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Chapter 8 : Mouse Model of Tuberculosis

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Abstract:

This chapter describes how the mouse model has evolved over the past century from the simple but beautiful experiments of Koch to present-day models based on sophisticated gene targeting. In the process, the authors describe the course of the infection in the mouse after inoculation by various routes and their growing picture of how the host immune response is mobilized against the infecting organism. They also describe various mouse models that involve immunodeficiency; these may prove useful not only in the further dissection of the cellular immune response but also in applied strategies of chemotherapy and immunotherapy. The growth of in mice has been extremely well characterized, with the organism giving rise to highly characteristic distribution patterns in target organs after inoculation. A week or so after inoculation of mice with a sublethal intravenous dose of , a population of CD4 cells that are capable of adoptively transferring protective immunity emerges in the spleen. In the mouse model of tuberculosis, enriched populations of immune CD8 T cells transferred some degree of resistance, albeit rather weakly, and in vivo depletion of CD8 T cells by intravenous administration of monoclonal antibody was shown to diminish resistance to some extent. The cytokine response to probably begins almost immediately after infection of host macrophages, as these cells begin to transcribe message from a number of early response genes.

Citation: Orme I, Collins F. 1994. Mouse Model of Tuberculosis, p 113-134. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch8
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Figure 1

Course of infection in mice given 10 viable bacilli intravenously. The infection grows quickly in the spleen over the first 10 to 14 days, triggering the emergence of protective immunity. The liver is more resistant to the infection; it does not permit rapid growth initially and continues to slowly clear the infection (in contrast, the disease remains chronic in both the spleen and lungs). Note the characteristic distribution of the inoculum: about 90% is taken up in the liver, about 10% is taken up in the spleen, and about 1% is taken up in the lungs (uptake that exceeds 5% in the lungs is a sure sign that the inoculum is clumped).

Citation: Orme I, Collins F. 1994. Mouse Model of Tuberculosis, p 113-134. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch8
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Figure 2

Course of infection in mice given approximately 20 viable bacilli by aerosol. The infection progresses in the lungs over the first 20 to 30 days before being contained by the emerging immune response. At around this time, significant numbers of bacteria can be detected in the spleen (and liver); these bacilli probably arose from a few organisms that eroded early from the lungs into the bloodstream (hematogenous spread).

Citation: Orme I, Collins F. 1994. Mouse Model of Tuberculosis, p 113-134. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch8
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Figure 3

Intravenous injection of mice. Following warming under a heat lamp for a few minutes to induce vasodilation, the mouse is gently positioned in this simple restraining device. The bacterial inoculum is injected into a lateral tail vein with a 26-gauge needle.

Citation: Orme I, Collins F. 1994. Mouse Model of Tuberculosis, p 113-134. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch8
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Figure 4

Aerosol infection of mice. The venturi unit at the front of the generator creates an aerosol that is pumped into a central sealed chamber containing the animals. The operator is wearing a Racal AC3 helmet for added protection (this device includes a small HEPA filter, worn on a waist belt, that blows sterilized air up and through the helmet). The aerosol generator suite is negative with respect to atmospheric pressure, and all air leaving the room is HEPA filtered.

Citation: Orme I, Collins F. 1994. Mouse Model of Tuberculosis, p 113-134. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch8
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Figure 5

The potential fate of immune CD4 T cells. Sensitized protective T cells release cytokines (IFN-γ, migration inhibition factor, TNF, etc.) that activate the parasitized macrophage to contain the intracellular infection. In addition, these materials recruit monocytes into the lesion to initiate granuloma formation. We currently speculate that memory T cells arise from the same lineage but express a longer-lived phenotype as a result of emigration from the infectious site. Of course, it is equally possible that memory cells arise from a completely separate lineage. This issue remains to be resolved.

Citation: Orme I, Collins F. 1994. Mouse Model of Tuberculosis, p 113-134. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch8
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Figure 6

Possible role of CD8 T cells. These cells become sensitized by presentation of mycobacterial antigens in association with class I MHC molecules. As the infection progresses in the lungs, these cells may play a vital role in releasing bacteria that have eroded into local tissues (such as the lung endothelial cells). This speculative model is based on the work of Flynn and her colleagues ( ).

