Leishmania donovani: cellular and humoral immune responses in Indian langur monkeys, Presbytis entellus.

We have previously reported that disease mimicking human visceral leishmaniasis can be established in Presbytis entellus, the Indian langur monkey, following a single intravenous challenge of 10(8) Leishmania donovani amastigotes. In the present report, infection was assessed in monkeys infected intravenously with a single dose of 10(8) amastigotes (HDA group), three weekly doses of 10(7) amastigotes (LDA group) and three weekly doses of 5 x 10(7) promastigotes (HDP group). Typical clinical infection was established in all three groups with significant parasite load. There was a gradual and sustained rise in anti-leishmania specific immunoglobulin G response, and a severe fall in the lymphoproliferative response to the T cell mitogens PHA and Con A by day 80 post infection (p.i.). The antibody level remained elevated until death in monkeys of the HDA and HDP groups; the T-cell responses showed a recovery prior to death. T-cell responses to leishmania antigen, however, could not be demonstrated in any of these monkeys prior to death. One monkey of the LDA group survived for 155 days and two monkeys spontaneously eradicated the infection. Surprisingly, one monkey of the HDA group also achieved spontaneous cure. In the three monkeys which eradicated infection spontaneously, the antibody level declined to baseline levels on day 180 p.i. with a well demonstrable antigen specific lymphoproliferative response; no parasites could be demonstrated in splenic aspirates by direct examination of culture. These data demonstrate that disease severity may be the function of the total inoculum dose rather than the stage of the parasite and that the immunological responses in the Indian langur model parallel the reported changes in human visceral leishmaniasis. This makes the langur a potentially useful model for the evaluation of candidate anti-leishmanial drugs and vaccines.     

Dichotomous effects of complete versus partial class II major histocompatibility complex deficiency on circulating autoantibody levels in autoimmune-prone mice

OBJECTIVE: To assess the effects of altered class II major histocompatibility complex (MHCII) expression on circulating autoantibody levels in C57BL/6 (B6) mice congenic for the Sle1 (B6.Sle1 mice) or Nba2 (B6.Nba2 mice) regions. METHODS: H-2Ab(+/+) (MHCII-intact), H-2Ab(+/-) (MHCII-intermediate), and H-2Ab(-/-) (MHCII-deficient) littermate B6.Sle1 and B6.Nba2 mice were evaluated for spleen cell phenotype, numbers of splenic Ig-secreting cells, and serum levels of total IgM, total IgG, IgG antichromatin, IgG antihistone, and IgG anti-double-stranded DNA (anti-dsDNA). RESULTS: Compared with their MHCII-intact littermates, MHCII-deficient B6.Sle1 and B6.Nba2 mice developed markedly decreased circulating levels of IgG autoantibodies, along with decreased circulating levels of total IgG. In sharp contrast, MHCII-intermediate mice developed increased circulating levels of IgG autoantibodies. This was associated with increased numbers of splenic Ig-secreting cells and serum levels of total IgG in B6.Sle1 mice, but it occurred without concomitant increases in the numbers of splenic Ig-secreting cells or serum total IgG levels in B6.Nba2 mice. CONCLUSION: In 2 clinically healthy strains of mice with a genetic proclivity for developing autoantibodies, the effects of class II MHC expression on levels of circulating IgG autoantibodies were found to be complex. In the absence of MHCII expression, circulating IgG autoantibody levels were minimal. With full MHCII expression, circulating IgG autoantibody levels were considerable. With intermediate MHCII expression, circulating IgG autoantibody levels were even greater. These last findings may help explain why heterozygosity at the H-2 locus is associated with increased autoantibody titers and aggravated disease in certain lupus-prone mice.     

Genetic variation in the humoral immune responses of mice to the nematode Trichuris muris

