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1.
A series ofH-2 and non-H-2 congenic resistant (CR) strains on a C57BL/10Sn background were infected with 107 amastigotes ofLeishmania donovani. Non-H-2 congenic strains B10.LP-H-3 b and B10.CE(30NX) and (B10.LP-H-3 b × B10)F1 hybrids showed a very rapid decrease in liver-parasite burdens beyond day 21. Parasite counts for these strains at day 35 were significantly lower than for all other strains tested. The rapid decrease in parasite numbers, massive lymphocellular infiltration into the liver and strong delayed hypersensitivity reactions to parasite antigens in strains congenic for a portion of chromosome 2 indicated that acquired immunity toL. donovani was controlled by a dominant gene at or near theIr-2 locus. In addition, B10.129(10M) mice, which differ from C57BL/10Sn at theH-11 locus, showed highly significant increases in parasite numbers at day 35. Other observations supporting the absence of acquired immunity in B10.129(10M) included negative delayed hypersensitivity tests to parasite antigens and the absence of lymphocellular infiltrate into the liver. Although the differences were not as pronounced,H-2 CR strains withH-2 b ,H-2 a , andH-2 k haplotypes also showed significantly greater decreases in parasite numbers by day 35 as compared to otherH-2 CR strains.  相似文献   

2.
Single gene control of resistance to cutaneous leishmaniasis in mice   总被引:6,自引:0,他引:6  
A series of inbred, congenic resistant, and hybrid strains of mice were intradermally inoculated with 106 promastigotes of Leishmania tropica. These mice were divided into susceptible and resistant groups using the criteria of lesion size, development of metastatic foci and skin-test reactivity. At 16 weeks of infection, resistant strains A/J, DBA/1J, AKR/J, CBA/J, C3H/HeJ, NZB/BINJ, C57BL/6J, C57BL/10Sn, B10.D2, B10.129(10M), and B10.CE(30NX) had completely resolved their lesions, while susceptible SWR/J and BALB/cJ mice demonstrated large, nonhealing cutaneous lesions. In addition, BALB/cJ developed metastatic lesions on the extremities which progressively increased in size. All BALB/cJ and SWR/J mice died by 7 1/2 months of infection. The BALB/cJ x C57BL/6JF1 hybrid behaved in an intermediate fashion showing a slower expansion of cutaneous ulcers and a delayed development of metastatic foci, however, the infection ultimately proved fatal. The F2 generation could be separated into three distinct groups: resistant, intermediate, and susceptible mice with a lesion size distribution pattern in conformity with a 1:2:1 ratio. Male/female susceptibility differences were not noted. These data indicated that development of acquired resistance may be under the control of a single, autosomal gene. The gene did not appear to be H-2-, Ir-2-, or H-11-linked as is seen with Leishmania donovani infections.  相似文献   

3.
Neonatal mouse heart fragments were grafted under the ear skin of adult recipients. Cardiac allograft survival was evaluated by visual observation of pulsation, electrocardiography, and histology. Employing a series of congenic resistant strains differing from C57BL/10Sn at theH-1, H-3,H-4, H-7, H-8, H-9, H-10, H-11, andH-12 loci, the median survival times of the heart grafts to and from C57BL/10Sn were obtained. The various interallelic combinations resulted in a wide variation of graft survival. Reciprocal transplants frequently showed different survival times.H-1 c grafts were rejected by B10.129(5M)/nSn female mice with a median survival time of 90 days.H-1 b grafts were not rejected by C57BL/10Sn mice for the experiment's duration of 200 days. The weaker the histocompatibility barrier, the more variable the survival times and the smaller the ratio of rejected to total grafted heart fragments. Female recipients were observed to reject their grafts more rapidly and to reject a higher proportion than males of the same strain. Although the strength of the different non-H-2 barriers generally paralleled that determined by skin transplants, the rankings of the strongest minor barriers were not the same for both tissues.  相似文献   

