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M M Stevenson

Publications and source records attributed to M M Stevenson.

At least 55 records · Page 3Linked to original sources
PubMed1994

Zinc deficiency impairs T cell function in mice with primary infection of Heligmosomoides polygyrus (Nematoda).

This study was designed to determine whether severe zinc deficiency would prolong the course of a primary Heligmosomoides polygyrus infection in mice, and whether this could be related to impaired T cell function. Female BALB/c mice were fed a zinc-sufficient (Zn+; 60 mg/kg), a zinc-deficient (Zn-; 0.75 mg/kg) or an energy restricted (PF; 60 mg zinc/kg) diet. After four weeks, some mice in each dietary group were given a primary infection with 100 larvae; nutritional, parasitological and immunological parameters were assayed over the following five weeks. Liver zinc concentrations were significantly reduced in Zn- mice compared with Zn+ mice. In certain cases, PF mice also had reduced liver zinc concentrations, showing the negative effects of restricted food intake on zinc status. Zinc deficiency prolonged the course of a primary infection, with the effects being most evident five weeks post-infection when Zn+ mice had only 40% as many worms as Zn- mice. Parasite infection induced strong immunological responses in Zn+ mice in contrast to Zn- mice. The reduced production of IL-4 and IFN-gamma, the reduced peripheral eosinophilia and reduced serum levels of IgE and IgG1 in Zn- mice were attributed to the zinc deficiency, whereas the reduced delayed type hypersensitivity response to parasite antigen and reduced production of IL-5 were in certain instances attributed to reduced energy intake rather than zinc deficiency. These results show that zinc deficiency significantly impairs functions normally attributed to both Th1 and Th2 cell populations, and that these alterations are associated with elevated worm numbers in zinc-deficient mice.

Animals↗
PubMed1994

Differential requirements for an intact spleen in induction and expression of B-cell-dependent immunity to Plasmodium chabaudi AS.

The requirement for an architecturally intact spleen in the afferent and efferent arms of immunity to the murine malaria parasite Plasmodium chabaudi AS was analyzed. C57BL/6 mice with intact spleens develop a single, patent parasitemia and resolve the infection. In contrast, surgically splenectomized mice experience persistent waves of patent parasitemia interrupted briefly by periods of parasitologic crises. Transfer of spleen cells from immune donors, but not transfer of spleen cells from normal mice, into splenectomized mice enabled the recipients to resolve the infection similar to mice with intact spleens. B-cell depletion, but not T-cell depletion, of spleen cells prior to transfer abrogated the ability of splenectomized recipients to resolve the infection. Compared with mice with intact spleens, splenectomized mice exhibited a delayed antibody response whereas all groups of immune cell recipients had an accelerated antibody response. Nevertheless, splenectomized mice and recipients of B-cell-depleted cells failed to resolve infections, despite the development of high-titer antibodies late during the course of infection. Analysis of immunoglobulin G isotype responses showed a lower representation of immunoglobulin G2a in mice which failed to resolve infections. The latter mice had characteristic histopathologic changes in the liver. These observations indicate a unique role of the splenic microenvironment for the induction and development of an effective B-cell-dependent response against malarial parasites.

Animals↗
PubMed1994

Inhibition of in vitro erythropoiesis by soluble mediators in Plasmodium chabaudi AS malaria: lack of a major role for interleukin 1, tumor necrosis factor alpha, and gamma interferon.

By using erythropoietin-dependent proliferation of splenic erythroid cells as an in vitro erythropoiesis model system, we demonstrate that spleen cells from Plasmodium chabaudi AS-infected C57BL/6 mice potently inhibited erythroid cell proliferation. Inhibitory activity was detected in spleen cell conditioned media (SPCM) prepared from infected mice but not from uninfected mice. The inhibitory activity in SPCM was characterized as being heat sensitive, macromolecular, and host derived. The inhibitory activity was not reversed by increasing the erythropoietin concentration and was found to be specific for the late erythroid lineage. Mouse strains, which differ in their resistance to P. chabaudi AS infection, produced and responded to the inhibitory activity to a similar extent. Putative immune mediators, interleukin 1 alpha, interleukin 1 beta, and gamma interferon, were found to be potent inhibitors of erythroid cell proliferation. However, antibody neutralization experiments failed to demonstrate a major role for these cytokines in the inhibitory activity of SPCM. Our results suggest that the elaboration of inhibitor(s) of erythropoiesis in hemopoietic organs of Plasmodium-infected mice may impair erythroid regeneration. The identity of the inhibitory mediator(s) is presently unknown but is distinct from interleukin 1, tumor necrosis factor alpha, and gamma interferon.