Genetically based differences in the antibody responses to the large intestinal nematode Trichuris muris were studied in two groups of H-2 congenic strains of mice that differed in their relative resistance to infection with this parasite. The primary antibody response to parasite excretory/secretory (E/S) antigen was predominantly an IgG response with the strains forming two distinct groups, defined by their genetic background. The more susceptible B10 genetic background mice had strikingly higher antibody levels than mice of the BALB genetic background. Superimposed upon these background effects were clearly defined influences attributable to H-2-linked genes, strains which differed genetically only at H-2 loci exhibiting differences in the kinetics of the antibody response. Only B10.G and B10.BR mice showed any great increase in IgM levels post-infection. No IgA specific to E/S antigen was detected in the peripheral circulation of any strain at any time post-infection. Antibody responses to a 40-43 kD antigen revealed clear H-2-linked gene effects, with mice sharing the H-2k haplotype (B10.BR, BALB/K) exhibiting considerably higher total antibody levels than strains expressing other haplotypes; mice of the H-2d haplotype (BALB/c, B10.D2/n) responded very weakly to this antigen. A Western blot analysis of antigen recognition by antibody revealed similarities between the mouse strains in their total antibody responses to T. muris E/S antigen. However, immunoprecipitation studies showed that in general the more susceptible B10 congenic strains had wider spectra of antigen recognition than the BALB congenics. Strains sharing the same H-2 haplotype had dissimilar antigen recognition profiles, but strains sharing the H-2b haplotype (B10, BALB/B) recognized a low mol. wt antigen (20-23 kD) not recognized by any other strain, suggesting an exclusively H-2b restriction in the recognition of this antigen. These results support the conclusion that both H-2-linked and background genes play important roles in controlling the humoral immune response to T. muris infection.     

MHC-restricted antibody responses to Trichuris muris excretory/secretory (E/S) antigen

Two panels of H-2 recombinant mice were used in a detailed serological study to analyse the role of H-2-linked genes in the control of the antibody response to excretory/secretory (E/S) antigens of Trichuris muris. An apparent H-2q (I-Aq) restriction on the early development of high levels of IgG1 antibody to E/S antigen was revealed by ELISA. No such restriction was demonstrated for the specific IgG2a response patterns. Recognition of two high molecular weight antigens (90-95 kDa, 105-110 kDa) by IgG antibodies was also shown to be almost exclusively H-2q restricted and may be related at least in part to the high antibody levels seen for H-2q strains of mice. Immune serum from resistant (B10.BRxB10.G) F1 hybrid mice (H-2q/k) containing high levels of IgG1 antibodies specific for T. muris E/S and IgG antibodies which recognized the 90-95 kDa and 105-110 kDa E/S antigens was effective in transferring protection to the non-responsive B10.BR mouse strain as seen on day 35 post-infection (p.i.). It is suggested that the IgG responses described for the generally very resistant H-2q mouse strains may contribute to, but not be an absolute requirement for, protective immunity, antibody-mediated damage facilitating a subsequent cellular attack in certain strains of mice.     

Contrasting effects of Trichinella spiralis and Trichuris muris antigens on the infection by Leishmania infantum in BALB/c mice

The interaction of Trichinella spiralis and Trichuris muris derived antigens with the infection by Leishmania infantum was investigated in BALB/c mice. Infection with 10(6) promastigotes of L. infantum did not induce relevant serum antibody (IgG subclasses), nor cytokine (IFN-gamma, IL-4) responses despite that mice could partially control the infection. Immunization with T. spiralis activated a moderate IgG1 and secondarily an IgG2a anti-leishmanial response whereas immunization with T. muris elicited only a weak and late activation of IgG1 anti-leishmanial response. Immunization with T. muris caused an elevation of serum IFN-gamma levels which was drastically reinforced by the L. infantum infection, and that was accompanied by almost complete parasitological cure of infected mice. Immunization with T. spiralis induced an elevation of serum IL-4 levels but this response was greatly (about 60%) neutralized by the infection with L. infantum, and this was associated to exacerbation of the infection.     

MHC-restricted antibody responses to Trichuris muris excretory/secretory (E/S) antigen

Summary Two panels of H-2 recombinant mice were used in a detailed serological study to analyse the role of H-2-linked genes in the control of the antibody response to excretory/secretory (E/S) antigens of Trichuris muris. An apparent H-2 ^q ( 1-A ^q) restriction on the early development of high levels of IgGl antibody to E/S antigen was revealed by ELISA. No such restriction was demonstrated for the specific IgG2a response patterns. Recognition of two high molecular weight antigens (90–95 kDa, 105–110 kDa) by IgG antibodies was also shown to be almost exclusively H-2 ^q restricted and may be related at least in part to the high antibody levels seen for H-2 ^q strains of mice. Immune serum from resistant (B10.BR × B10.G) Fl hybrid mice ( H-2 ^qk) containing high levels of IgGl antibodies specific for T. muris E/S and IgG antibodies which recognized the 90–95 kDa and 105–110 kDa E/S antigens was effective in transferring protection to the non-responsive B10.BR mouse strain as seen on day 35 post-infection (p.i.). It is suggested that the IgG responses described for the generally very resistant H-2 ^q mouse strains may contribute to, but not be an absolute requirement for. protective immunity, antibody-mediated damage facilitating a subsequent cellular attack in certain strains of mice.     