Citation: Orme I, Collins F. 1994. Mouse Model of Tuberculosis, p 113-134. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch8
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Figure 7

Mouse macrophage containing several intact bacterial particles. The apparent paradox whereby the bacteria are healthy and intact yet strong immunity can be generated can be explained by the hypothesis that the macrophage is presenting secreted/export proteins of the bacillus rather than constitutive proteins. The ability of the bacilli to survive under such conditions is also a matter of debate; recent data (Sturgill-Koszycki et al., submitted) now suggests that the mycobacteria have an unknown property that prevents the fusion of proton-ATPase complex-containing vesicles to the bacterial phagosome, thus preventing acidification of this compartment. (Photo courtesy of David Russell.)

Citation: Orme I, Collins F. 1994. Mouse Model of Tuberculosis, p 113-134. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch8
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Figure 8

Culture filtrate proteins of Erdman. This protein pool contains multiple targets of IFN-γ-secreting protective CD4 T cells harvested from infected mice. Note the differing protein content depending on whether the filtrate is harvested at mid-log phase (M) or several days earlier (short-term filtrate; S). Numbers at right are molecular sizes in kilodaltons. (Courtesy of John Belisle.)

Citation: Orme I, Collins F. 1994. Mouse Model of Tuberculosis, p 113-134. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch8
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Figure 9

IFN-γ and IL-4 responses by CD4 T cells to antigens. In this experiment, CD4 T cells were harvested from infected mice at the times indicated and overlaid in vitro on macrophages presenting filtrate protein antigens. Three days later, the supernatants were harvested and tested for IFN-γ or IL-4 by enzyme-linked immunosorbent assay. These data indicate that the CD4 response consists of an early Th1-like response associated with containment and initial clearance of the infection followed after about a month by the emergence of a Th2-like response that presumably drives the humoral response to dead bacteria. In addition, while the Th1 response seems to be preferentially directed against the secreted/export proteins, the Th2 response is broader, including strong recognition of the hsp60 antigen (see text).

Citation: Orme I, Collins F. 1994. Mouse Model of Tuberculosis, p 113-134. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch8
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Figure 10

CD4 T-cell depletion of thymectomized mice by in vivo administration of monoclonal antibody. One injection of 250 μg of highly purified anti-CD4 (clone GK1.5) almost completely eliminates the host CD4 T-cell population. The data are expressed as contour maps following analysis of CD3CD4 cells in the spleen by flow cytometry. FITC, fluorescein isothiocyanate.

Citation: Orme I, Collins F. 1994. Mouse Model of Tuberculosis, p 113-134. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch8
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References

