Role of endogenous pyrogen in the rabbit febrile responses to muramyl dipeptide (Abstract)
Muramyl dipeptide (MDP) is a low molecular weight synthetic adjuvant, analogue of a streptococcal peptidoglycan sub-unit. MDP was shown to represent the minimal active structure of peptidoglycan for both the adjuvant effect and the pyrogenicity. The immunoadjuvant activity of MDP is not strictly related to its pyrogenicity since synthetic analogues obtained with minor modifications are potent adjuvants without inducing any febrile response. Moreover, indomethacin completely inhibits the pyrogenic effect of MDP but does not modify the MDP-induced leucopenia. This treatment does not affect its immunostimulant properties. There is a general agreement that production of endogenous pyrogen by the host is the first step in the febrile response to bacterial pyrogens. Likewise the presence of transferable circulating endogenous pyrogen was demonstrated in the blood of rabbits made febrile with MDP. In vitro MDP is also able to release leukocytic pyrogen from rabbit phagocytic cells. As expected, production of endogenous pyrogen was not decreased in indomethacin treated animals. However, an injection of nitrogen mustard, which did not modify the febrile response to MDP, inhibited the production of endogenous pyrogen. This result has suggested that MDP fever can be caused by a direct action on thermosensitive brain structures.