Anemia↗
PubMed1994

Blood transfusion alters the course and outcome of Plasmodium chabaudi AS infection in mice.

The importance of severe anemia in the mortality of susceptible A/J mice during blood-stage Plasmodium chabaudi AS infection was assessed. Blood transfusion during and 2 to 3 days after peak parasitemia rescued 90% of susceptible mice from severe anemia and death and allowed these mice to clear the infection and acquire immunity to reinfection. However, blood transfusion prolonged the patency of the infection for up to 5 days after peak parasitemia. Blood transfusions in resistant C57BL/6 mice produced an identical effect, that is, prolongation of the patency of parasitemia. In addition, blood transfusion increased the numbers of gametocytes in both mouse strains. In both strains of mice, the rapid reduction in parasitemia, which occurs during crisis, was associated with the development of moderate levels of anemia. The possible mechanisms for the modulation of parasitemia by blood transfusion and the implications of the present observations for our understanding of the events which occur during crisis are discussed. It is proposed that parasitologic crisis is induced and/or maintained by physiological alterations associated with anemia.

Anemia↗
PubMed1993

Differential induction of helper T cell subsets during blood-stage Plasmodium chabaudi AS infection in resistant and susceptible mice.

The induction of T helper cell subsets during the course of non-lethal or lethal blood-stage Plasmodium chabaudi AS infection was investigated using inbred strains of mice which differ in the level of resistance to this intraerythrocytic parasite. Resistant C57Bl/6 mice experience a non-lethal course of infection characterized by moderate levels of both parasitaemia and anaemia and resolution of primary acute infection by 4 weeks, while susceptible A/J mice experience lethal infection with fulminant parasitaemia and severe anaemia. T helper subset function was assessed during infection by determining the kinetics of spleen cell production in vitro of the Th1-derived cytokine, interferon-gamma (IFN-gamma), and of the Th2-derived cytokine, IL-5, using sandwich ELISAs. Spleen cells from resistant C57Bl/6 mice were found to produce high levels of IFN-gamma within 1 week of infection in response to both the mitogen concanavalin A (Con A) and malaria antigen. Furthermore, CD4+ T cells were found to be the source of IFN-gamma while both CD4+ and CD8+ T cells were found to produce IL-5. Decreased IFN-gamma production after day 10 was concomitant with significant production of IL-5 between 2 and 3 weeks post infection. In contrast, spleen cells from susceptible A/J mice produced high levels of IL-5 within the first week of infection. In addition, these animals were found to have high serum levels of IL-5. These results, thus, confirm previous observations that resolution of primary blood-stage P. chabaudi infection occurs by sequential activation of Th1 CD4+ T cells followed by activation of the Th2 subset, and in addition, suggest that induction of a strong Th2 response early in infection may lead to a severe and lethal course of malaria.

Animals↗
PubMed1992

Plasmodium chabaudi AS: erythropoietic responses during infection in resistant and susceptible mice.

The course of anemia and the erythropoietic response in the bone marrow, spleen, and blood were studied during Plasmodium chabaudi AS infection in resistant C57BL/6 (B6) and susceptible A/J (A) mice. Infections in B6 mice were characterized by moderate levels of both parasitemia and anemia and survival. In contrast, A mice experienced high parasitemia, severe anemia, and high mortality rates. During the period of anemia, erythropoiesis, as measured by in vivo 59Fe incorporation, was significantly more depressed in bone marrow and more increased in the spleen in resistant B6 mice. The increase in splenic 59Fe incorporation was a function of the size of the spleen. Bone marrow CFU-E were decreased to 50% of control in both strains, while splenic CFU-E were increased twofold greater in B6 mice compared to those in A mice. However, the absolute numbers of CFU-E per spleen in the two strains were not significantly different during peak parasitemia. Bone marrow BFU-E were transiently increased before peak parasitemia whereas splenic BFU-E peaked during peak parasitemia. A mice had significantly lower numbers of BFU-E per spleen on all days except at peak parasitemia. The frequency of blood-borne BFU-E and plasma erythropoietin titers was increased earlier and to a greater extent in A mice. These results suggest that an impaired amplification of late-stage splenic erythropoiesis may be an important determinant in the severity of anemia and lethality of infection with P. chabaudi AS in A mice. Moreover, these results demonstrate that the defective amplification of splenic erythropoiesis in A mice is neither caused by a defect in the mobilization of BFU-E from the bone marrow to the spleen nor caused by a defect in erythropoietin production.