/content/book/10.1128/9781555818357.chap8
1. Abou-Zeid, C.,, I. Smith,, J. M. Grange,, T. L. Ratlin,, J. Steele,, and G. A. W. Rook. 1988. The secreted antigens of Mycobacterium tuberculosis and their relationship to those recognized by the available antibodies. J. Gen. Microbiol. 134: 531 538.
2. Andersen, P.,, D. Askgaard,, L. Ljungqvist,, J. Bennedsen,, and I. Heron. 1991. Proteins released from Mycobacterium tuberculosis during growth. Infect. Immun. 59: 1905 1910.
3. Andersen, P.,, and I. Heron. 1993. Specificity of a protective memory immune response against Mycobacterium tuberculosis. Infect. Immun. 61: 844 851.
4. Augustin, A.,, R. T. Kubo,, and G. Sim. 1989. Resident pulmonary lymphocytes expressing the γδ T cell receptor. Nature (London) 340: 239 241.
5. Barnes, P. F.,, D. Chatterjee,, J. S. Abrams,, S. H. Lu,, E. Wang,, M. Yamamura,, P. J. Brennan,, and R. L. Modlin. 1992. Cytokine production induced by Mycobacterium tuberculosis lipoarabinomannan—relationship to chemical structure. J. Immunol. 149: 541 547.
6. Born, W.,, L. Hall,, A. Dallas,, J. Boymel,, T. Shinnick,, D. Young,, P. Brennan,, and R. O'Brien. 1990a. Recognition of a peptide antigen by heat shock reactive γδ T lymphocytes. Science 249: 67 69.
7. Born, W.,, M. P. Happ,, A. Dallas,, C. Reardon,, R. Kubo,, T. Shinnick,, P. Brennan,, and R. O'Brien. 1990b. Recognition of heat shock proteins and γδ cell function. Immunol. Today 11: 40 43.
8. Born, W. K.,, R. L. O'Brien,, and R. L. Modlin. 1991. Antigen-specificity of γδ T lymphocytes. FASEB J. 5: 2699 2705.
9. Bosma, G. C.,, R. P. Custer,, and M. J. Bosnia. 1983. A severe combined immunodeficiency mutation in the mouse. Nature (London) 301: 527 530.
10. Brett, S.,, J. M. Orrell,, J. Swanson Beck,, and J. Ivanyi. 1992. Influence of H-2 genes on growth of Mycobacterium tuberculosis in the lungs of chronically infected mice. Immunology 76: 129 132.
11. Brown, I. N., 1983. Animal models and immune mechanisms in mycobacterial infection, p. 173 234. In C. Ratledge, and J. Stanford (ed.), Biology of Mycobacteria, vol. 2. Academic Press Ltd., London.
12. Browning, C. H.,, and R. Gulbransen. 1926. Studies on experimental tuberculosis in mice. The susceptibility of mice to inoculation with tubercle bacilli. J. Hyg. 25: 323 332.
13. Chan, J.,, X. Fan,, S. W. Hunter,, P. J. Brennan,, and B. R. Bloom. 1991. Lipoarabinomannan: a possible virulence factor involved in persistence of Mycobacterium tuberculosis within macrophages. Infect. Immun. 59: 1755 1761.
14. Chase, M. W. 1945. The cellular transfer of cutaneous hypersensitivity to tuberculin. Proc. Soc. Exp. Biol. Med. 59: 134 146.
15. Chatterjee, D.,, A. D. Roberts,, K. Lowell,, P. J. Brennan,, and I. M. Orme. 1992. Structural basis of capacity of lipoarabinomannan to induce secretion of tumor necrosis factor. Infect. Immun. 60: 1249 1253.
16. Collins, F. M. 1979. Cellular antimicrobial immunity. Crit. Rev. Microbiol. 7: 27 91.
17. Collins, F. M. 1982. Immunology of tuberculosis. Am. Rev. Respir. Dis. 125: S42 S49.
18. Collins, F. M., 1984. Protection against mycobacterial disease by means of live vaccines tested in experimental animals, p. 787 839. In G. P. Kubica, and L. G. Wayne (ed.), The Mycobacteria: a Sourcebook. Marcel Dekker, Inc., New York.
19. Collins, F. M.,, and G. B. Mackaness. 1970. The relationship of delayed hypersensitivity to acquired antituberculous immunity. I. Tuberculin sensitivity and resistance to reinfection in BCG-vaccinated mice. Cell. Immunol. 1: 253 265.
