Augmentation of immune responses by a muramyl dipeptide analog, MDP-Lys(L18)

Abstract

The effects of N2-(N-acetyl-muramyl-L-alanyl-D-isoglutamyl)-N6-stearoyl-L-lysine (MDP-Lys(L18], a muramyl dipeptide (MDP) analog, on the immune responses in mice were studied. MDP-Lys(L18) augmented the mitogenic responses of splenic lymphocytes to phytohemagglutinin (PHA) and lipopolysaccharide (LPS) at 0.1-10 micrograms/ml, and antibody formation to sheep red blood cell (SRBC) in normal and immunosuppressed mice, and to dinitrophenyl (DNP)-Ficoll. In addition, MDP-Lys(L18) potentiated polyclonal B cell activation both in vivo and in vitro. It was also found that MDP-Lys(L18) augmented the cellular immune responses, such as mixed lymphocyte reaction (MLR) and delayed type hypersensitivity (DTH). These effects of MDP-Lys(L18) were more potent than those of MDP. These findings may be attributed to the interleukin 1 (IL-1)-inducing activity of MDP-Lys(L18).

Synergistic Effect of Romurtide with Ampicillin against Pneumococcal Pneumonia in Mice

“…The primary importance of alveolar macrophages in lung defense against bacterial infections has been well verified [24,[31][32][33], and the predom inant appearance of macrophages in pneu monic lesions has been regarded as a histopathological sign for the resolution process of this disease in human [21,22] as well as in ex perimental infection [23,24], The peripheral white cell response of the pneumonic mice treated additionally with ro murtide was due mainly to increases in the counts of neutrophils and monocytes, as has been previously reported for healthy mice [7], Since a prompt and persistent rise of the blood monocyte level was a characteristic finding observed in the pneumonic mice treated addi tionally with romurtide, it is highly likely that the macrophages appearing increasingly in the pneumonic lungs were of blood monocyte origin [20,33]. Furthermore, the compound has been verified to primarily stimulate mac rophages for the production of various humo ral factors such as granulocyte and monocyte/ macrophage colony-stimulating factors [11,12] and interleukin 1 [1,8], the biological activities of which are known to augment microbicidal functions of the well-matured phagocytes [34], The priming effect of the compound on circu lating monocytes for production of reactive oxygen intermediates has been reported pre viously [8]. Thus, stimulation by romurtide of hematopoiesis together with activation of ef fector cells (phagocytes including alveolar macrophages) is highly beneficial for an en hancement of host defenses against infection that occurs locally in the lungs.…”

“…The purposes of this paper are (1) to clarify the synergistic effect of romurtide with ampicillin against experimental pneumococcal pneumonia developed in mice deficient in the third component of complement (C3) [24] and (2); to elucidate a possible mechanism of the synergism, with a special reference to the he matopoietic potency of the compound.…”

“…Recently, romurtide has been found to in crease the number of peripheral neutrophils and monocytes when injected subcutaneously in mice [7], monkeys [8], and humans [9,10], Its mechanism is reported to be at least an augmenting effect of the compound on the production of colony-stimulating factors [8,9,11,12] and of interleukin 1 [1,8], One of the ex pansive and possible interpretations of these findings is that such a hematopoietic stimula tion of host by the compound probably corre lates with its anti-infective activity, since leu kocytes, especially neutrophils and mono cytes, are definitely involved in nonspecific host defenses [13][14][15][16][17][18][19], Pneumococcal pneumo nia caused by Streptococcus pneumoniae is probably suitable to investigate for such a cor relation, since the development of infection has been studied well both clinically [20][21][22] and experimentally [23], Our previous report [24] also showed clearly the central role of al veolar macrophages as well as the importance of the complement system, especially of its al ternative pathway, in the lung defenses against S. pneumoniae infection in mice.…”

“…Romurtide, N2-[(N-acetylmuramoyl)-L-alanyl-L>-isoglutaminyl]-N6-stearyol-L-lysine, a synthetic muramyl dipcptide (MDP) deriva tive [MDP-Lys (L18) or muroctasin], has been verified to augment cellular and humoral im munities [1] as well as to augment nonspecific host resistance against various experimental microbial infections [2], Except for a few in teresting findings concerning polymorphonu clear leukocyte activation [3,4], the precise mechanism of the anti-infective activity of the compound has not been clarified yet, although the primary importance of macrophages has been supposed for such a mechanism of the mother compount MDP [5,6].…”