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Biomedical subjects

F M Collins

Publications and source records attributed to F M Collins.

At least 73 records · Page 4Linked to original sources
PubMed1984

Demonstration of acquired resistance in Bcgr inbred mouse strains infected with a low dose of BCG montreal.

The relationship between natural resistance to Mycobacterium bovis BCG, expressed by the Bcg gene, and the generation of acquired resistance to this infection in various selected inbred strains of mice was investigated. Consistent with previous findings, a low dose (approximately 10(4)) of BCG Montreal grew progressively in the spleens of inbred mouse strains previously designated susceptible to BCG (Bcgs), but grew poorly in resistant strains (Bcgr). In contrast, however, little difference was observed in the growth of the organism in the liver or lungs of these mice, whereas furthermore, all animals behaved as Bcgs when infected with the World Standard preparation of BCG, BCG Pasteur. Moreover, four strains tested (Bcgr; A/J, C3H/HeJ, and Bcgs; B10.A/J, BALB/c), all showed evidence of the generation of acquired resistance to a small inoculum of BCG Montreal, as demonstrated by their substantial protection against a subsequent intravenous challenge with virulent M. tuberculosis. These findings are interpreted as being inconsistent with the Bcg gene hypothesis and call into doubt the usage of the term Bcg as a gene designation.

Animals↗
PubMed1984

Immune responsiveness in mice heavily infected with Mycobacterium kansasii.

Growth of Mycobacterium kansasii TMC 1203 in B6D2 F1 hybrid mice was associated with increased splenic cellular proliferation, hyperplasia and the generation of non-specific antibacterial resistance. Both responses were dose dependent; the larger the inoculum, the more rapid and extensive the cellular response. However, such mice were still unable to reduce the mycobacterial load within the tissues, apparently because of their inherent resistance to inactivation by immunologically activated macrophages. On the other hand, mice infected with the non-persistent strain of M. kansasii 1214 exhibited only a transient increase in non-specific (anti-listeria) resistance which rapidly declined as the number of viable mycobacteria within the spleen fell below an arbitrary threshold level. Mice infected with either M. kansasii 1203 or 1214 could be immunized with sheep red blood cells (SRBCs), an unrelated T cell-dependent antigen. The humoral (PFC) response was not affected by the mycobacterial load within the spleen. However, the delayed footpad swelling reaction was severely depressed. The latter could be restored merely by increasing the size of the intravenous sensitizing inoculum 100-fold. The present study indicates that mice chronically infected with M. kansasii are not severely immunosuppressed (as had been inferred from earlier in vitro lymphoproliferation studies) but are fully capable of responding to appropriate in vivo stimuli.

Animals↗
PubMed1983

Protection against Mycobacterium tuberculosis infection by adoptive immunotherapy. Requirement for T cell-deficient recipients.

The results of this study demonstrate that spleen cells taken from mice at the height of the primary immune response to intravenous infection with Mycobacterium tuberculosis possess the capacity to transfer adoptive protection to M. tuberculosis-infected recipients, but only if these recipients are first rendered T cell-deficient, either by thymectomy and gamma irradiation, or by sublethal irradiation. A similar requirement was necessary to demonstrate the adoptive protection of the lungs after exposure to an acute aerosol-delivered M. tuberculosis infection. In both infectious models successful adoptive immunotherapy was shown to be mediated by T lymphocytes, which were acquired in the donor animals in response to the immunizing infection. It is proposed that the results of this study may serve as a basic model for the subsequent analysis of the nature of the T cell-mediated immune response to both systemic and aerogenic infections with M. tuberculosis.

Animals↗
PubMed1983

Fate of Pasteurella hemolytica in conventionally raised and germfree mice.

When Pasteurella hemolytica was introduced into conventionally raised ICR mice by a variety of routes (intraperitoneal, aerogenic, and oral), the inoculum was rapidly eliminated, and none of the mice died. Even when the inoculum was injected intraperitoneally into sublethally irradiated (600 rads) mice, the organisms were eliminated rapidly unless suspended in 10% hog gastric mucin. When germfree ICR mice were orally infected with P. hemolytica, the infection established itself in the intestinal tract and spread to the mesenteric lymph nodes but did not progress beyond this point. Despite the inability of P. hemolytica to establish itself systemically, the organism multiplied freely in mouse blood and a homogenate of normal mouse lung in vitro. Normal mouse peritoneal macrophages could phagocytose P. hemolytica in vitro, although not as efficiently as the control Listeria monocytogenes suspensions. The addition of hyperimmune bovine serum (opsonin) to the P. hemolytica suspension increased phagocytosis but did not greatly affect the subsequent bactericidal activity of the macrophages in vitro. The reason for the lack of pathogenicity shown by P. hemolytica in normal mice remains enigmatic.

