An interaction between thymus or thoracic duct cells and antibody-forming cell precursors has been implicated in the response of mice to sheep erythrocytes (1). The possibility was raised that the thymus contributes cells to the circulating pool of lymphocytes which recognize antigen (ARC) and which influence the differentiation of antibody-forming cell precursors (AFCP) to hemolysin-forming cells. The experimental system employing reconstituted neonatally thymectomized mice failed to detect the existence of AFCP in inoculated lymphoid cell suspensions.Previous work from this laboratory (2) had demonstrated that thoracic duct and spleen cells were capable of affecting the appearance of hemolytic foci in the spleens of heavily irradiated recipients injected with sheep erythrocytes. If such loci represent clusters of antibody-forming cells, then either the inoculum must contain cells potentially capable of producing hemolysins, or the host must provide AFCP which are extremely radio-resistant.In this paper, we present the results of experiments designed to determine whether both ARC and AFCP are present in populations of cells from thymus, thoracic duct lymph, or bone marrow. Materials and MethodsA,imals.--Mice of the highly inbred strains CBA and C57BL, and Ft hybrids from crosses between these strains were used. The origin and maintenance of these mice have been described in the previous paper (1).Cell suspensions were prepared as before (1). 0t~¢ra~i~e Procedures.--Thymeetomy or sham operation was performed in young adult mice, 4--6 wk old, as previously described (3). Checks for the presence of thymus remnants
Summary The course of the disease, cutaneous leishmaniasis, caused by the intracellular protozoan parasite Leishmania tropica, differs markedly amongst various common inbred mouse strains. After intradermal injection of 1 × 106 promastigotes to young female specific pathogen‐free (SPF) derived mice, persistent infection characterized by an expanding ulcerous lesion is seen in BALB/c and DBA/2 mice. In the strains CBA/H, C3H/He and A/J, lesions resolve within 8 weeks, and in C57Bl/6 mice no real lesion typical of cutaneous leishmaniasis develops at the injection site. NZB mice are highly resistant. Macrophages harvested from the thioglycollate‐stimulated peritoneal cavity of NZB and C57Bl/6 mice appear to differ from macrophages of the other mouse strains in not supporting multiplication of L. tropica organisms in vitro. Nevertheless, hypothymic nude (nu/nu) mice of C57B1/6 genotype, as well as CBA/H‐nu/nu and BALB/c‐nu/nu mice, develop large lesions with metastases to other cutaneous and visceral locations. In the intact mice in which infection resolves spontaneously, resistance to reinfection is complete. Using mouse antipromastigote sera and an indirect fluorescent antibody test in carefully controlled experiments, L. tropica antigens were detected on in vitro infected macrophages of both highly susceptible BALB/c and relatively resistant CBA/H genotypes. After incubation with a crude soluble antigen preparation from cultured promastigotes, infected macrophages of both genotypes) in being unable to sensitize syngeneic recipients for a delayed‐type hypersensitivity response to that antigen. When infected and uninfected macrophages were used as “blocking cell” in an in vitro alloreactive cytotoxic T cell system involving cells from congenic mice, evidence was obtained for reduced H‐2d expression on infected macrophages of the susceptible mouse strain, BALB/c. The data in this model system of cutaneous leishmaniasis raise the possibility that genetic susceptibility is associated with both a permissive macrophage and defective T cell recognition of parasite antigens on infected macrophage. Defective recognition may be the result of reduced functional expression of H‐2d antigens on infected BALB/c macrophages required for efficient recognition by syngeneic T cells of one or more sub‐populations.