Identification of immunodominant Leishmania major antigenic markers of the early C57BL/6 and BALB/c mice infection stages

The C57BL/6 mouse strain is resistant to Leishmania (L.) major infection and, unlike susceptible BALB/c, develops small self‐healing cutaneous lesions. The specific antibody responses of C57BL/6 and BALB/c mice were previously characterized by the predominance of IgG2a (‘resistant’ isotype associated with Th1) and IgG1 (‘pathogenic’ isotype associated with Th2) antibodies, respectively. In this study, we looked for the presence of antigens able to elicit an exclusive or predominant IgG1 production during the early stages of C57BL/6 lesion development and checked whether they are recognized or not by BALB/c mice. We demonstrate first that IgG2a predominance in C57BL/6 sera occurs only late after infection, whereas in BALB/c, IgG1 antibodies dominate mostly in the early stages. Interestingly, soon after inoculation of live amastigotes, C57BL/6 displayed an exclusive IgG1 reactivity against particular L. major antigens but with MWs different from those identified in BALB/c. Furthermore, mice immunized with killed amastigotes displayed striking differences in their immunodetection profiles, particularly for the IgG1 isotype. Taken together, the observed differences in the specific antibody repertoires between infected mice resulted, at least in part, from immunological events independent from those triggered by the replicating parasite, and bring new insights into the selection of future vaccine candidates.     

Schedule-dependency assessments of ribonucleoside diphosphate reductase inhibitors when used in combination with platinum compounds plus cyclophosphamide in the treatment of advanced L1210 leukemia.

Each of three ribonucleoside diphosphate reductase inhibitors was used as a third drug in combination with selected antitumor platinum (Pt) agents and cyclophosphamide (CY) in the treatment of advanced L1210 leukemia in C57BL/6 x DBA/2 mice. Each was synergistic with the various Pt plus CY combinations but the effect was highly schedule dependent. The collective cure rate was 68% when hydroxyurea (HU) was given as a single injection with Pt plus CY; the cure rate was 15% when HU was administered on a divided-dose schedule with Pt plus CY. The collective cure rate was 53% when guanazole was given as a single injection with Pt plus CY, but was only 8% when it was given on a divided-dose schedule with Pt plus CY. The effect of 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone, when used as a third drug with the various Pt plus CY regimens, was not schedule dependent as assessed by the collective cure rate. A therapeutic synergy between CY and each of the three ribonucleoside diphosphate reductase inhibitors was also observed.     

Resistance to Listeria monocytogenes in mice: genetic control by genes that are not linked to the H-2 complex.

After mice of several inbred strains were injected with Listeria monoyctogenes, two parameters of resistance, the 50% lethal dose and the suppression of bacterial proliferation in spleen, were determined. The strains of mice tested could be segregated into two groups: the resistant C57BL/10Sn mice and the sensitive A/J and DBA/2J mice. Congenic resistant strains of mice were used because they would express the H-2 haplotype of the sensitive strains (H-2a or H-2d) on the background of a resistant strain, C57BL/10Sn. Both the B10.A/SgSn (H-2a) and the B10.D2/Sn (H-2d) mice were as resistant as mice from their background strain and were significantly more resistant than the strains that donated their H-2 locus (A/J or DBA/2J). Therefore, the resistance of mice to Listeria, although genetically controlled, is not controlled by gene (s) linked to the H-2 haplotype. On the other hand, the level of specific immunity to listeria antigens (as indicated by the footpad reaction) was higher in the C57BL/10Sn (H-2b) mice than in either the A/J and B10.A/SgSn (H-2a) mice or the DBA/2J and B10.D2/Sn (H-2d) mice. This observation suggests an H-2 linkage of specific immunity to Listeria.     