Anemia↗
PubMed1992

Identification of immunodominant Trypanosoma musculi antigens recognized by monoclonal antibody and curative immunoglobulin G2a antibody.

Trypanosoma musculi obtained from normal or irradiated (900 rad) hosts or from in vitro cultures were lysed and analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). Similar protein banding patterns with a molecular weight (mol. wt) range from 34 to 68 kDa were observed between the two bloodstream forms. In comparison, lysates of cultured parasites showed a unique banding pattern of antigens within the same mol. wt range. Western blot of bloodstream form lysates, probed with immune plasma (IP), revealed a wide range of parasite proteins. However, when probed with the IgG2a-enriched fraction of IP, a major band of approximately 66 kDa was detected on the blot. Several bands of higher mol. wt were also observed. When anti-T. musculi monoclonal antibodies were used to probe the blot, the 66 kDa protein was again recognized. Using indirect fluorescence, live bloodstream form parasites were analysed by flow cytometry and the p66 protein was determined to be a surface molecule. Finally, lysates of 35S-methionine-labelled trypanosomes were immunoprecipitated with Sepharose linked anti-T. musculi monoclonal antibodies and the eluted ligand analysed by SDS-PAGE and autoradiographed. The 66 kDa band was identified, therefore confirming that this protein was of parasite origin.

Animals↗
PubMed1992

Macrophage activation during Plasmodium chabaudi AS infection in resistant C57BL/6 and susceptible A/J mice.

Macrophage activation was examined in resistant C57BL/6 and susceptible A/J mice during the course of blood-stage infection with Plasmodium chabaudi AS. Three parameters of macrophage activation (lipopolysaccharide [LPS]- and malaria antigen-induced tumor necrosis factor [TNF] production in vitro, phorbol myristate acetate [PMA]-induced production of oxygen metabolites in vitro, and Ia antigen expression) were assessed during infection in populations of peritoneal and splenic macrophages recovered from infected mice of the two strains. The peak level of LPS-induced TNF production in vitro by splenic macrophages from both infected C57BL/6 and infected A/J mice occurred on day 7, which was 3 days before the peak of parasitemia. Although the kinetics of TNF production in vitro in response to either LPS, soluble malaria antigen, or intact parasitized erythrocytes varied in some of the other macrophage populations during infection, there was no significant difference in the peak level of production. Peritoneal and splenic macrophages from infected C57BL/6 mice exhibited significantly increased PMA-induced production of H2O2 in vitro on day 7. Peritoneal macrophages from infected A/J mice also exhibited significant PMA-induced H2O2 production on day 7, while production by splenic macrophages from these hosts was not increased in comparison with production by cells from normal animals. Only peritoneal macrophages from infected C57BL/6 mice produced significantly increased levels of O2-, and this occurred on day 7 postinfection. Ia antigen expression by both peritoneal and splenic macrophages from resistant C57BL/6 and susceptible A/J mice was significantly increased during P. chabaudi AS infection. However, the percentage of Ia+ peritoneal macrophages on days 8 and 10 postinfection and Ia+ splenic macrophages on day 3 postinfection was significantly higher in C57BL/6 than in A/J mice. Thus, these results demonstrate that macrophages from P. chabaudi AS-infected A/J mice exhibit defects in oxygen metabolism and Ia antigen expression which may contribute to the susceptibility of these hosts to this intraerythrocytic parasite. The cause-and-effect relationship between these defects and the susceptibility of A/J mice to P. chabaudi AS is unknown.

Animals↗
PubMed1991

CD4+ and CD8+ T lymphocytes both contribute to acquired immunity to blood-stage Plasmodium chabaudi AS.