20. Collins, F. M.,, and V. Montalbine. 1975. Relative immunogenicity of streptomycin-resistant and -sensitive strains of BCG. II. Effect of route of inoculation on growth and immunogenicity. Am. Rev. Respir. Dis. 111: 43 51.
21. Collins, F. M.,, and V. Montalbine. 1976. Distribution of in vivo grown mycobacteria in the organs of intravenously infected mice. Am. Rev. Respir. Dis. 113: 281 286.
22. Collins, F. M.,, and M. M. Smith. 1969. A comparative study of the virulence of Mycobacterium tuberculosis measured in mice and guinea pigs. Am. Rev. Respir. Dis. 100: 631 639.
23. Collins, F. M.,, L. G. Wayne,, and V. Montalbine. 1974. The effect of cultural conditions on the distribution of Mycobacterium tuberculosis in the spleens and lungs of specific pathogen-free mice. Am. Rev. Respir. Dis. 110: 147 156.
24. Cooper, A. M.,, D. K. Dalton,, T. A. Stewart,, J. P. Griffin,, D. G. Russell,, and I. M. Orme. 1993. Disseminated tuberculosis in interferon-? gene-disrupted mice. J. Exp. Med. 178: 2243 2247.
25. Cox, J. H.,, B. C. Knight,, and J. Ivanyi. 1989. Mechanisms of recrudescence of Mycobacterium bovis BCG infection in mice. Infect. Immun. 57: 1719 1724.
26. Dalton, D. K.,, S. Pitts-Meek,, S. Keshaw,, I. S. Figari,, A. Bradley,, and T. A. Stewart. 1993. Multiple defects of immune cell function in mice with disrupted interferon ? genes. Science 259: 1739 1742.
27. Davies, P. D. 0. 1985. A possible link between vitamin D deficiency and impaired host defense to Mycobacterium tuberculosis. Tubercle 66: 301 306.
28. De Bruyn, J.,, R. Bosmans,, J. Nyabenda,, and J. P. Van Vooren. 1989. Effect of zinc deficiency on the appearance of two immunodominant protein antigens (32 kDa and 65 kDa) in culture filtrates of mycobacteria. J. Gen. Microbiol. 135: 79 84.
29. DeLibero, G.,, I. Flesch,, and S. H. E. Kaufmann. 1988. Mycobacteria-reactive Lyt-2+ T cell lines. Eur. J. Immunol. 18: 59 66.
30. Dubos, R. J. 1945. Rapid and submerged growth of mycobacteria in liquid media. Proc. Soc. Exp. Biol. Med. 58: 361 362.
31. Dubos, R. J.,, and C. H. Pierce. 1956. Differential characteristics in vitro and in vivo of several substrains of BCG. IV. Immunizing effectiveness. Am. Rev. Tuberc. 74: 699 717.
32. Fenner, F. 1951. The enumeration of viable tubercle bacilli by surface plate counts. Am. Rev. Tuberc. 64: 353 380.
33. Fenner, F.,, S. P. Martin,, and C. H. Pierce. 1949. The enumeration of viable tubercle bacilli in cultures and infected tissues. Ann. N.Y. Acad. Sci. 52: 751 764.
34. Flynn, J. L.,, J. Chan,, K. J. Triebold,, D. K. Dalton,, T. A. Stewart,, and B. R. Bloom. 1993. An essential role for IFN-? in resistance to M. tuberculosis infection. J. Exp. Med. 178: 2248 2253.
35. Flynn, J. L.,, M. M. Goldstein,, K. J. Triebold,, B. Roller,, and B. R. Bloom. 1992. Major histocompatibility complex class I-restricted T cells are required for resistance to Mycobacterium tuberculosis infection. Proc. Natl. Acad. Sci. USA 89: 12013 12017.
36. Follows, G. A.,, M. E. Munk,, A. J. Gatrill,, P. Conradt,, and S. H. E. Kaufmann. 1992. Gamma-interferon and interleukin-2, but not interleukin-4, are detectable in γδ T-cell cultures after activation with bacteria. Infect. Immun. 60: 1229 1231.