Host genetics and resistance to acute Trypanosoma cruzi infection in mice. I. Antibody isotype profiles

Some strains of inbred mice survive acute infection with Trypanosoma cruzi while others die within a few weeks after infection. Mice which express B10 background genes and either the H-2q or H-2^d haplotypes are resistant and survive. However, mice which share the B10 genetic background but express H-2^k alleles die, usually within 4 weeks following infection. These data confirm that at least 1 gene in the major histocompatibility complex can determine whether an animal lives or dies during the acute phase. Expression of the H-2^q haplotype on the B10 genetic background or in DBA/l mice is associated with resistance, but H-2^q mice expressing the C3H background are susceptible. Therefore, at least I gene in the genetic background also influences resistance. Our data suggest that genes associated with resistance must be present in both the MHC and the genetic background or the animal will die. The isotypes and specificities of parasite reactive antibodies found in the serum of different inbred mouse strains were assessed during acute infection. Levels of IgM were higher in sera from mice which express the resistant B10 background than in sera from mice expressing the susceptible C3H background. Conversely, mice which share the C3H background genes produced high levels of anti-parasite IgG2a when compared to B10 congenic strains. Antigen specificity, however, may be influenced by both background and MHC genes, as congenic strains expressing different MHC haplotypes recognized different constellations of T. cruzi antigens. These data suggest a correlation between genes which influence antibody specificity or isotype and the genes which determine the ability of various inbred mouse strains to survive acute infection with T. cruzi.     

Suppression of antibody response to an unrelated antigen in experimental murine paracoccidioidomycosis: effect of cyclophosphamide and indomethacin.

A suppressive effect of experimental paracoccidioidomycosis on the IgE antibody response to an unrelated antigen (ovalbumin) has been previously observed in mice. This effect was restricted to a short period, reaching maximum levels when OA was administered on the third day of Pb-infection. In order to study possible mechanisms involved in the establishment of this suppression, resistant (A/SN) and susceptible (B10.A) mice were treated with either a low dose of cyclophosphamide (CY) or indomethacin (INDO), a potent inhibitor of prostaglandin synthesis. While treatment with the first drug in A/SN mice induced only a recovery of the IgE anti-OA antibody response, in B10.A mice this effect was extended to IgG1, IgG2a and total levels of anti-OA antibodies. On the other hand, treatment with INDO reverted the anti-OA antibody suppression regarding each antibody class tested and in both strains of mice. These results suggest the participation of prostaglandins and of a cyclophosphamide-sensitive mechanism in the induction of the suppressive phenomenon in the human system.     

Transplantation of Autoimmune Potential. I. Development of Antinuclear Antibodies in H-2 Histocompatible Recipients of Bone Marrow from New Zealand Black Mice

Antinuclear autoantibodies (ANA) appeared in the plasma of lethally irradiated H-2d histocompatible DBA/2 and BALB/c mice several weeks after intravenous transplantation of 2 to 4 x 10(6) bone marrow cells from 3-week-old animals of the autoimmune New Zealand Black (NZB) strain. Little or no ANA development was observed in DBA/2 or BALB/c strains when syngeneic or nonautoimmune allogeneic marrow was grafted, or when NZB marrow was injected into untreated DBA mice or mice receiving 200 rads of x-irradiation. Transfer of 5 x 10(6) spleen cells from 8-day-old NZB mice into lethally irradiated BALB/c mice effected substantial ANA formation by the ninth day after transfer, compared to a 20-day latency following transfer of the same number of bone marrow cells. This earlier conversion with splenocytes may have been due to the presence of immunocompetent T and B cells, since stem cell numbers of the two tissues were similar. Transplantation of NZB marrow to lethally irradiated H-2 incompatible SJL/J (H-2s) and C57B1/6 (H-2b) strains brought about less ANA conversion than the transfer of compatible (SJL x NZB)F1 and (C57B1 x NZB)F1 marrow cells to the respective nonautoimmune SJL or C57B1 parental strain. Graft-versus-host reactions thus did not appear to play a requisite or determining role in the autoimmune development observed following grafting of NZB hemopoietic tissues. Reconstitution of lethally irradiated NZB mice with BALB/c or SJL/J bone marrow depressed the recurrence of ANA for 30 days, compared to rapid ANA recovery following NZB marrow injection. The characteristics that ultimately provoke or permit spontaneous auto-reactivity are inherent in the hemopoietic stem cell population of the NZB strain.     