In the present study, the contribution of CD4+ and CD8+ T lymphocytes to acquired immunity to blood-stage infection with the murine malaria species Plasmodium chabaudi AS was investigated. C57BL/6 mice, which are genetically resistant to infection with this hemoprotozoan parasite and exhibit a transient course of infection, were treated intraperitoneally with monoclonal antibodies to T-cell epitopes, either anti-Thy-1, anti-CD4, or anti-CD8. After intraperitoneal infection with 10(6) parasitized erythrocytes, control C57BL/6 mice exhibited a peak parasitemia on day 9 of approximately 35% parasitized erythrocytes and eliminated the infection within 4 weeks. Mice depleted of Thy-1+ or CD4+ T cells had significantly higher parasitemias on day 7 as well as significantly higher peak parasitemias. These mice were unable to control the infection and developed a persistent, high parasitemia that fluctuated between 40 and 60% until the experiment was terminated on day 56 postinfection. Depletion of CD8+ T lymphocytes was found to have no effect on the early course of parasitemia or on the level of peak parasitemia. However, mice depleted of CD8+ T cells experienced two recurrent bouts of parasitemia during the later stage of the infection and required more than 5 weeks to eliminate the parasites. After the peak parasitemia, which occurred in control and experimental animals on day 9, there was a sharp drop in parasitemia coinciding with a wave of reticulocytosis. Therefore, the contribution of the influx of reticulocytes, which are not the preferred host cell of this hemoprotozoan parasite, to limiting the parasitemia was also examined by determining the course of reticulocytosis during infection in control and T cell-depleted animals. Early in infection, there was a marked and comparable reticulocytosis in the peripheral blood of control and T cell-depleted mice; the reticulocytosis peaked on day 12 and coincided with the dramatic and sudden reduction in parasitemia occurring in all groups. In both control and CD8-depleted mice the percentage of reticulocytes decreased as the infection was resolved, whereas in CD4-depleted mice marked reticulocytosis correlated with high, persistent parasitemia. These results thus demonstrate that both CD4+ and CD8+ T cells are involved in acquired immunity to blood-stage P. chabaudi AS and that the influx of reticulocytes into the blood that occurs just after the peak parasitemia may contribute temporarily to limiting the parasitemia.

Animals↗
PubMed1991

Cells within the vascular system capable of mediating trypanocidal activity in vitro.

Cure of Trypanosoma musculi infection involves an effector mechanism mediated by immunoglobulin G2a antibody, C3, and an unidentified effector cell. In the present study, experiments were designed to identify the cell(s) within the vascular system that may be responsible for cure of trypanosomiasis. The ability of various cell populations to mediate killing of trypanosomes in the presence of C3 and immune plasma (IP) was tested in vitro. Blood-derived platelets or leukocytes or Bio-Gel-elicited macrophages or neutrophils were incubated at various concentrations with T. musculi, C3, and IP diluted up to 1 in 8. Trypanocidal activity was dependent upon the presence and concentration of IP and on the number of cells in the wells. Macrophages, neutrophils, and platelets were shown to kill with different potencies. With a 2:1 cell-to-parasite ratio, both macrophages and neutrophils reduced parasite numbers by 2 log, while platelets at a 40:1 ratio mediated a 1 log decrease. In addition, even in the absence of C3, the phagocytes were capable of killing trypanosomes while platelet trypanocidal activity was abrogated. The time course of trypanocidal activity was monitored for macrophages and neutrophils. The number of parasites decreased by 0.5 log by 4 h and 1 to 2 log by 8 h and by 20 h was reduced to zero. Cultured monolayers of endothelial cells were also tested for trypanocidal activity and shown to kill the parasites in the presence of IP and C3. The level of trypanocidal activity was dependent on the concentration of IP.

Animals↗
PubMed1990

Role of interferon-gamma and tumor necrosis factor in host resistance to Plasmodium chabaudi AS.

The contribution of the T cell- and macrophage-derived cytokines, interferon-gamma (IFN-gamma) and tumor necrosis factor (TNF), respectively, in the cell-mediated mechanisms leading to acquired immunity to blood-stage Plasmodium chabaudi AS was investigated. To examine the contribution of IFN-gamma, resistant C57BL-derived mice were treated during infection with two different neutralizing, anti-murine IFN-gamma mAbs. Such treatment impaired the ability of the host to limit parasite multiplication just before and at the time of the peak parasitemia but did not abrogate the development of acquired immunity resulting in control and elimination of acute infection. The requirement of endogenous IFN-gamma around the time of the peak parasitemia was confirmed by quantification of IFN-gamma production in vitro by spleen cells from infected animals in response to malaria antigen. To investigate the role of TNF, resistant C57BL/6 and susceptible A/J mice were treated with rTNF during P. chabaudi AS infection. Treatment with 10(3) or 10(5) U rTNF resulted in increased resistance in A/J hosts (that is, increased survival and a less severe course of infection); there was no difference between control and treated C57BL/6 mice in the course of infection but there was increased mortality among the animals treated with rTNF. Splenic macrophages harvested from C57BL/6 mice during infection were found to produce high levels of TNF from day 3 to day 28 post-infection. In conclusion, both IFN-gamma and TNF appear to contribute to host resistance to blood-stage infection with P. chabaudi AS.