4.
A series of H-2 and non-H-2 congenic resistant (CR) strains on a C57BL/10Sn background were infected with 10(7) amastigotes of Leishmania donovani. Non-H-2 congenic strains B10.LP-H-3b and B10.CE(30NX) and (B10.LP-H-3b x B10)F1 hybrids showed a very rapid decrease in liver-parasite burdens beyond day 21. Parasite counts for these strains at day 35 were significantly lower than for all other strains tested. The rapid decrease in parasite numbers, massive lymphocellular infiltration into the liver and strong delayed hypersensitivity reactions to parasite antigens in strains congenic for a portion of chromosome 2 indicated that acquired immunity to L. donovani was controlled by a dominant gene at or near the Ir-2 locus. In addition, B10.129(10M) mice, which differ from C57BL/10Sn at the H-11 locus, showed highly significant increases in parasite numbers at day 35. Other observations supporting the absence of acquired immunity in B10.129(10M) included negative delayed hypersensitivity tests to parasite antigens and the absence of lymphocellular infiltrate into the liver. Although the differences were not as pronounced, H-2 CR strains with H-2b, H-2a, and H-2k haplotypes also showed significantly greater decreases in parasite numbers by day 35 as compared to other H-2 CR strains.  相似文献   

5.
A.BY, B10.LPa, and B10.129(5M) mice were presensitized in vivo against B10.A(5R) cells and then restimulated in vitro by the same cells in the standard CML assay. The effector cells thus generated lysed not only B10.A(5R), but also C57BL/6 targets, indicating that, in addition to anti-H-2Dd response [measured on the B10.A(5R) targets], response to minor histocompatibility (H) antigens (measured on the C57BL/6 targets) also occurred. The latter response was directed against multiple minor H antigens in the case of the A.BY effectors, and against H-1 and H-3 antigens in the case of B10.129(5M) and B10.LPa effectors, respectively. The sensitization against minor H antigens occurred in the context of H-2Kb H-2Dd antigens, but by testing the response on C57BL/6 targets, only cells reacting with minor H antigens in the context of H-2Kb were assayed. The same effector cells were then tested against H-2b mutant strains, in which theH-2K b allele was replaced by a mutant one. All three effector types [A.BY, B10.LPa, and B10.129(5M)] behaved in a similar way: they all reacted with theH-2 bg1 mutant to the same degree as withH-2 b, they did not react at all or reacted only weakly with theH-2 bd andH-2 bh mutants, and they reacted moderately or strongly with theH-2 ba mutant. The degree of crossreactivity with the mutants reflects, with one exception, the degree of relatedness of these mutants toH-2 b, as established by other methods. The one exception is theH-2 ba mutant, which is the most unrelated toH-2 b, and yet it crossreacted strongly. Further testing, however, suggested that in this instance the crossreactivity was probably directed against H-2 antigens: the anti-H-2Dd effectors apparently crossreacted with the H-2Kba antigens. This finding is an example of cell-mediated crossreactivity between the products of two differentH-2 genes (H-2K andH-2D). It is also an example of anH-2 mutation generating an antigenic determinant known to be present in another strain.  相似文献   

6.
Leishmania donovani and Leishmaniainfantum infections cause fatal visceral leishmaniasis, and Leishmaniamajor causes self healing cutaneous lesions. It is poorly understood what genetic differences between these Leishmania species are responsible for the different pathologies of infection. To investigate whether L.donovani species-specific genes are involved in visceral Leishmania infection, we have examined a L.donovani species-specific gene Ld1590 (ortholog of LinJ15_V3.0900) that is a pseudogene in L.major. We have previously shown that transgenic expression of L.donovani Ld1590 in L.major significantly increased the liver and spleen parasite burdens in infected BALB/c mice. In this study we report that Ld1590 potentially encodes a nucleotide sugar transporter (NST) which localizes in the L.donovani Golgi apparatus. Surprisingly, although transgenic expression of the Ld1590 NST increased L.major survival in visceral organs, deletion of Ld1590 NST in L.donovani had no significant effect on L.donovani survival in mice. These observations suggest that loss of the functional Ld1590 gene in L.major may have been associated with reduced virulence in visceral organs in its animal reservoir and could have contributed to L.major’s tropism for cutaneous infections.  相似文献   