The antifertility effect of passive immunization of mice against progesterone is influenced by genetic factors other than H-2 haplotype

The anti-fertility effect of passive immunization against progesterone is influenced by genotype in mice. In order to quantify this finding we determined the effective dose that blocks pregnancy in 50% of treated mice (ED50) for two different anti-progesterone monoclonal antibodies (DB3 and 11/32) in four different strains of mice (BALB/cJ, CBA/Ca, Tuck's no. 1 and F1C). Efficacy was greatest in the two inbred strains (BALB/cJ and CBA/Ca) with ED50 values of 0.46-1.4 nmol. The F1C hybrid mice were more resistant to antibody treatment (ED50 2.2-3.0 nmol), while the outbred Tuck's no. 1 strain required much higher doses (ED50 7.0-8.2 nmol). There were no intrastrain differences between the two monoclonal antibodies. We have examined the possible role of the H-2 haplotype on antibody efficacy in different strains and crosses. The antibody was highly effective in blocking implantation in three congenic BALB strains of different H-2 haplotype, in another inbred strain CBA/Ca, and in reciprocal BALB/cJ x CBA/Ca crosses. The F1 hybrid crosses were somewhat resistant, but the C57BL/10Sn and B10.BR congenic strains were most resistant to treatment. The results show that the pregnancy-blocking effect of the anti-progesterone antibody was not influenced by the H-2 haplotype, but rather by background genes.     

Genetic-linked variation in susceptibility of mice to Schistosomiasis mansoni

Summary Genetic dependence of susceptibility to primary infection with Schistosoma mansoni was studied in inbred strains of mice. Eight weeks after the subcutaneous injection of 30 cercariae, C3H/HeJ (H-2^k), DBA/1J (H-2^q) and BALB/cJ (H-2^d) had the highest number of adult worms per animal (8–0–9–8); DBA/2J (H-2^d) and 129/J (H-2^b) had an intermediate number (6–2–6–4); C57BL/6J (H-2^b), BUB/BnJ (H-2^q) and CBA/CaJ (H-2^k) had the lowest number (3–4–4–0). Studies in congenic mice further suggested that genes within the major histocompatibility complex do not have a major influence on determining the ability of schistosomes to develop into mature adult worms. Results of experiments in which adult worm loads in the F| generation of C57BL/6J x BALB/cJ were compared with F, x C57BL/6J and F, x BALB/cJ backcrosses are consistent with homozygosity for a polygenic phenomenon controlling susceptibility to primary S. mansoni infection. Strain associated differences in parasite development appeared to be related to host defense processes directed against maturing adult worms.     

Vaccine development against cutaneous leishmaniasis. Subcutaneous administration of radioattenuated parasites protects CBA mice against virulent Leishmania major challenge

Experiments described in this paper were aimed at determining whether subcutaneous inoculation of live, avirulent Leishmania major would protect mice against infection by the virulent parasite. To this effect, promastigotes or amastigotes of a highly virulent strain of L. major (MRHO/IR/76), used in human trials of leishmanization, and which induces non-healing skin lesions in both CBA and BALB/c mice, were rendered non-pathogenic by gamma irradiation. A dose of 150 krad was required to abrogate the virulence of the parasite as tested on BALB/c mice. Strikingly, however, not all leishmanias were completely inactivated by this procedure since live parasites were detected in the footpads and/or the inguinal lymph nodes as long as 28 days (CBA) or 18 weeks (BALB/c) after injection. Furthermore, 150 krad-irradiated promastigotes retained the capacity to transform into amastigotes intracellularly in vitro. Subcutaneous inoculation of this irradiated 'vaccine' confered onto CBA mice a high degree of protection against challenge by both the homologous and a heterologous (MRHO/SU/59/P) strains of L. major. Lymph node cells from protected animals acquired the capacity to activate infected macrophages in vitro to kill intracellular L. major. To allow for maximum development of immunoprotection, the irradiated promastigotes had to remain viable, perhaps reflecting a requirement for transformation into amastigotes in the vaccinated host.     

Polyspecific malaria antibodies present at the time of infection inhibit the development of immunity to malaria but antibodies specific for the malaria merozoite surface protein,MSP1, facilitate immunity

Serum taken from mice immune to malaria as a result of infection and drug cure, or from mice immunized with a recombinant form of the merozoite surface protein, MSP1, can provide passive protection of recipient mice against the lethal parasite, Plasmodium yoelii YM. However, recipients of MSP1-immune serum go on to develop long-term immunity, whereas recipients of serum from mice naturally immune to malaria rapidly lose their resistance to infection. We demonstrate that 'infection/cure' serum suppresses the development of both antibody and cell-mediated parasite-specific responses in recipients, whereas these develop in recipients of MSP1-specific antibodies. These data have profound implications for our understanding of the development of malaria immunity in babies who passively acquire antibodies from their mothers.     

