**4.1 CY and its action on CHS**

Low dose of CY activates mainly of subpopulation of oil- or thioglycolate- induced peritoneal macrophages which are able to present hapten and subsequently activate trigger of Th1 mediated immune CHS response and diminishes the bioactivity of high density subpopulation of macrophages. That subpopulation induces specific immunologic unresponsiveness as a result of activating a network excess of efferent suppressor cells and mainly cooperates with T suppressor CD8+ hapten specific cells (Treg) and mediates the hapten specific tolerance. (Szczepanik et al. 1993; Marcinkiewicz et al. 1994, Bryniarski et al. 2004 & 2009). The question arises as to how treatment with ACR or NM converts tolerogenic Mf into immunogenic Mf. One possibility is that these CY metabolites disrupt the function of the Mf subpopulation that induces Treg cells. Alternatively they can enhance the activity of Mf subpopulation responsible for the induction of Th1 cells that mediates CHS reaction. Finally these two possibilities are not mutually exclusive and the increased production of IL-12 and IL-6, and the simultaneously decreased production of anti-inflammatory IL-10 and TGF- cytokines, make these later assumptions most likely.