7.
To determine the locus in theH-2 complex that affects susceptibility to the development of pulmonary adenomas in mice,H-2 congenic and recombinant strains of mice with A/Wy, BALB/c, C3H, and B10 backgrounds were subjected to treatment with urethane. The average number and the incidence of adenoma foci were recorded five months after the treatment. InH-2 congenic strains on the A/Wy background, the average number of adenoma foci per mouse was significantly higher in mice of the A/Wy, A/J, and A-Tla b (H-2 a ) strains than in A.BY (H-2 b ) mice. In BALB/c and C3H congenic strains, the strains carrying theH-2 k haplotype were more susceptible than those carrying theH-2 b haplotype. InH-2 congenic strains on the B 10 background, the average number and incidence of foci was also higher in haplotypesa, h2, k, andj than in haplotypesb, s, f, d, r, h4, i3, i5, and4. The average numbers of adenoma foci in (A/J × A.BY)F1 (H-2 a /H-2 b ) and (B10 × B10.A)F1 (H-2 b /H-2 a ) were intermediate between the numbers in the parental strains. In [B10.A (4R) × B10.A (3R)]F1 (H-2 h4 /H-2 i3 ) and [B10.A (4R) × B10.A (5R)]F1 (H-2 h4 /H-2 i5 ), the numbers of adenoma foci were higher than in resistant parental recombinants. These patterns of response to urethane matched the patterns of the immune response to lactate dehydrogenase-B (LDH-B) and immunoglobulin gamma 2a (IgG2a) proteins. These differences between mice in their susceptibility to the development of pulmonary adenomas is probably due to the polymorphism of the class II genes in theH-2 complex.  相似文献   

8.
Comparison of the Leishmania infantum genome with Leishmania braziliensis and Leishmania major genomes has identified 25 L. infantum species‐specific genes that are absent or pseudogenes in L. major and L. braziliensis. To determine whether these L. infantum species‐specific genes are involved in visceral Leishmania infection, we cloned the orthologues of 14 L. infantum species‐specific genes from the genetically closely related Leishmania donovani and introduced them into L. major. Two of these L. donovani species‐specific genes were found to significantly increase L. major survival in visceral organs in BALB/c mice. One (orthologue of LinJ28_V3.0340; Ld2834) of these two genes was further investigated. The L. donovani Ld2834 null mutants displayed dramatically reduced virulence in BALB/c mice and were unable to survive in axenic amastigote culture conditions arguing that Ld2834 plays a crucial role in enabling L. donovani survive at the increased temperature typically associated with visceral organs. Ld2834 encodes a 50 kDa protein that is localized in the cytoplasma and has no significant sequence similarity with other known genes. This study validates the importance of comparative genomics for understanding Leishmania species pathology and argues that Leishmania species‐specific genes play important roles in tissue tropism and virulence.  相似文献   

9.
This report confirms and expands on the original preliminary observations made by Bonner and Slavkin that corticosteroid-induced cleft palate in mice is associated with H-2 haplotype. Using three congenic strains, B10, B10.A, and B10.D2, our studies demonstrate that B10.A (H-2 b) is most susceptible and B10.D2 (H-2 d) is least susceptible, B10 (H-2 b) being intermediate. Variation in fetal loss among strains accounts for less than 1 percent of the variation in cleft-palate frequency among strains; variation in H-2 haplotype, however, accounts for more than 60 percent of the variation in cleft-palate frequency. With regard to all possible reciprocal F1 hybrids, our results indicate that while there is a significant maternal effect, maternal haplotype can account for only 11 percent of the variation in cleft-palate frequency among crosses. Embryonic haplotype accounts for 17 percent of the variation, which is indicative of an important embryonic effect. Finally, our studies suggest that susceptibility to corticosteroid-induced cleft palate is associated with the K end of the H-2 complex.  相似文献   