Immune serum from both susceptible and resistant strains of mice increases phagocytosis of Leishmania mexicana amazonensis by macrophages

Immune sera obtained from either BALB/c mice (susceptible) at 7 weeks, or C57BL/6 mice (resistant), at 7 weeks after infection with L. m. amazonensis, were effective in increasing internalization of homologous promastigotes into starch-induced peritoneal macrophages (from both mouse strains). Both the internalization enhancing effect and the levels of anti-leishmanial antibody (ELISA) were removed from sera by absorption with heat-killed promastigotes. Sera at 1/200 dilution obtained from either mouse strain at 2 weeks after infection did not enhance parasite internalization into macrophages. The factors leading to susceptibility or resistance during leishmaniasis do not appear to be related to differences in antibody-mediated opsonic activity.     

Transfer of idiotypic protein primed allogeneic marrow grafts elicits potent graft-versus-myeloma effects in mice

The active immunization of bone marrow (BM) donors with myeloma immunoglobulin (Ig) results in an idiotypic T cell response that can be transferred to the recipient. Using a murine model we evaluated the effectiveness, side-effects and underlying mechanisms of this approach. Balb/c (H-2d) mice were given a dose of HOPC-1F myeloma cells secreting the monoclonal IgG2a followed by lethal total body irradiation (7.5 Gy) 2 days later and a subsequent transplantation of 2 x 10(7) allogeneic MHC-matched DBA/2-derived marrow cells. Donors were pre-immunized with three i.p. injections of HOPC(IgG2a) or control Ig given with incomplete Freund's adjuvants (IFA) spaced 1 week apart. In some experiments, donor-spleen cells were additionally transferred 2 h post transplant. Injection of HOPC-myeloma led to death of all animals after a median survival time (MST) of 42 days. A lethal dose of TBI followed by transfer of unmanipulated marrow grafts plus splenocytes resulted in moderate antimyeloma effects with 8% of mice achieving long-term survival. Nearly the same results were obtained after transplantation of BM immunized with the control Ig. In contrast, transplantation of marrow grafts from HOPC(IgG2a) immunized donors exerted a significant GVM effect with 63% long-term survival for more than 180 days. The additional transfer of 2 x 10(7) immune splenocytes derived from the same donor resulted in even stronger anti-myeloma effects (FFR 87%). No increase in the incidence of severe acute GVHD was observed. In vitro data suggest that allogeneic CD8+ idiotype-specific T cells may be the major effector cells. Our results demonstrate that active immunization of the donor with the myeloma-specific Ig can induce powerful graft-versus-myeloma effects after allogeneic BMT.     

Natural resistance to salmonellae in mice: control by genes within the major histocompatibility complex

Determinations of 50% lethal dose (LD50) values in H-2 congenic B10 lines showed that late-emerging resistance (postimmune response phase) to salmonellae of intermediate virulence was less in H-2b and H-2d than in H-2a, H-2k, and H-2f mice. Association of resistance to H-2 was confirmed by backcross analysis, and LD50 determinations on H-2 recombinant haplotype strains showed that resistance maps to the I-E subregion. Bacterial growth curves in liver and spleen showed that susceptible mice carried bacteria for longer in the reticuloendothelial system than did resistant mice and that susceptible mice showed greater splenomegaly. Association of resistance and susceptibility to H-2 was not different when sister transductant salmonellae expressing somatic antigens O4 and O9 were used. Thus a gene(s) within the major histocompatibility complex controls natural resistance to salmonellae in mice by influencing the ability to clear bacteria from the reticuloendothelial system in the later phase of the infection, and the immunodominant O antigen cannot be solely involved.     

Experimental fusarial hyalohyphomycosis in a murine model

The pathogenicity of two clinical strains of Fusarium solani was studied in normal and transiently neutropenic outbred CF1 and CD1 male mice. Three inocula (5 x 10(5), 1 x 10(6), and 5 x 10(6) spores/animal) were tested. Groups of 10 mice each were injected with a single intravenous dose of one inoculum. Mortality correlated with the dose of inoculum, as survival was significantly shorter in mice injected with 5 x 10(6) cfu/mouse than in mice that received 1 x 10(6) or 5 x 10(5) cfu/mouse (P less than .001). Necrotizing abscesses with acute branching septate hyphae, neutrophil and macrophage infiltration, and hemorrhage were observed. The median survival of neutropenic mice was shorter than that of normal mice (P less than .001). Neutropenic mice did not show evidence of an inflammatory cellular reaction and exhibited significantly higher numbers of fungi per gram of infected tissue (P less than .001). Intact host defenses in normal mice were able to confine the infection to the kidneys after initial dissemination. In contrast, disseminated infection persisted in most organs in immunosuppressed animals.