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PubMed2002

Manipulation of immune responses to Mycobacterium bovis by vaccination with IL-2- and IL-18-secreting recombinant bacillus Calmette Guerin.

Bacillus Calmette Guerin (BCG) has been reported to show variable efficacy as a vaccine against tuberculosis. We demonstrated that the secretion of biologically active IL-2 (rBCG/IL-2),but not IL-18 (rBCG/IL-18), by BCG improves its ability to induce and maintain a strong type 1 immune response in BALB/c mice. rBCG/IL-2 induced significantly higher Ag-specific proliferative responses, high IFN-gamma production and serum titres of IgG2a 16 weeks after vaccination. This immune profile was correlated to an increased rate of clearance of non-pathogenic mycobacteria (live BCG delivered intranasally). Surprisingly, however,this strong type 1 immune profile induced no greater protective immunity against aerosol challenge with virulent Mycobacterium bovis than that induced by normal BCG (nBCG). By comparison,vaccination with rBCG/IL-18 was found to induce significantly less IFN-gamma production in splenic lymphocytes than nBCG. This impaired induction of IFN-gamma was correlated to a significantly lower protective efficacy against M. bovis challenge, as compared to nBCG. The data suggest that manipulation of the immune response to tuberculosis and tuberculosis vaccines will require a more complete understanding of the factors that are important in generating a protective immune response.

Animals↗
PubMed2003

Oral delivery of Mycobacterium bovis BCG in a lipid formulation induces resistance to pulmonary tuberculosis in mice.

A lipid-based formulation has been developed for oral delivery of Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccine. The formulated M. bovis BCG was fed to BALB/c mice to test for immune responses and protection against M. bovis infection. The immune responses included antigen-specific cytokine responses, spleen cell proliferation, and lymphocyte-mediated macrophage inhibition of M. bovis. Oral delivery of formulated M. bovis BCG to mice induced strong splenic gamma interferon levels and macrophage inhibition of virulent M. bovis compared with results with nonformulated M. bovis BCG. Formulated oral M. bovis BCG significantly reduced the bacterial burden in the spleen and lungs of mice following aerosol challenge with virulent M. bovis. Our data suggest that oral delivery of formulated M. bovis BCG is an effective means of inducing protective immune responses against tuberculosis. Lipid-based, orally delivered mycobacterial vaccines may be a safe and practical method of controlling tuberculosis in humans and animals.

Administration, Oral↗
PubMed1984

Protective effect of muramyl dipeptide analogs in combination with trehalose dimycolate against aerogenic influenza virus and Mycobacterium tuberculosis infections in mice.

The effects of two aminobutyryl and four seryl analogs of the synthetic muramyl dipeptide (MDP) against aerosol infections with influenza virus and Mycobacterium tuberculosis were studied. Regardless of the MDP analog employed, there was no evidence that the resistance against viral and bacterial aerosol infections was enhanced in the treated mice. In parallel studies, significant protection against influenza virus and M. tuberculosis infections was induced by the combination of MDP or analogs with the mycobacterial glycolipid trehalose dimycolate (TDM). Resistance conferred by the MDP + TDM combination against influenza virus was present 1 week after pretreatment and could be abrogated by macrophage inhibitory agents silica, dextran sulfate, and carrageenan. Splenic cells from MDP + TDM-pretreated animals generated markedly enhanced levels of luminol-dependent chemiluminescence in response to influenza A and B viruses.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1993

Helper activity of CD4+ alpha beta T cells is required for the avian gamma delta T cell response.