Animals↗
PubMed1990

Dependence on cell-mediated mechanisms for the appearance of crisis forms during Plasmodium chabaudi AS infection in C57BL/6 mice.

The appearance of crisis forms or degenerate, intraerythrocytic parasites in the peripheral blood of C57BL/6 hosts during the course of Plasmodium chabaudi AS infection was analysed. Following intraperitoneal injection with 10(6) parasitized erythrocytes, C57BL/6 hosts, which are resistant to this species of rodent Plasmodium, eliminate the parasite from the peripheral blood by 4 weeks and recover from acute infection. Elimination of the parasite coincides with the appearance in the peripheral blood of almost all the parasites as crisis forms. A role for cell-mediated immunity in the induction of crisis forms of Plasmodium species has previously been suggested. To define the role of cell-mediated immunity in the appearance of intraerythrocytic crisis forms in the peripheral blood during acute malaria, the outcome of P. chabaudi AS infection, the course of parasitemia and the appearance of crisis forms in mice with either genetically determined or experimentally induced immunodeficiencies on the resistant C57BL-derived background were examined. The mice used were either B-cell deficient (mu-suppressed from birth). T-cell deficient (nu/nu mice), C5 deficient or splenectomized prior to infection. The appearance of intraerythrocytic crisis forms in the peripheral blood during the course of P. chabaudi AS infection is shown to be dependent on cell-mediated mechanisms which require the presence of T cells as well as an intact spleen for the most efficient elimination of this parasite.

Animals↗
PubMed1990

Role of endogenous gamma interferon in host response to infection with blood-stage Plasmodium chabaudi AS.

The role of gamma interferon (IFN-gamma), a pluripotent lymphokine capable of activating macrophages, in acquired immunity to blood-stage malaria was investigated. C57BL-derived, lipopolysaccharide-resistant C57BL/10ScN mice, which were found to be resistant to intraperitoneal (i.p.) infection with 10(6) Plasmodium chabaudi AS parasitized erythrocytes, were treated with monoclonal anti-IFN-gamma antibody (MAb). Two MAbs were used: R4-6A2, a rat anti-mouse, neutralizing immunoglobulin G1, which was prepared against natural murine IFN-gamma, and DB-1, a murine anti-rat immunoglobulin G1 prepared against recombinant rat IFN-gamma, which can neutralize the murine molecule as well as the rat molecule. C57BL/10ScNH mice were injected i.p. with 200 micrograms of R4-6A2 1 day before infection and every 3 days through day 21. Control mice were treated with normal rat serum. In separate experiments, DB-1 (1.0 mg per week for 4 weeks) was administered i.p. to C57BL/10ScNH mice beginning on the day of infection; control mice were untreated. Control and MAb-treated mice were infected i.p. with 10(6) P. chabaudi AS parasitized erythrocytes, and the course and outcome of infection were determined. Control mice exhibited a course of infection that was characterized by a peak parasitemia between 30 and 40% parasitized erythrocytes and elimination of the parasite by 4 weeks. MAb-treated mice exhibited a significantly greater parasitemia 1 to 2 days before the peak parasitemia as well as a significantly greater peak parasitemia but also completely cleared the infection by 4 weeks. Thus, these results suggest that treatment with anti-IFN-gamma MAb impairs but does not completely abrogate host resistance to P. chabaudi AS. We also examined the kinetics of IFN-gamma production by spleen cells cultured in vitro with malaria antigen or concanavalin A. Spleen cells were recovered from individual C57BL/6 mice at various times after i.p. infection with 10(6) P. chabaudi AS parasitized erythrocytes. The amount of IFN-gamma produced was quantitated by enzyme-linked immunosorbent assay. In each case, the peak of IFN-gamma production occurred just before the peak parasitemia, followed by a decrease to little or no IFN-gamma production through 42 days postinfection. There was thus a parallel between the kinetics of production of IFN-gamma in vitro by spleen cells from infected animals and the requirement in vivo for the endogenous molecule just before and at the time of peak parasitemia. In conclusion, these results suggest that IFN-gamma-dependent and -independent mechanisms contribute to host resistance to P. chabaudi AS.

Animals↗
PubMed1990

Review: cytokines and malaria.

