Effect of Neonatal Thymectomy and Antithymocytic Serum on Susceptibility of Rats to Mycobacterium leprae Infection

Ah, Fieldsteel; Ah, McIntosh

doi:10.3181/00379727-138-35908

Cited by 13 publications

(4 citation statements)

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“…Other animals reported to be susceptible to infection with M. leprae are rats (6,11) and the nine-banded armadillo (13,14). Attempts to infect monkeys have been unsuccessful (3,12).…”

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confidence: 99%

Minimal Inhibitory Concentration of Dapsone for Mycobacterium leprae in Rats

Peters

Gr²,

Murray³

et al. 1975

Antimicrob Agents Chemother

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To define the minimal inhibitory concentration (MIC) of dapsone (DDS) for Mycobacterium leprae in rats, we determined the relationship between dietary and plasma levels of DDS in uninfected male and female Lewis rats. This knowledge was applied to the design of experiments using rats inoculated in the footpads with M. leprae. The MIC for DDS in male and female rats, respectively, was 1.5 to 4.0 ng and 1.8 to 3.0 ng of DDS/ml of plasma, even though the sexes exhibited markedly different concentrations of DDS when receiving the same dietary level of DDS. These values for the MIC of DDS for M. leprae in rats are nearly identical to the previously determined MIC of DDS for M. leprae in mice.The establishment of the mouse footpad infection with Mycobacterium leprae as a tool for leprosy research (27) opened up avenues of investigation that had been blocked since 1873. In that year, Hansen (3, 10) first reported that human leprosy was caused by M. leprae. Despite many attempts in the intervening years, no one has successfully cultivated this bacterium in vitro. All our present knowledge of the sensitivity or resistance of M. leprae to drugs has been derived from the application of the mouse footpad test system (25, 29).Of the several drugs known to be active against M. leprae infections, dapsone (4,4'-diaminodiphenyl sulfone, DDS) is the most thoroughly studied and the most widely used for the treatment of leprosy in man (28). It is extremely potent. The estimated minimal inhibitory concentration (MIC) against M. leprae in the mouse footpad test system ranges from 1 to 10 ng per ml of plasma (2,20). From chemotherapeutic studies in leprosy patients using very low doses of DDS (2) or its repository form, N,N'-diacetyl DDS (19,20,22,23), we can estimate that the MIC of DDS for M. leprae in man is c30 ng per ml of plasma Although the infection of immunologically normal mice with M. leprae has been a valuable tool, this infection does not provide a model of human lepromatous leprosy suitable for chemotherapeutic studies. Multiplication of M. leprae in the footpads of these mice is selflimiting, reaching a plateau of about 106 bacteria 4 to 6 months after infection with the usual inoculum of 5 x 103 bacteria (24, 27). Also, these rodents differ both qualitatively and quantitatively from man in the disposition of DDS (7, 15).Other animals reported to be susceptible to infection with M. leprae are rats (6, 11) and the nine-banded armadillo (13,14). Attempts to infect monkeys have been unsuccessful (3,12). Recent studies in neonatally thymectomized rats have suggested that M. leprae multiply to greater numbers in these animals than in intact mice (4, 5). In addition, other studies (16) have demonstrated that the disposition of DDS in rats is more like that in man than in mice. Thus, a rat footpad test system may provide certain advantages over that of mice for research.The current studies were undertaken to establish the relationship between dietary levels of DDS and plasma concentrations of the drug in normal male and female...

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“…Other animals reported to be susceptible to infection with M. leprae are rats (6,11) and the nine-banded armadillo (13,14). Attempts to infect monkeys have been unsuccessful (3,12).…”

mentioning

confidence: 99%

Minimal Inhibitory Concentration of Dapsone for Mycobacterium leprae in Rats

Peters

Gr²,

Murray³

et al. 1975

Antimicrob Agents Chemother

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“…The specific immunological defect induced by the i.v. injection of M. leprae does not permit the unrestricted growth of viable M. leprae that is seen in nonspecifically immunocompromised animals such as neonatally thymectomized or athymic rats (3,4). This overall growth restriction in this system may indicate the existence of a mechanism of resistance that is not dependent on the CMI functions that we measured or that may be a result of the innate resistance of rats to disseminated infection with M. leprae.…”