We have studied the in vitro activation of chicken gamma delta T cells. Both splenic alpha beta and gamma delta T cells obtained from complete Freund's adjuvant-primed chickens proliferated in vitro when stimulated with mycobacterial sonicate or purified protein derivative of Mycobacterium tuberculosis. When CD4+ cells or alpha beta T cell receptor (TcR)-positive cells were removed, both the proliferation and the blast formation of gamma delta T cells in response to mycobacterial antigens were abrogated. The response was restored if supernatant from concanavalin A (Con A)-activated lymphocyte cultures (CAS) as a source of helper factors was added together with the specific antigen purified protein derivative. The CD4- or alpha beta TcR-depleted cells still proliferated in response to Con A, although a decrease of the response was observed. To analyze the gamma delta T cell response more specifically we stimulated peripheral blood cells with immobilized monoclonal antibodies against T cell receptor. Anti-gamma delta TcR antibody alone did not induce significant proliferation. When CAS was added together with the anti-gamma delta TcR monoclonal antibody, a strong proliferation of gamma delta T cells was observed. In contrast, both V beta 1- and V beta 2-expressing alpha beta T cells proliferated in vitro in response to stimulation with the relevant anti-TcR monoclonal antibody alone. Depletion of either V beta 1+ or V beta 2+ T cell subset alone had no negative effect on the proliferation or blast formation of gamma delta T cells stimulated with mycobacterial antigens. Taken together our results suggest that CD4+ alpha beta T cells (both V beta 1- and V beta 2-expressing) play a role in the activation and response of chicken gamma delta T cells.

Animals↗
PubMed1998

Suppression of lymphoproliferation by alveolar macrophages in the guinea pig.

SETTING: The relationship between alveolar macrophages (AM) and lymphocytes may be important in the early establishment of infection with Mycobacterium tuberculosis. AM in several species have been shown to suppress lymphoproliferation by producing inhibitors that include nitric oxide (NO). OBJECTIVE: To study this phenomenon in the guinea pig, the mitogen-induced proliferation of splenic lymphocytes was quantified under various conditions of co-culture with resident AM. RESULTS: Guinea pig AM consistently and profoundly suppressed proliferation in the co-cultures at AM:lymphocyte ratios of 1:4 or greater. The inclusion of a NO synthesis inhibitor, N-monomethyl-L arginine (NMMA), in the co-culture medium did not influence the suppression of Con A-induced lymphoproliferation by resident guinea pig AM. No nitrite could be detected in supernatant fluids of co-cultured AM and splenocytes. Attempts to stimulate guinea pig AM with LPS in combination with recombinant murine and human IFN-gamma, infection with live Listeria monocytogenes, or incubation with the supernatants from ConA-activated guinea pig lymphocytes failed to generate NO metabolites. The addition of catalase or indomethacin to the Con A-induced AM-splenocyte co-cultures, to inhibit hydrogen peroxide (H2O2) or prostaglandin E2 (PGE2), respectively, did not counteract the suppression mediated by AM. Cell contact was necessary for the co-cultures to generate their inhibitory effects on lymphoproliferation, however, the suppression was actually mediated, at least in part, by soluble factors produced in the co-cultures. CONCLUSION: These results suggest that resident alveolar macrophages suppress lymphocyte proliferation in the guinea pig, but that the effect is not mediated by NO, PGE2 or H2O2. The failure to demonstrate NO synthesis under a variety of stimulatory conditions, which resulted in macrophage activation, suggests that the guinea pig is similar to the human in that regard.

Analysis of Variance↗
PubMed1973

Inhibition of migration of mouse macrophages by tuberculin-sensitive mouse lymphocytes and by mouse migration inhibitory factor.

The guinea pig migration inhibition technique, an accepted in vitro correlate of delayed hypersensitivity, has been adapted to a murine system. Peritoneal exudate cells from CF-1 mice vaccinated with viable cells of the H37Ra strain of Mycobacterium tuberculosis were inhibited in vitro by purified protein derivative (PPD) or whole H37Ra microorganisms. Peritoneal exudate cells from the inbred C57Bl/6 mice immunized with H37Ra cells also were inhibited in vitro by PPD or whole H37Ra microorganisms. Migration inhibitory factor (MIF) was produced by splenic lymphocytes from the H37Ra-immunized C57Bl/6 mice when incubated with either antigen. Intravenous injection of PPD or viable H37Ra organisms into H37Ra mice resulted in MIF production in vitro by splenic lymphocytes without further antigenic stimulation. Peritoneal exudate cells from nonimmunized C57Bl/6 mice and supernatant fluids from cultures of lymphocytes from nonimmunized C57Bl/6 mice were not inhibited in the presence of antigen. The production of MIF by splenic lymphocytes from immunized C57Bl/6 mice depended upon the conditions under which the lymphocytes were cultured, the time of exposure to antigen (3 days), the use of a higher concentration of PPD for stimulation of lymphocytes than that required for guinea pig cells, and also the use of cells from a highly inbred mouse strain.