Animals↗
PubMed1983

Bactericidal activity of alveolar and peritoneal macrophages exposed in vitro to three strains of Pasteurella multocida.

Normal ICR mice were infected intravenously, intraperitoneally, or aerogenically with Pasteurella multocida strains isolated from a turkey (S68), calf (V90), or rabbit (J20) lung. Both the turkey and calf isolates were highly virulent for mice and multiplied logarithmically in the lungs, liver, and spleen, resulting in death of the animals in 18 to 36 h. The rabbit strain was avirulent for mice, but repeated passage in mice did result in some increased virulence. All three strains of P. multocida were inactivated rapidly by normal mouse peritoneal macrophages, provided that the organisms were opsonized with specific hyperimmune serum before being exposed to the macrophage monolayers. P. multocida was slowly inactivated by normal mouse alveolar macrophages when the organisms were preopsonized. However, the surviving organisms later multiplied extensively in vitro. Macrophages harvested from hyperimmunized mice were no better at inactivating opsonized P. multocida cells than were normal mouse cells. The relative importance of the different phagocytic cell populations in the uptake and killing of opsonized P. multocida cells is discussed in relation to immunity to this important animal pathogen.

Animals↗
PubMed1983

Advantages of measuring changes in the number of viable parasites in murine models of experimental cutaneous leishmaniasis.

Previously published studies of experimental cutaneous leishmaniasis in the mouse have relied almost exclusively on measuring changes in lesion size to follow the course of the infection. The purposes of the studies reported here were to develop a technique to quantitate the number of viable organisms in the tissues and to use the technique to follow the development and resolution of the primary infection as well as the development of acquired resistance to Leishmania tropica in a resistant (C3H/He) and a susceptible (BALB/c) mouse strain. It was found that individual L. tropica amastigotes derived from infected tissues would transform to promastigotes and repeatedly divide to form discrete, countable colonies on rabbit blood agar. The plating efficiency was approximately 88%. Using the blood agar plating technique to quantitate the organism against time of the infection, we obtained data that suggest that acquired resistance develops in C3H/He mice earlier than is suggested by reduction in lesion size. In addition, although this resistance eliminates the parasites from the primary lesion in 10 weeks, 1,000 to 10,000 parasites persist for months in the lymph node draining the lesion site. In these studies, we found no evidence of acquired resistance in the susceptible BALB/c mice. The organism grows progressively, and the infection can disseminate to the spleen within 2 weeks. These studies illustrate the advantages of quantitating viable parasites in studies of immunity in cutaneous leishmaniasis.

Animals↗
PubMed1983

Kinetics of the delayed-type hypersensitivity response in tuberculous guinea pigs and mice tested with several mycobacterial antigen preparations.

Specific pathogen-free B6D2 mice and Hartley guinea pigs were infected subcutaneously with selected strains of Mycobacterium tuberculosis, M. bovis, M. kansasii, the MAIS complex, M. nonchromogenicum, and M. vaccae, and the in vivo growth behavior of the organisms was correlated with the level of tuberculin hypersensitivity and immunity to tuberculosis that subsequently developed. The peak level of tuberculin hypersensitivity varied depending on the host species, the immunogenicity of the infecting organism, and the dose and route of inoculation. However, the skin or footpad swelling profiles observed in mice and guinea pigs sensitized with live or heat-killed M. tuberculosis (persistor) or M. vaccae (nonpersistor) were very similar when a soluble test antigen was used, peaking between 24 and 36 h and already declining by 48 h. However, if sonically disrupted or whole-cell antigens were used, the swelling response was skewed significantly, with some residual swelling still present at 72 h. However, no evidence for two distinct cellular hypersensitivity responses was obtained in either mice or guinea pigs, regardless of the growth behavior of the mycobacteria in vivo.