The major cell surface glycoconjugate of Leishmania major, a putative parasite receptor for macrophages, is a lipophosphoglycan containing 81.6% (wt/wt) carbohydrate, 17.0% (wt/wt) phosphate, and 1.4% (wt/wt) lipid. It has been purified to homogeneity by hydrophobic chromatography and consists of a polydisperse family of molecules with Mr 5000-40,000. It contains galactose, mannose, glucose, arabinose, glucosamine, and inositol in the molar ratio of 51:21:5:6:1:1. The lipophosphoglycan has a complex structure, consisting mainly of tri-and tetrasaccharide units linked by phosphodiester bonds, which are cleaved by HF hydrolysis. The phosphate groups are located on the 6-hydroxyl of both galactose and mannose residues. The lipophosphoglycan is anchored to the parasite surface by a 1-O-alkyl-snglycero-3-phosphoinositol moiety. This conclusion is supported by analysis of the products of nitrous acid deamination, HF hydrolysis, and Staphylococcus aureus phosphatidylinositol specific-phospholipase C treatment. The 24:0 and 26:0 alkyl chains accounted for 93% of the ether-linked fatty acids in the lipid anchor. The results are also consistent with a glycosidic linkage between the inositol and a non-N-acetylated glucosamine residue. The lipophosphoglycan membrane anchor shares limited structural homology with the glycosylphosphatidylinositol anchors of several eukaryotic proteins, indicating that this type of membrane anchor is not limited to proteins. Vaccination of mice with the purified L. major lipophosphoglycan in liposomes induced resistance against cutaneous leishmaniasis.Essential for the establishment of infection by the obligatory intramacrophage parasite Leishmania major are four sequential events: recognition, intracellular entry, survival, and replication (1,2). A family of lipoglycoconjugates on the cell surface of L. major, the etiological agent of cutaneous leishmaniasis, are putative parasite recognition molecules for macrophages of the mammalian host (3). A molecule with similar chemical properties has been isolated from Leishmania donovani, the etiological agent of visceral leishmaniasis, and partially characterized as a lipophosphoglycan (LPG) containing mannose, galactose, and phosphate (4, 5). The presence of a hydrophobic lipid moiety in the Leishmania LPGs was indicated by their amphipathic properties and by biosynthetic labeling with fatty acids (4, 6, 7). This lipid could be removed by treatment of LPG with phospholipase C (3). These glycoconjugates are part of a polymorphic family of similar but antigenically distinct molecules present in all Leishmania species (6,8) and have formed the basis for the classification of Leishmania.The localization of the L. major LPG on the surface of both the promastigote and infected macrophage (6) made it an attractive candidate for a vaccine. This was confirmed by studies showing that L. major LPG, immunoaffinity purified from detergent extracts by using the monoclonal antibody WIC-79.3, protected mice against cutaneous leishmaniasis (9).In this ...
Antigen-induced arthritis was established in the mouse by immunization with methylated bovine serum albumin (mBSA) in complete Freund's adjuvant with B pertussis vaccine. The knee joint was injected after 21 days with mBSA in saline. The arthritis was chronic, antigen-specific, and T-cell dependent in hypothymic nu/nu mice. C57BL and BALB/c mice were susceptible, whereas CBA mice were relatively resistant. Susceptibility was dominant: one gene was loosely linked to the "b" allele of the H-2 complex of C57BL mice. and macrophages in the rheumatoid synovium. In animals various experimental diseases of articular and periarticular tissues have been induced by infective, chemical, endocrine, physical, and immunologic procedures. The models that most closely resemble rheumatoid arthritis depend upon either infectious agents (1,2) or immunologic responses (3-5). Antigen-induced arthritis was induced initially by intraarticular injection of antigen in immunized rabbits, and may be the closest experimental analogue of human rheumatoid arthritis ( 5 ) . This model was therefore established in mice to investigate humoral and cell-mediated immunity in the induction and persistence of disease, and to study genetic aspects of susceptibility and resistance. MATERIALS AND METHODSMice. Ten-week-old male and female mice were used.The strains were BALB/c, CBA/CaH WEHI, C3H/HeJ and the closely related C3H.SW, and C57BL/6J WEHI and the closely related BIO.BR. F, and F, hybrids and backcross mice were selectively bred. The mice were reared in a specific pathogen-free (SPF) facility and maintained conventionally after 6 weeks of age. Hypothymic "nude" (nu/nu) mice of CBA and BALB/c strains were used at 6 weeks of age. The BALB/c. nu/nu and CBA. nu/nu mice were derived from the eighth backcross to BALB/c and CBA respectively. These mice, which are homozygous for the recessive mutation "nude," so called because they are hairless, suffer from thymic hypoplasia and are highly deficient in T cells. The heterozygotes (nu/+) are normal. Antigens. The antigens included bovine serum albumin (BSA, Cohn fraction V ) from Armour Pharmaceutical Com-
authors request that the following correction be noted. Recent nucleotide sequence analysis has established that a C residue was omitted at position 628 of the Sj26 cDNA sequence presented in Fig. 2. The amended nucleotide sequence and the altered prediction of the COOH-terminal structure of Sj26 are given below. This correction does not otherwise affect the conclusions of the paper. ABSTRACT Mice of the inbred strain 129/J bred at this Institute (WEHI 129/J) are relatively resistant to chronic infection with the parasitic helminth Schistosomajaponicum. In contrast to more permissive mouse strains such as BALB/c, the WEHI 129/J mice are high responders to a Mr 26,000 adult worm antigen designated Sj26. Cloned cDNAs corresponding to Sj26 have been identified in a S. japonicum phage Xgtll amp3 expression library, and their nucleotide sequences have been deduced. The predicted amino acid sequence of the antigen specified by these cDNAs shows striking homology with class it isozymes of mammalian glutathione S-transferases (RX:glutathione R-transferase, EC 2.5.1.18). Extracts of adult worms contain glutathione S-transferase activity, and affinity chromatography of enzyme activity on glutathione columns leads to the purification of a Mr 26,000 molecule that comigrates with Sj26. Although vaccination studies in mice with a .3-galactosidase-Sj26 fusion protein from Escherichia coli are encouraging, more immunogenic preparations of the antigen are likely to be required to establish the utility of Sj26 as a model vaccine.
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