Animals↗
PubMed1977

The production of a lymphocyte inhibitory factor (LyIF) by bursal and thymic lymphocytes.

In this study the migration and migration inhibition of different lymphoid cell populations from immunized and control birds were evaluated. Bursal, thymic, and splenic cells migrated in a capillary tube with thymic cells forming the characteristic cone of cells within 4 hours of culture. Both thymic and bursal cell populations from birds sensitized by Mycobacterium tuberculosis produced a lymphocyte inhibitory factor (LyIF) when stimulated by specific antigen in vitro. The ability of bursal cells to release LyIF declined subsequent to 10 weeks of age while LyIF was not apparent in thymic lymphocytes until 9 weeks of age and remained high until 27 weeks of age. The active material generated in specifically stimulated cultures from sensitized bursal cells appeared to be antigen dependent whereas thymic cell mediator is antigen independent. The production of LyIF in chickens, while correlating with delayed type hypersensitivity, does not solely reflect T-cell function but B-cell response as well.

Age Factors↗
PubMed2004

Sarcoidosis manifesting as massive splenomegaly: a rare occurrence.

Sarcoidosis is a multisystemic granulomatous disease of unknown origin occurring worldwide and affecting people of all races and ages. This disease manifests most frequently with bilateral hilar lymphadenopathy, pulmonary infiltrates, and skin and ocular lesions. Granulomatous inflammation of the spleen is common in patients with sarcoidosis, but splenic enlargement is unusual and massive splenomegaly quite rare. Splenomegaly is usually homogeneous, but multiple low-attenuating nodular lesions are occasionally seen and easily mistaken for lymphoma, metastases, or infections such as tuberculosis. We describe an unusual case of sarcoidosis in a woman who presented with massive splenomegaly with extensive nodularity that cleared completely with corticosteroid therapy.

Adult↗
PubMed1971

Temporal development of resistance to pulmonary tuberculosis in Swiss albino mice.

The course of pulmonary tuberculosis was followed in control and BCG-vaccinated mice. Resistance was evaluated by determining the numbers of virulent mycobacteria recovered from the organs at various intervals after airborn infection. A limited but significant retardation of growth of challenge bacilli was observed in both pulmonary and splenic tissues of successfully vaccinated animals. This retardation was manifested chiefly during the early stages of the infection. However, the numbers of virulent organisms recovered from the organs of either vaccinated or control animals were much the same at later stages of the infection. The appearance of pulmonary immunity was related to the stage of development in vivo of the vaccinal population. Only after large numbers of vaccinal bacilli could be recovered from the tissues was heightened resistance observed.

Aerosols↗
PubMed1988

The role of host factors for the chemotherapy of BCG infection in inbred strains of mice.

Host factors have previously been considered to play a role in the efficacy of "incomplete" antituberculous chemotherapy. We investigated this aspect using a model of intravenous infection with M. bovis-BCG in three inbred strains of mice. Viable splenic counts of bacilli (CFU) were monitored following a three week regimen of rifampicin (R) and isoniazid (H) given either immediately or from three weeks after infection. At the end of the immediate (0-3 weeks) therapy the spleens of all mice were sterile and only a minority of animals had demonstrable CFU's at 23 weeks after infection. However, following the delayed-onset (3-6 weeks) therapy we found a pronounced relapse of BCG growth which was about 10 times higher in CBA/Ca and BALB/C than in C57B1/6 mice. These results indicated that host immunity which developed during the first three weeks after infection may have aggravated the relapse of bacterial growth following chemotherapy. This interpretation was corroborated by the finding that the immunosuppressive drug cyclosporin given concurrently with R/H reduced the splenic viable counts of BCG.

Animals↗
PubMed1995

Influence of mouse strain and vaccine viability on T-cell responses induced by Mycobacterium bovis bacillus Calmette-Guérin.

