaining using anti-TF and anti-macrophage MoAbs. Fibrin deposition was only observed around TF-positive macrophages in the stroma of DTH reaction sites and the deposition was not seen in the periphery of other TF-positive tissues (epidermis, trichoepithelium, and blood vessels). The development of induration and the extent of fibrin deposition paralleled an increase of TF-positive macrophages in the DTH reaction sites. In PPD-injected skin sites of nonsensitized monkeys, neither TF-positive macrophages nor fibrin were seen but epidermis, trichoepithelium, and blood vessels were TF-positive. Moreover, the development of induration was inhibited by simultaneous administration of anti-TF MoAb and PPD into BCG-sensitized monkeys. These results suggest that TF expression on macrophages in the reaction site is a key factor for the DTH reaction, through the activation of blood coagulation, resulting in fibrin deposition.