37. Fu, X.-Y.,, R. Cranfill,, M. Vollmer,, R. VanDerZee,, R. L. O'Brien,, and W. Born. 1993. In vivo response of murine γδ T cells to a heat shock protein-derived peptide. Proc. Natl. Acad. Sci. USA 90: 322 326.
38. Furney, S. K.,, A. D. Roberts,, and I. M. Orme. 1990. Effect of rifabutin on disseminated Mycobacterium avium infections in thymectomized, CD4 T-cell-deficient mice. Antimicrob. Agents Chemother. 34: 1629 1632.
39. Gray, D. F.,, and C. Cheers. 1967. The steady state in cellular immunity. Aust. J. Exp. Biol. Med. Sci. 45: 407 416.
40. Griffin, J. P.,, M. H. Fox,, L. W. Armstrong,, and I. M. Orme. Phenotypic identification of a IFN-γ-secret-ing CD4+ T cell subset in the spleens of mice infected with mycobacteria that appears concomitantly with the expression of protective immunity. Submitted for publication.
41. Griffin, J. P.,, K. V. Harshan,, W. K. Born,, and I. M. Orme. 1991. Kinetics of accumulation of γδ receptor-bearing T lymphocytes in mice infected with live mycobacteria. Infect. Immun. 59: 4263 4265.
42. Gros, P.,, E. Skamene,, and A. Forget. 1981. Genetic control of natural resistance to Mycobacterium bo-vis (BCG) in mice. J. Immunol. 127: 2417 2421.
43. Gunn, F. D.,, W. J. Nungester,, and E. T. Hougen. 1933. Susceptibility of the white mouse to tuberculosis. Proc. Soc. Exp. Biol. Med. 31: 527 529.
44. Haas, W.,, P. Pereira,, and S. Tonegawa. 1993. Gamma/ delta cells. Annu. Rev. Immunol. 11: 637 685.
45. Hartley, J. W.,, T. N. Fredrickson,, R. A. Yetter,, M. Makino,, and H. C. Morse. 1989. Retrovirus-induced murine acquired immunodeficiency syndrome: natural history of infection and differing susceptibility of inbred mouse strains. J. Virol. 63: 1223 1231.
46. Huygen, K.,, D. Abramowicz,, P. Vandenbussche,, F. Jacobs,, J. De Bruyn,, A. Kentos,, A. Drowart,, J. P. Van Vooren,, and M. Goldman. 1992. Spleen cell cytokine secretion in Mycobacterium bovis BCG-infected mice. Infect. Immun. 60: 2880 2886.
47. Huygen, K.,, A. Drowart,, M. Harboe,, R. ten Berg,, J. Cogniaux,, and J.-P. Van Vooren. 1993. Influence of genes from the major histocompatibility complex on the antibody repertoire against culture filtrate antigens in mice infected with live Mycobacterium bovis BCG. Infect. Immun. 61: 2687 2693.
48. Inoue, T.,, Y. Yoshikai,, G. Matsuzaki,, and K. Nomoto. 1991. Early appearing 78-bearing T cells during infection with Calmette Guerin bacillus. J. Immunol. 146: 2754 2762.
49. Janis, E. M.,, S. H. E. Kaufmann,, R. H. Schwartz,, and D. M. Pardoll. 1989. Activation of γδ T cells in the primary immune response to Mycobacterium tuberculosis. Science 244: 2754 2762.
50. Janssen, O.,, S. Wesselborg,, B. Heckl-Ostreicher,, K. Pechhold,, A. Bender,, A. Schondelmaier,, G. Molden-hauer,, and D. Kabelitz. 1991. T cell receptor/CD3 signalling induces death by apoptosis in human T cell receptor γδ + T cells. J. Immunol. 146: 35 39.
51. Kaufmann, S. H. E. 1990. Heat shock proteins and the immune response. Immunol. Today 11: 129 136.
52. Kaufmann, S. H. E.,, and H. Hahn. 1981. The role of cell-mediated immunity in bacterial infections. Rev. Infect. Dis. 3: 1221 1250.
53. Kaufmann, S. H. E.,, B. Schoel,, A. Wand-Wurttenberger,, U. Steinhoff,, M. E. Munk,, and T. Koga. 1990. T-cells, stress proteins, and pathogenesis of mycobacterial infections. Curr. Top. Microbiol. Immunol. 155: 125 141.
54. Khansari, D. N.,, A. J. Murgo,, and R. E. Faith. 1990. Effects of stress on the immune system. Immunol. Today 11: 170 175.