C57BL/6 and BALB/c mice were vaccinated with either live or heat-killed Mycobacterium bovis bacillus Calmette-Guérin (BCG) organisms, and splenic T cells were used to screen the stimulatory potential of fractionated somatic and secreted mycobacterial proteins by production of gamma interferon (IFN-gamma). Maximum responses were obtained with fractionated secreted proteins of Mycobacterium tuberculosis. There was no single dominant antigen, but five regions of mycobacterial proteins induced high concentrations of IFN-gamma. However, only two of the five regions stimulated T cells from both mouse strains: two were exclusively recognized by T cells from BALB/c mice, and one was exclusively recognized by T cells from C57BL/6 mice. T cells from mice vaccinated with heat-killed M. bovis BCG organisms failed to respond to fractionated secreted proteins but recognized several somatic antigen fractions. As late as 1 year after primary vaccination, memory T cells responded to similar protein regions, and IFN-gamma production was intensified by secondary infection. Our data confirm a central role for secreted proteins in immunity to mycobacteria. Moreover, we demonstrate that a major set of mycobacterium-reactive T cells is stimulated only by vaccination with live but not with heat-killed M. bovis BCG organisms. Because a major impact of genetic host factors on antigen recognition was observed, we favor the use of live carrier organisms which secrete mycobacterial proteins over subunit vaccines as an improved antituberculosis vaccine.

Animals↗
PubMed1995

Recall of long-lived immunity to Mycobacterium tuberculosis infection in mice.

Our study investigates the recall of immunity in the mouse model of memory immunity to tuberculosis infection. The results provide evidence that recall of immunity is expressed as an accelerated accumulation of potent effector cells in the infected target organs. These effector cells were recruited from the resting pool of memory cells and were immediately triggered to exert their effector functions, leading to a massive release of Th1 cytokines detectable both in splenic extracts and in the serum within the first 24 h of infection. During a primary infection, in contrast, a 14-day delay was observed before significant cytokine levels were reached. After the initial effector phase, the cells blasted and entered into clonal expansion, resulting in a rapid increase in the total number of CD4 CD45RBlow cells in the spleen. The recall of memory immunity was highly efficient and controlled an infectious challenge within the first week. The molecules recognized by the memory effector subset were the proteins secreted from Mycobacterium tuberculosis during growth. By separating the CD4 population into CD45RBhigh and CD45RBlow subsets, the memory effector cells were demonstrated to reside predominantly in the activated population of CD45RBlow CD44high LFA-1high L-selectinlow cells. The key antigenic targets recognized by these cells were identified as Ag85B and a secreted 6-kDa protein (ESAT-6) that elicited the release of exceedingly high levels of IFN-gamma. ESAT-6 was biochemically purified, characterized, and the gene encoding the protein was cloned.

Amino Acid Sequence↗
PubMed1984

Granulomas of spleen and liver in hairy cell leukaemia.

In 15 patients with hairy cell leukaemia splenic epithelioid granulomas were demonstrated in 4 out of 13 investigated cases (31%) and liver granulomas in 2 out of 10 cases (20%). Granulomas were never found in bone marrow specimens. Histological stains for mycobacteria, fungi and bacteria failed to demonstrate an etiological agents and culture (sputum) for mycobacteria were only performed in 3 cases, 1 showing Mycobacterium Tuberculosis. Attention to the possible role of atypical mycobacterial infections as an explanation to the often reported unresponsive fever of unknown origin in hairy cell leukaemia and the use of lymph node and/or liver biopsies for culture as well as histology is recommended.

Adult↗
PubMed2004

Role of L-lysine HCl in adoptive immune therapy towards development of suitable tuberculosis vaccination.

L-Lysine HCI is being proposed to be a possible biocompatible adjuvant to enhance immune response by virtue of its probable non-specific bridging action and cellular proliferation properties. This proposal has been tried to be substantiated by designing an in vitro culture protocol, varying the concentration of L-lysine HCI and its further in vivo application. Splenic lymphocyte population has been extracted from mice and co-cultured with extracted mice macrophage population in presence of either Bacille Calmette Guerrin (BCG) or Hepatitis B surface antigen (HbsAg) and added L-lysine hydrochloride in culture media. Post incubation of these cultures, "taught" cell population has been adoptively transferred in naïve mice. These mice were then challenged by respective antigen dose, Change in Immune response with this challenge was noted. Antibody titre was followed in all the experiments as a measure of immune response. In adoptive immune transfer experiment of with HbsAg (AIT-HbsAg), similar to that with BCG (AIT-BCG), after the incubation period, antibody titre was higher in added lysine containing cultures in comparison with the control ones. Post transfer followed by antigen challenge, in AIT-BCG the expected augmentation in immune response was hardly visible. But in AIT-HbsAg, with the help of lysine booster, the animals responded better as far as the antibody titre is concerned.