10.
The initial 7 steps of the glycolytic pathway from glucose to 3-phosphoglycerate are localized in the glycosomes in Leishmania, including step 6, catalyzed by the enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In L. donovani and L. mexicana, there exists a second GAPDH enzyme present in the cytosol that is absent in L. braziliensis and that has become a pseudogene in L. major. To investigate the role of the cytosolic GAPDH (cGAPDH), an L. donovani cGAPDH-null mutant was generated, and conversely, the functional L. donovani cGAPDH was introduced into L. major and the resulting engineered parasites were characterized. The L. donovani cGAPDH-null mutant was able to proliferate at the same rate as the wild-type parasite in glucose-deficient medium. However, in the presence of glucose, the L. donovani cGAPDH-null mutant consumed less glucose and proliferated more slowly than the wild-type parasite and displayed reduced infectivity in visceral organs of experimentally infected mice. This demonstrates that cGAPDH is functional in L. donovani and is required for survival in visceral organs. Restoration of cGAPDH activity in L. major, in contrast, had an adverse effect on L. major proliferation in glucose-containing medium, providing a possible explanation of why it has evolved into a pseudogene in L. major. This study indicates that there is a difference in glucose metabolism between L. donovani and L. major, and this may represent an important factor in the ability of L. donovani to cause visceral disease.  相似文献   

11.
This study describes the levels of interleukin-1 alpha (IL-1α), tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) in the sera and parenchymal organs of various congenic mouse strains infected with Borrelia garinii. A significant elevation of inflammatory cytokine levels was found in the organs of C3H/HeN (H-2k) and B10.BR (H-2k) mice but not in those of BALB/c mice (H-2d). Focally produced cytokines can contribute to antimicrobial defense against these organisms. High levels of IL-1α were observed in the sera of C3H/HeN, B10.BR and B10 (H-2b) mice infected with B. garinii and they were associated with the presence of spirochetes in the skin. Thus, susceptible mice demonstrated a stronger cytokine response than resistant mice. This study presents in vivo evidence that B. garinii infection affects the immunopathogenesis of Lyme disease.  相似文献   

12.
The line B6.M505 is congenic with C57BL/6JY and carries a mutant form of theH-2 b haplotype designatedH-2 bd . The mutant site 505 was located by the F1 tests in theK end of theH-2 gene complex. The M505 mice are histoincompatible with the B6.C(Hz1) line (haplotypeH-2 ba ) carrying another mutation in theK end ofH-2 b . Inability of M505 to complement Hz1 in tests with B6 skin grafting is considered as an evidence that the same gene was altered by both mutations. The gained H antigens of two mutants can cross-react in vivo as revealed by accelerated rejection of Hz1 skin grafts by B6 recipients presensitized with M505 spleen cells. The lost antigenic determinants are not identical as shown by accelerated rejection of B6 skin grafts by Hz1 hosts preimmunized with M505 spleen cells. Absorptions of the antiserum ASY-015, (d×a) anti-i, anti-H-2.33 with M505 spleen cells did not clear forH-2 i ,H-2 b andH-2 ba , and absorptions with Hz1 did not clear forH-2 i ,H-2 b , andH-2 bd . These results show that changes of histocompatibility determinants may be accompanied by loss of some haptenic determinants in the Hz1 and M505 mutations.  相似文献   

13.
Two new double congenic strains, B10-H-2 a H-7 b /Wts and B10-H-2 d H-7 b /Wts, were selected to differ from B10.A and B10.D2/o, respectively, at theH-7 locus. The survival time ofH-7-incompatible skin grafts is dependent upon theH-2 haplotype of recipient and donor.  相似文献   

14.
Zinkernagel  Rolf M.  Klein  Jan 《Immunogenetics》1977,4(1):581-590
B10.A(3R) (H-2K b ) mice infected with lymphocytic choriomeningitis virus (LCMV) or vaccinia virus generate cytotoxic T cells capable of specifically lysing virus-infected macrophage target cells fromH-2K b mutant mice M505 (H-2K bd ), and vice versa. Similarly, virus-immune B10.A(4R) (H-2K k ) T cells specifically lyse infected targets from M523 (H-2K ka ), and vice versa. In contrast, virus-specific cytotoxic T cells from neither M504 (H-2D da ) and B10.A(5R) (H-2D d ) nor M506 (H-2K fa ) and B10.M(11R) (H-2K f ) mutually crossreact at the cytotoxic effector-cell level. As far as tested, the crossreactivity patterns between wild-type and mutantK orD specificities are identical for LCMV- and vaccinia virus-immune spleen cells. Although this finding is no proof for either the altered self nor the dual recognition concept of T-cell recognition, it may be compatible with the latter model.  相似文献   