55. Kim, T. H.,, and G. P. Kubica. 1972. Long-term preservation and storage of mycobacteria. Appl. Microbiol. 24: 311 317.
56. Kim, T. H.,, and G. P. Kubica. 1973. Preservation of mycobacteria: 100% viability of suspensions stored at -70°C . Appl. Microbiol. 25: 956 960.
57. Kindler, V.,, A. P. Sappino,, G. E. Grau,, P. F. Piguet,, and P. Vassilli. 1989. The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell 56: 731 740.
58. Kumararatne, D. S.,, A. S. Pithie,, P. Drysdale,, J. S. H. Gaston,, R. Kiessling,, P. B. lies,, C. J. Ellis,, J. Innes,, and R. Wise. 1990. Specific lysis of mycobacterial antigen-bearing macrophages by class II MHC-restricted polyclonal T cell lines in healthy donors or patients with tuberculosis. Clin. Exp. Immunol. 80: 314 323.
59. Lambert, H. P. 1960. The influence of chemoprophylaxis on immunity in experimental tuberculosis. Am. Rev. Respir. Dis. 82: 619 626.
60. Lefford, M. J. 1971. The effect of inoculum size on the immune response to BCG infection in mice. Immunology 21: 369 381.
61. Lefford, M. J. 1975. Transfer of adoptive immunity to tuberculosis in mice. Infect. Immun. 11: 1174 1181.
62. Lefford, M. J., 1984. Diseases in mice and rats, p. 947 977. In G. P. Kubica, and L. G. Wayne (ed.), The Mycobacteria: a Sourcebook. Marcel Dekker, Inc., New York.
63. Lui, Y.,, and C. A. Janeway. 1990. Interferon y plays a critical role in induced cell death of effector T cells: a possible third mechanism of self-tolerance. J. Exp. Med. 172: 1735 1739.
64. Mackaness, G. B. 1968. The immunology of anti-tuberculous immunity. Am. Rev. Respir. Dis. 97: 337 344.
65. McDonough, K. A.,, Y. Kress,, and B. R. Bloom. 1993. Pathogenesis of tuberculosis: interaction of Mycobacterium tuberculosis with macrophages. Infect. Immun. 61: 2763 2773.
66. McKee, C. M.,, G. Rake,, R. Donovick,, and W. P. Jambor. 1949. The use of the mouse in a standardized test for antituberculous activity of compounds of natural or synthetic origin. Am. Rev. Tuberc. 60: 90 108.
67. McMurray, D. N.,, C. L. Mintzer,, C. L. Tetzlaff,, and M. A. Carlomagno. 1986. The influence of dietary protein on the protective effect of BCG in guinea pigs. Tubercle 67: 31 39.
68. Moreno, C.,, J. Taverne,, A. Mehlert,, C. A. W. Bate,, R. J. Brealey,, A. Meager,, G. A. W. Rook,, and J. H. L. Playfair. 1989. Lipoarabinomannan from Mycobacterium tuberculosis induces the production of tumor necrosis factor from human and murine macrophages. Clin. Exp. Immunol. 76: 240 245.
69. Mosier, D. E.,, R. A. Yetter,, and H. C. Morse. 1985. Retroviral induction of acute lymphoproliferative disease and profound immunosuppression in adult C57BL mice. J. Exp. Med. 161: 766 784.
70. Mosmann, T. R.,, and R. E. Coffman. 1989. Heterogeneity of cytokine secretion patterns and functions of helper T cells. Adv. Immunol. 46: 111 147.
71. Muller, I.,, S. Cobbold,, H. Waldmann,, and S. H. E. Kaufmann. 1987. Impaired resistance to Mycobacterium tuberculosis infection after selective in vivo depletion of L3T4 + and Lyt-2 + T cells. Infect. Immun. 55: 2037 2041.
72. Munk, M. E.,, A. J. Gatrill,, and S. H. E. Kaufmann. 1990. Target cell lysis and IL-2 secretion by γδ T lymphocytes after activation with bacteria. J. Immunol. 145: 2434 2439.
73. North, R. J. 1973. Importance of thymus-derived lymphocytes in cell-mediated immunity to infection. Cell. Immunol. 7: 166 176.