Section: Discussionmentioning

confidence: 81%

Induction of antigen-specific immunity and tolerance to Mycobacterium leprae in Lewis rats

Winters

Humphres

1990

Infect Immun

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Intradermal (i.d.) immunization of Lewis rats with autoclaved Mycobacterium leprae resulted in antigenspecific proliferation responses and interleukin-2 release from spleen and lymph node cells that were detectable as early as 21 days, persisted for at least 9 months, and were dependent on the dose of antigen administered. Immunized animals were also completely resistant to a footpad challenge with viable M. leprae. In contrast, intravenous (i.v.) administration of at least 108 irradiated M. leprae isolates induced a state of nonresponsiveness characterized by the absence of proliferation and interleukin-2 release by antigen-stimulated lymphoid cell cultures; however, in vitro responses to mitogenic stimulation and in vivo responses to keyhole limpet hemocyanin and Listeria monocytogenes were normal. Animals that received an i.v. injection of M. leprae remained nonresponsive to M. Ieprae antigens even after a subsequent i.d. immunization. This state of nonresponsiveness persisted for at least 6 months after induction. Results of footpad challenge experiments showed that the ability of animals rendered nonresponsive by an i.v. injection of M. leprae to control the growth of viable M. leprae in the footpad was not different from that of untreated rats. In addition, animals receiving an initial i.v. injection and a subsequent i.d. immunization with M. leprae were not protected from a viable * Corresponding author. t Deceased. 495on July 31, 2020 by guest http://iai.asm.org/ Downloaded from

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“…However, most significant was the observation that 52 of these footpads had counts ranging from 1 x 107 to 2.86 x 107, whereas the greatest number of M. leprae found in the footpads of intact mice at any period was only 1.65 x 106, and that was noted 4 months after inoculation. Possibly, had thymectomy been carried out in the immediate neonatal period, the intact and thymectomized groups would have shown a more striking difference, such as that seen in rats thymectomized in the immediate neonatal period (1). Nevertheless, mice thymectomized at 3 to 5 days of age appear to retain some degree of immunological incompetence, and thus they have an increased susceptibility to, footpad infection with M. leprae.…”

Section: Discussionmentioning

confidence: 99%

Effect of thymectomy and antilymphocyte serum on Mycobacterium leprae infection in mice

Fieldsteel¹,

Gartner²

1975

Infect Immun

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BALB/c mice thymectomized at 3 to 5 days of age were studied to determine if this procedure would result in enhanced susceptibility to infection with Mycobacterium leprae and, if so, whether or not administration of antilymphocyte serum would further increase this susceptibility. The plateau for growth in the footpads of intact mice occurred 4 months after inoculation, whereas in the thymectomized and thymectomized plus antilymphocyte serum-treated groups the plateau occurred between months 11 and 12 after inoculation. Thymectomy resulted in at least a 10-fold increase in the number of M. leprae found in the footpads. Antilymphocyte serum did not appear to further enhance the M. leprae infection in the thymectomized mice. Although growth of M. leprae in the testes of both intact and thymectomized mice was erratic, the number of organisms reached a higher ceiling in the thymectomized groups. M. leprae harvested from all groups was passaged into intact mice at various intervals after inoculation to test for viability. Viable M. leprae were found at all intervals tested including 22 months after infection in the intact mice, suggesting that a chronic infection occurred that probably lasted during the entire life of the animals.

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Effect of Neonatal Thymectomy and Antithymocytic Serum on Susceptibility of Rats to Mycobacterium leprae Infection

Cited by 13 publications

References 2 publications

Minimal Inhibitory Concentration of Dapsone for Mycobacterium leprae in Rats

Minimal Inhibitory Concentration of Dapsone for Mycobacterium leprae in Rats

Induction of antigen-specific immunity and tolerance to Mycobacterium leprae in Lewis rats

Effect of thymectomy and antilymphocyte serum on Mycobacterium leprae infection in mice

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