15.
A series of congenic mice on the BALB/c genetic background have been employed to localize a teratocarcinoma transplantation rejection locus, Gt-1, to the K side of the H-2 locus on chromosome 17. Previous studies have placed the Gt-1 sv allele about 8 centimorgans away from the H-2 b or H-2 bv1 locus. Teratocarcinomas derived from 129/sv mice, Gt-1 sv (H-2K bv1/H-2D bv1), are rejected by BALB/c (H-2K d/H-2Dd) and BALB-G mice (H-2K d/H2D-b, but form tumors in BALB-B (H-2K b/H2D b) and BALB/5R5 mice (H-2K b/H2D d). In the reciprocal tumor-rejection test, a BALB/c teratocarcinoma was rejected by immunized BALB·B mice, but formed tumors in the immunized isogenic BALB/c mouse. These studies demonstrate the reciprocal expression of two Gt-1 alleles, one Gt-1 c, in BALB/c mice, and the other, Gt-1 sv, in the congenic BALB·B mice. Shedlovsky and co-workers have placed the Gt-1 locus in a similar location on the K side of the H-2 locus on chromosome 17.  相似文献   

16.
Rejection of tailskin grafts exchanged between two male hybrids of the cross B10.M × B10.RIII(71NS) revealed a mutation in theH-2 f haplotype from the B10.M congenic line. Complementation studies with skin grafting and cell-mediated lympholysis showed the mutant, namedH-2 fb , to be different from anotherH-2 f mutant,H-2 fa , and further, that the HH-2 fb mutation occurred in theD end of theH-2 complex. Reciprocal skin grafts exchanged between mutant and normal mice were rejected. Hemagglutinating antibody reactive with B10.M cells was raised in the mutant mice. Mutant spleen cells responded weakly, but significantly, to wild-type cells in a mixed lymphocyte culture and in a graftversus-host assay, but no response was seen in the opposite direction. However, cytotoxic effector cells were generated against target cells in both directions in a cell-mediated lympholysis assay.  相似文献   

17.
Genes outside of the mouse major histocompatibility complex (H-2) were found to be capable of specifically reversing the previously described nonresponsiveness to hen egg-white lysozyme (HEL) owing to H-2 b immune response (Ir) genes. C3H.SW, BALB.B, and C57L, all of the H-2 b haplotype, showed responsiveness to HEL, but not to human lysozyme (H UL). Mapping of the reversing gene(s) was attempted by testing H-2 b recombinant inbred (RI) strains of mice carrying C3H, BALB, and C57L non-H-2 b genes. Analysis of the strain distribution pattern of responsiveness with both CXB and BXH RI strains was consistent with the location of the responsible site within the H-3 region on chromosome 2. The anti-HEL proliferative responsiveness in two H-3 congenic strains of mice, B10.C(28NX) SN and B10.C-H-3 cH-3 a , that have BALB/c genes within the H-3 region confirmed the mapping, as well as localized the reversing gene(s) near the Ir-2 gene. The data are discussed with regard to the site of expression of the reversing gene(s) and its mechanism of action.Abbreviations used in this paper MHC major histocompatibility complex - HEL hen egg-white lysozyme - Ir immune response gene - HUL human lysozyme - SDP strain distribution pattern - PFC plaque-forming cells; 2 m, 2-microglobulin - CFA complete Freund's adjuvant - PT-LN parathymic lymph nodes - RI recombinant inbred mice  相似文献   