Animals↗
PubMed1999

Role of interleukin-18 (IL-18) in mycobacterial infection in IL-18-gene-disrupted mice.

Immunity to mycobacterial infection is closely linked to the emergence of T cells that secrete cytokines, gamma interferon (IFN-gamma), interleukin-12 (IL-12), and tumor necrosis factor alpha (TNF-alpha), resulting in macrophage activation and recruitment of circulating monocytes to initiate chronic granuloma formation. The cytokine that mediates macrophage activation is IFN-gamma, and, like IL-12, IL-18 was shown to activate Th1 cells and induce IFN-gamma production by these cells. In order to investigate the role of IL-18 in mycobacterial infection, IL-18-deficient mice were infected with Mycobacterium tuberculosis and Mycobacterium bovis BCG Pasteur, and their capacities to control bacterial growth, granuloma formation, cytokine secretion, and NO production were examined. These mice developed marked granulomatous, but not necrotic, lesions in their lungs and spleens. Compared with the levels in wild-type mice, the splenic IFN-gamma levels were low but the IL-12 levels were normal in IL-18-deficient mice. The reduced IFN-gamma production was not secondary to reduced induction of IL-12 production. The levels of NO production by peritoneal macrophages of IL-18-deficient and wild-type mice did not differ significantly. Granulomatous lesion development by IL-18-deficient mice was inhibited significantly by treatment with exogenous recombinant IL-18. Therefore, IL-18 is important for the generation of protective immunity to mycobacteria, and its main function is the induction of IFN-gamma expression.

Animals↗
PubMed2006

Pseudo-rationale design of efficient TB vaccines: lesson from the mycobacterial 27-kDa lipoprotein.

To develop or improve acellular vaccines against tuberculosis, scientists are in quest for the most efficient Th1 antigens. Immunization of mice with the M. tuberculosis 27-kDa antigen resulted in a strong Th1 immune response as indicated by serum analysis, splenocyte proliferation and cytokines secretion profile. Unexpectedly, mice immunized with 27-kDa turned out to be more susceptible to mycobacterial challenge as we found significant increase in the splenic cfu count compared to control groups. Moreover, the protection provided by BCG or other mycobacterial antigens was completely abolished once the 27-kDa antigen was added to the vaccine preparations. Further analysis of 27-kDa revealed that this lipoprotein is a B-cell mitogen, a feature that is known to be linked to enhanced virulence of the pathogen. However, by using the non-acylated form, 27DeltaSP, we excluded the involvement of the mitogenicity of 27-kDa in its deleterious effect. Currently, there is no explanation to the fact that the 27-kDa interferes with the protective immunity of other mycobacterial antigens; however, it is clear that 27-kDa need to be excluded from any future vaccine preparations. Indeed, we developed a multivalent vaccine that consists of six other mycobacterial antigens: 85B, 38-kDa, ESAT-6, CFP21, Mtb8.4 and 16-kDa. Immunization of mice with these antigens emulsified in Ribi adjuvant system and supplemented with recombinant IFN-gamma, resulted in strong Th1 immune response and a high protection level that was comparable to that of BCG.

Adjuvants, Immunologic↗
PubMed1991

[Use of dimephosphon in pathogenetic therapy of experimental tuberculosis].

The results of a study of a new synthetic drug dimephosphon used as a pathogenetic means in the treatment of experimental tuberculosis are presented. Dimephosphon was found to be responsible for both the in vivo and in vitro decrease of the degree of MBT resistance to rifampicin. The findings of macroscopic, histologic and bacteriologic examinations demonstrated a significant increase in the effectiveness of antituberculous therapy. Dimephosphon monotherapy in mice elicited manifested stimulation of peritoneal macrophages: increase in O2- production, and decline in extracellular 5-nucleotidase activity. Nemolysine-synthetic cellular splenic activity in mice rose essentially. No direct stimulating influence of dimephosphon on functional macrophage activity in vitro was found.

Animals↗