Animals↗
PubMed1983

Infection with Mycobacterium kansasii and efficacy of vaccination against tuberculosis.

The purpose of the present study was to examine further the recent hypothesis that subcutaneous infection with Mycobacterium kansasii resulted in the generation of a cell-mediated hypersensitivity reaction ('Koch' reaction) which could, it was argued, subsequently interfere with the generation of acquired immunity following vaccination of the animal with BCG. The results of the present study were unable to confirm this hypothesis in that they show, firstly, that subcutaneous M. kansasii infection was associated with the development of substantial Arthus-like reactivity which masked the detection of any subsequent delayed response, and that furthermore, attempts to adoptively transfer this form of delayed reaction by means of passive transfer of cells were unsuccessful. Furthermore, the results show that, despite the presence of the M. kansasii infection, BCG-vaccinated animals were fully resistant to subsequent aerosol-delivered challenge with virulent M. tuberculosis.

Animals↗
PubMed1983

Resistance of various strains of mycobacteria to killing by activated macrophages in vivo.

A variety of experimental infections with pathogenic mycobacteria are associated with the development of persistent disease, in which little or no changes in the numbers of the infectious organism can be detected. This report describes a simple experimental model designed to test the hypothesis that this persistence may reflect in part the ability of these organisms to resist the enhanced bacteriostatic and bactericidal properties acquired by host macrophages as a result of these mycobacterial infections. To examine this possibility mice were inoculated with test organisms at a time when these animals were expressing very high levels of nonspecific resistance, and hence macrophage activation, as a result of a prior intravenous infection with Mycobacterium bovis bacillus Calmette-Guerin (BCG). The results show that the test organisms fall into three groups; (a) those, such as Mycobacterium tuberculosis, which were sensitive to the presence of activated macrophages, (b) those, such as Mycobacterium avium and Mycobacterium kansasii, which were insensitive, and (c) one organism, Mycobacterium intracellulare, in which progressive growth of the infection was significantly improved. These results are consistent with the hypothesis that some mycobacteria, particularly those associated with persistent disease, possess an intrinsic resistance to host bactericidal and bacteriostatic mechanisms in vivo.

Animals↗
PubMed1983

Fernandez and Mitsuda reactivity in guinea pigs sensitized with heat-killed Mycobacterium leprae: persistence and specificity of skin reactivity to soluble and particulate antigens.

Guinea pigs were sensitized with 500 micrograms dry weight of heat-killed Mycobacterium leprae, M. tuberculosis H37Rv, M. vaccae, or M. nonchromogenicum suspended in saline. Significant Fernandez (peak swelling at 48 hr) and Mitsuda (peaking at 21 days) reactions were observed when all four groups of animals were skin tested with 10 micrograms of the homologous whole-cell antigen (WCA) preparations one month after sensitization. Some of the guinea pigs were given a booster injection of the homologous suspension three months later and were then retested with the four WCA preparations. The Fernandez (rather than the Mitsuda) reactivity was enhanced by the second immunization and was still substantial when tested eight months after boosting. The Mitsuda-type responses observed 12 months after the primary sensitization peaked earlier than in the first- and four-month tests, regardless of the vaccinating organism. The M. leprae-sensitized guinea pigs produced larger Fernandez skin reactions than those seen in the other three groups of sensitized animals, but there was substantial crossreactivity between M. leprae and M. tuberculosis antigens, as well as somewhat lesser responsiveness in the M. vaccae- or M. nonchromogenicum-sensitized animals skin tested with lepromin. The present study indicates that saline suspensions of heat-killed M. leprae induced a highly persistent state of lepromin hypersensitivity which was quantitatively superior to that observed in animals sensitized with the three other mycobacteria.

Animals↗
PubMed1982

Correlations between structure and antimycobacterial activity in a series of 2-acetylpyridine thiosemicarbazones.