74. North, R. J.,, G. B. Mackaness,, and R. W. Elliott. 1972. The histogenesis of immunologically committed lymphocytes. Cell. Immunol. 3: 680 694.
75. O'Brien, R.,, M. P. Happ,, A. Dallas,, E. Palmer,, R. Kubo,, and W. K. Born. 1989. Stimulation of a major subset of lymphocytes expressing T cell receptor γδ by an antigen derived from Mycobacterium tuberculosis. Cell 57: 667 674.
76. O'Brien, R. L.,, Y. Fu,, R. Cranfill,, A. Dallas,, C. Ellis,, C. Reardon,, J. Lang,, S. R. Carding,, R. Kubo,, and W. Born. 1992. Heat shock protein Hsp60-reactive γδ cells: a large, diversified Tlymphocyte subset with highly focused specificity. Proc. Natl. Acad. Sci. USA 89: 4348 4352.
77. Ohmen, J. D.,, P. F. Barnes,, K. Uyemura,, S. Z. Lu,, C. L. Grisso,, and R. L. Modlin. 1991. The T-cell receptors of human ?? T-cells reactive to Mycobacterium tuberculosis are encoded by specific-V genes but diverse V-J junctions. J. Immunol. 147: 3353 3359.
78. Ordway, D. J.,, and I. M. Orme. 1993. Unpublished observations.
79. Orme, I. M. 1987a. The kinetics of emergence and loss of mediator T lymphocytes acquired in response to infection with Mycobacterium tuberculosis. J. Immunol. 138: 293 298.
80. Orme, I. M. 1987b. Aging and immunity to tuberculosis: increased susceptibility of old mice reflects a decreased capacity to generate mediator T lymphocytes. J. Immunol. 138: 4414 4418.
81. Orme, I. M. 1988a. Characteristics and specificity of acquired immunologic memory to Mycobacterium tuberculosis infection. J. Immunol. 140: 3589 3593.
82. Orme, I. M. 1988b. Evidence for a biphasic memory T cell response to high dose BCG vaccination in mice. Tubercle 69: 125 131.
83. Orme, I. M. 1988c. Induction of nonspecific acquired resistance and delayed-type hypersensitivity, but not specific acquired resistance, in mice inoculated with killed mycobacterial vaccines. Infect. Immun. 56: 3310 3312.
84. Orme, I. M. 1993a. The role of CD8+ T cells in immunity to tuberculosis infection. Trends Microbiol. 1: 77 78.
85. Orme, I. M. 1993b. Immunity to mycobacteria. Curr. Opin. Immunol. 5: 497 502.
86. Orme, I. M.,, P. Andersen,, and W. H. Boom. 1993a. T cell response to Mycobacterium tuberculosis. J. Infect. Dis. 167: 1481 1497.
87. Orme, I. M.,, and F. M. Collins. 1984a. Demonstration of acquired resistance in Beg r inbred mouse strains infected with a low dose of BCG Montreal. Clin. Exp. Immunol. 56: 81 88.
88. Orme, I. M.,, and F. M. Collins. 1984b. Passive transfer of tuberculin sensitivity from anergic mice. Infect. Immun. 46: 850 853.
89. Orme, I. M.,, and F. M. Collins. 1986. Crossprotection against nontuberculous mycobacterial infections by Mycobacterium tuberculosis memory immune T lymphocytes. J. Exp. Med. 163: 203 208.
90. Orme, I. M.,, S. K. Furney,, and A. D. Roberts. 1992a. Dissemination of enteric Mycobacterium avium infections in mice rendered immunodeficient by thymectomy and CD4 depletion or by prior infection with murine AIDS retroviruses. Infect. Immun. 60: 4747 4753.
91. Orme, I. M.,, J. P. Griffin,, A. D. Roberts,, and D. N. Ernst. 1993b. Evidence for a defective accumulation of protective T cells in old mice infected with Mycobacterium tuberculosis. Cell. Immunol. 147: 222 229.
92. Orme, I. M.,, E. S. Miller,, A. D. Roberts,, S. K. Furney,, J. P. Griffin,, K. M. Dobos,, D. Chi,, B. Rivoire,, and P. J. Brennan. 1992b. T lymphocytes mediating protection and cellular cytolysis during the course of Mycobacterium tuberculosis infection . J. Immunol. 148: 189 196.