Malaria, which is caused by hemoprotozoan parasites of the genus Plasmodium, has once again reached epidemic proportions. The resurgence of malaria has occurred because the parasite has developed resistance to the anti-malarial drugs and the mosquito vector has developed resistance to the insecticides. Added to these impediments is the problem that, in spite of intense efforts by researchers world-wide, there is yet no effective anti-malarial vaccine. Our lack of knowledge concerning the exact mechanism of the host immune response to infection with Plasmodium parasites has contributed significantly to the lack of an effective and safe vaccine. The role of an antibody-independent, cell-mediated mechanism which can result in the generation of soluble mediators or cytokines by T lymphocytes and macrophages in host defense against blood stage malaria is being actively investigated in humans and in mice with malaria. With the availability of recombinant lymphokines and monokines and neutralizing antibodies against these reagents it is now possible to determine the role of cytokines in the development of protective anti-malarial immunity. In this review, we discuss recent evidence from human studies and experimental murine models concerning the possible roles of cytokines in malaria.

Animals↗
PubMed1989

Histological changes in the spleen and liver of C57BL/6 and A/J mice during Plasmodium chabaudi AS infection.

The level of resistance to infection in inbred mice with the murine malaria species Plasmodium chabaudi AS is genetically determined. Resistant C57BL/6, which are able to eliminate the parasite by 4 weeks, develop marked splenomegaly and survive the infection. Susceptible A/J mice, which succumb to infection (mean survival time = 10 days), develop only minimal splenomegaly. In order to determine if gross differences in the organization, number, and type of spleen cells are related to the outcome of infection with P. chabaudi AS, the development of splenomegaly was examined by enzyme and immunohistochemical methods during the first week after infection. Cryostat sections of spleens removed from normal animals of both strains and at 4 and 7 days after intraperitoneal infection with 10(6) parasitized erythrocytes were stained for enzyme (acid phosphatase and nonspecific esterase) and immunohistochemistry with conventional monoclonal antibodies against T cells, B cells, and macrophages as well as with novel rat anti-mouse monoclonal antibodies which define discrete subpopulations of macrophages in the mouse spleen. The livers of normal and infected animals of each strain were also examined. The results of this study demonstrate (1) differences between normal, uninfected B6 and A/J mice in the organization and number of one subpopulation of macrophages in the spleen, the marginal metallophilic macrophages, and (2) marked histological changes in the spleen and liver during the course of infection in both resistant C57BL/6 and susceptible A/J mice. These changes include depletion of cells from the marginal zone of the spleen which, in the case of the marginal metallophilic macrophages, appears to be more severe in susceptible A/J mice.

Animals↗
PubMed1989

Role of mononuclear phagocytes in elimination of Plasmodium chabaudi AS infection.

The role of mononuclear phagocytes in acquired immunity resulting in the intraerythrocytic destruction and elimination of malarial parasites was investigated in the murine model of infection with Plasmodium chabaudi AS. Mice were treated 1 day before or 6 days after infection with agents which either result in augmentation or activation of the non-specific, microbicidal effector function of mononuclear phagocytes or in depletion of cells of this lineage. To examine the effect of agents which activate mononuclear phagocytes. A/J mice, which are susceptible to P. chabaudi AS and exhibit fulminant parasitaemia and death within 10 days of intraperitoneal infection with 10(6) P-RBC, were treated intravenously with muramyl dipeptide (MDP) or liposome-encapsulated MDP-glycerol dipalmitate (MDP-GDP). Treatment administered 1 day before infection was ineffective. Treatment on day 6 post-infection with liposome-encapsulated MDP-GDP (1 microgram) resulted in a significant decrease in parasitaemia on day 8 and survival, while treatment with free MDP (100 micrograms) resulted only in a significant decrease in parasitaemia. To examine the effect of depletion of mononuclear phagocytes, C57BL/6 mice, which are resistant to P. chabaudi AS infection and eliminate the parasite by 4 weeks, were treated intravenously with 3 mg silica. Silica administered 1 day before or 6 days post-infection abrogated resistance resulting in a delay in elimination of the parasite and host mortality. Treatment on day 6 was more effective, with death by day 13 post-infection of 70% of the normally resistant C57BL/6 mice which exhibited fulminant parasitaemia levels. These results thus provide in-vivo evidence that mononuclear phagocytes play a critical role in the elimination of infection with the murine malaria species P. chabaudi AS. Furthermore, these results suggest that the time of administration of agents which alter mononuclear phagocyte function may be important in determining their effect on host antimalarial defences.

Acetylmuramyl-Alanyl-Isoglutamine↗