The antimycobacterial activity of a new series of 2-acetylpyridine thiosemicarbazones was determined in vitro using Mycobacterium smegmatis ATCC 607. The resulting log minimal inhibitory concentration (mumol l-1) values were plotted against the partition coefficient (log P) values for each compound, and fell on a parabolic distribution curve having a log P opt of 3.0. Compounds having partition coefficients outside the range 2.0 to 4.0 were inactive against M. smegmatis. When similar assays were carried out using M. tuberculosis, M. kansasii, M. marinum, M. simiae, M. avium and M. intracellulare, a similar series of parabolic activity curves were obtained having log P opt values around 4.0. The significance of this shift in the log P opt value obtained using the slow-growing pathogenic mycobacteria compared to that observed with the rapid-growing M. smegmatis is discussed in relation to the structures of the variable substituents of these new 2-acetylpyridine thiosemicarbazone compounds.

Anti-Bacterial Agents↗
PubMed1982

Activity of 2-acetylpyridine and 2-acetylquinoline thiosemicarbazones tested in vitro in combination with other antituberculous drugs.

Determinations of minimal inhibitory concentrations (MIC) were carried out using three new 2-acetylpyridine and two new 2-acetylquinoline thiosemicarbazones tested against Mycobacterium tuberculosis, M. kansasii, M. simiae, M. avium, and M. intracellulare. Two of the compounds (Compounds L and 3I) exhibited MIC less than or equal to 5 micrograms per ml for all of the test organisms, except for M. simiae, which was resistant to most antituberculous drugs. The other thiosemicarbazones (Compounds 3L, 2N, 3G, and 2H) were relatively inactive against the nontuberculous mycobacteria. Rifampin, amikacin, and clofazimine were active when tested singly or in combination with Compounds L and 3I. Addition of compound 3I to a mixture of rifampin, amikacin, and clofazimine resulted in combination MIC of less than 0.6 microgram/ml against all of the nontuberculous mycobacteria, suggesting that combinations of this type may be suitable for the treatment of infections caused by these highly drug-resistant organisms.

Antitubercular Agents↗
PubMed1981

Systemic Mycobacterium kansasii infection and regulation of the alloantigenic response.

Specific-pathogen-free B6D2 F1 hybrid mice were infected intravenously with 10(7) to 10(8) viable Mycobacterium kansasii cells. The growth of the five test strains in vivo was correlated with the level of delayed hypersensitivity to a cytoplasmic protein antigen injected into the footpad. M. kansasii TMC no. 1201 and 1203 gave rise to persisting systemic infections with an early delayed hypersensitivity response (day 7) followed by a profound anergy to the cytoplasmic protein antigen injections. Strains 1204, 1214, and 1217 declined in viability relatively rapidly and failed to induce detectable levels of delayed hypersensitivity. Spleens harvested from mice infected 20 to 30 days earlier with 10(8) M. kansasii 1203 cells contained a T-cell subpopulation capable of suppressing mixed lymphocyte reactions between normal B6D2 and C3H(He) cells. On the other hand, splenic T-cells taken from M. kansasii 1214-infected mice enhanced, rather than suppressed, the indicator mixed lymphocyte reactions. The kinetics of stimulator-suppressor T-cell production within the spleens of the heavily infected mice differed as the two contrasting M. kansasii infections progressed. Such cellular interactions could well be responsible for the observed persistence of the systemic M. kansasii 1203 infection.

Animals↗
PubMed1981

The specificity of suppressor T cells induced by chronic Mycobacterium avium infection in mice.

Normal mice infected intravenously with 10(6) or 10(8) viable M. avium develop persistent infections of the lungs, liver and spleen. The liver and spleen counts remained relatively constant whereas those for the lung slowly increased until eventually some of the animals began to die as a result of the infection. None of the heavily infected mice developed delayed hypersensitivity (DTH) to the M. avium cytoplasmic protein antigen (CPA). Spleen cells harvested at increasing time periods after the M. avium infection were tested for their blastogenic responsiveness to PHA and M. avium CPA. The presence of suppressor T cells within the heavily infected spleens was demonstrated by means of cell-mixing experiments before and after treatment of the anergic spleen cells with anti-Thy-1.2 antiserum and complement. The specificity of the suppressor T cells was measured in terms of their ability to depress responsiveness to sheep erythrocytes and an allograft challenge. Initially, the suppressor T cell population affected all of the T cell-mediated responses but as the infection progressed, so the non-specific host responses tended to return gradually towards normal, whereas the specific M. avium CPA-mediated suppression persisted largely unchanged.

Animals↗