93. Orme, I. M.,, A. D. Roberts,, J. P. Griffin,, and J. S. Abrams. 1993c. Cytokine secretion by CD4 T lymphocytes acquired in response to Mycobacterium tuberculosis infection. J. Immunol. 151: 518 525.
94. Orme, I. M.,, R. W. Stokes,, and F. M. Collins,. 1985. Only two out of fifteen BCG strains follow the Beg pattern, p. 285 290. In E. Skamene (ed.), Genetic Control of Host Resistance to Infection and Malignancy. Alan R. Liss, Inc., New York.
95. Panchamoorthy, G.,, J. McLean,, R. L. Modlin,, C. T. Morita,, S. Isikawa,, M. B. Brenner,, and H. Band. 1991. A predominance of the T-cell receptor Wyll V82 subset in human mycobacteria-responsive T-cells suggests germline gene encoded recognition. J. Immunol. 147: 3360 3369.
96. Pierce, C. H.,, R. J. Dubos,, and W. B. Schaefer. 1956. Differential characteristics in vitro and in vivo of substrains of BCG. III. Multiplication and survival in vivo. Am. Rev. Tuberc. 74: 683 688.
97. Raleigh, G. W.,, and G. P. Youmans. 1949. The use of mice in experimental chemotherapy of tuberculosis. J. Infect. Dis. 82: 197 204.
98. Roach, T. I. A.,, C. H. Barton,, D. Chatterjee,, and J. M. Blackwell. 1993. Macrophage activation: lipoarabinomannan from avirulent and virulent strains of Mycobacterium tuberculosis differentially induces the early genes c-fos, KC., JE, and tumor necrosis factor-α. J. Immunol. 150: 1886 1896.
99. Rook, G. A. W.,, J. Steele,, S. Barnass,, J. Mace,, and J. L. Stanford. 1986. Responsiveness to live M. tuberculosis, and common antigens, of sonicatestimulated T cell lines from normal donors. Clin. Exp. Immunol. 63: 105 110.
100. Russell, D. G.,, A. M. Cooper,, D. Chatterjee,, and I. M. Orme. 1993. Unpublished observation.
101. Shier, D. R.,, and M. W. Long. 1971. The relation between infecting dosage and mean survival in tuberculous guinea pigs. Am. Rev. Respir. Dis. 104: 206 214.
102. Sprent, J. 1993. Lifespans of naive, memory and effector lymphocytes. Curr. Opin. Immunol. 5: 433 438.
103. Sturgill-Koszycki, S.,, P. H. Schlesinger,, P. Chakraborty,, P. L. Haddix,, H. L. Collins,, S. Gluck,, A. K. Fok,, R. D. Allen,, J. Heuser,, and D. G. Russell. Mycobacteria resist acidification of their phagosomes by selectively blocking incorporation of the vesicular proton-ATPase. Science, in press.
104. Suter, E. 1961. Passive transfer of acquired resistance to infection with Mycobacterium tuberculosis by means of cells. Am. Rev. Respir. Dis. 83: 535 543.
105. Verbon, A.,, S. Kutfper,, H. M. Jansen,, P. Speelman,, and A. H. Kolk. 1990. Antigens in culture supernatant of Mycobacterium tuberculosis: epitopes defined by monoclonal and human antibodies. J. Gen. Microbiol. 136: 955 964.
106. Wiegeshaus, E. H.,, and D. W. Smith. 1968. Experimental models for study of immunity to tuberculosis. Ann. N.Y. Acad. Sci. 154: 194 199.
107. Youmans, G. P. 1949. The use of the mouse for the testing of chemotherapeutic agents against Mycobacterium tuberculosis. Ann. N.Y. Acad. Sci. 52: 662 670.
108. Youmans, G. P.,, and J. C. McCarter. 1945. Streptomycin in experimental tuberculosis. Am. Rev. Tuberc. 52: 432 439.
109. Young, D. B.,, S. H. E. Kaufmann,, P. W. M. Hermans,, and J. E. R. Thole. 1992. Mycobacterial protein antigens: a compilation. Mol. Microbiol. 6: 133 145.

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