18.
A major genetic determinant of natural resistance to bone marrow allografts, designated asHh-3, was mapped to theH-2K region. This gene may code for or regulate the expression of cell surface structures selectively expressed on donor hemopoietic cells and recognized by naturally occurring cytotoxic effectors. Resistance was observed as failure of donor cell growth in the spleen of irradiated 129-strain (H-2 bc ) recipients of H-2k bone marrow cells. The mapping was accomplished by substituting donor cells bearingk alleles throughout theH-2 complex with cells of recombinant mouse lines bearingk alleles at definedH-2 regions. The host antigraft reaction underlying resistance was abrogated by pretreating 129-strain mice with either rabbit antimouse lymphocyte serum or the antimacrophage agent silica. Grafting of H-2Kk cells into mice ancestrally unrelated to 129 but sharing theH-2 bc or the similarH-2 b haplotype, and intoH-2 b/k ,H-2 k/bc , andH-2 k/d F1 hybrids revealed that resistance was unique to 129 mice, since mice of the other strains, including F1 hybrids, were susceptible to the grafts. Thus,Hh-3 incompatibility was a necessary but insufficient condition for the manifestation of allogeneic resistance; other genetic factors not associated withH-2 conferred responder status to 129-strain mice and nonresponder status to D1.LP, B10.129(6M), B10, B6, and possibly to F1 hybrid mice. The possible relationships between allogeneic resistance to H-2k marrow grafts, hybrid resistance to H-2k lymphomas, and F1 hybrid antiparental H-2k cytotoxicity induced in vitro are discussed.  相似文献   

19.

Background

Infection with Leishmania results in a broad spectrum of pathologies where L. infantum and L. donovani cause fatal visceral leishmaniasis and L. major causes destructive cutaneous lesions. The identification and characterization of Leishmania virulence genes may define the genetic basis for these different pathologies.

Methods and Findings

Comparison of the recently completed L. major and L. infantum genomes revealed a relatively small number of genes that are absent or present as pseudogenes in L. major and potentially encode proteins in L. infantum. To investigate the potential role of genetic differences between species in visceral infection, seven genes initially classified as absent in L. major but present in L. infantum were cloned from the closely related L. donovani genome and introduced into L. major. The transgenic L. major expressing the L. donovani genes were then introduced into BALB/c mice to select for parasites with increased virulence in the spleen to determine whether any of the L. donovani genes increased visceral infection levels. During the course of these experiments, one of the selected genes (LinJ32_V3.1040 (Li1040)) was reclassified as also present in the L. major genome. Interestingly, only the Li1040 gene significantly increased visceral infection in the L. major transfectants. The Li1040 gene encodes a protein containing a putative component of an endosomal protein sorting complex involved with protein transport.

Conclusions

These observations demonstrate that the levels of expression and sequence variations in genes ubiquitously shared between Leishmania species have the potential to significantly influence virulence and tissue tropism.  相似文献   

20.
C57BL/10 (B10) strains congenic at the mouse major histocompatibility locus (H-2) were injected with a modified ecotropic SL3-3 murine leukemia virus (MuLV) to determine the effect of the H-2 genes on the envelope gene structure of recombinant MuLVs. All tested strains rapidly developed T-cell lymphomas, and recombinant proviruses were detected in the tumor DNAs by Southern blot. The B10.D2 (H-2d), B10.Br (H-2k), B10.Q (H-2q), and B10.RIII (H-2r) strains exhibited a TI phenotype in which almost all tumors contained type I recombinants. These recombinants characteristically acquire envelope gene sequences from the endogenous polytropic viruses but retain the 5′ p15E (TM) gene sequences from the ecotropic virus. The parental B10 (H-2b) strain, however, had a novel phenotype that was designated NS for nonselective. Only 30% of the B10 tumors had detectable type I recombinants, whereas a proportion of the others appeared to contain type II recombinants that lacked the type I-specific ecotropic p15E gene sequences. Studies of other B10 congenic strains with hybrid H-2 loci and selected F1 animals revealed that the NS phenotype was regulated by a dominant gene(s) that mapped to the A region of H-2b. These results demonstrate that a host gene within the major histocompatibility complex can influence the genetic evolution of pathogenic retroviruses in vivo.  相似文献   

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