Exposure to Mycobacterium avium induces low-level protection from Mycobacterium bovis infection but compromises diagnosis of disease in cattle

We assessed the effect of exposure to Mycobacterium avium on the development of immune responses and the pathogenesis of disease observed following Mycobacterium bovis challenge. A degree of protection against M. bovis was observed in calves which were pre-exposed to M. avium as assessed by the extent of lesions and bacterial load compared to the M. bovis alone group. The immune response following M. bovis challenge in cattle previously inoculated with M. avium was biased towards antigens (PPD) present in M. avium, whereas the response following M. bovis alone was biased towards antigens present in M. bovis, indicating an imprinting of memory to avian antigens on T lymphocytes. A consequence of the memory to M. avium antigens was failure to diagnose M. bovis infection by the skin test or the IFN(gamma) assay in some of the animals which had lesions of tuberculosis at necropsy. The use of M. bovis specific antigens ESAT-6 and CFP-10 increased IFN(gamma) test specificity in animals previously exposed to M. avium but the responses to these antigens were lower than those observed in animals exposed to M. bovis alone. The implication is that responses to M. avium, although providing some immunity, may mask diagnosis of M. bovis infection, even when specific antigens are employed, potentially contributing to disease transmission in the field.     

Vaccination of neonatal calves with Mycobacterium bovis BCG induces protection against intranasal challenge with virulent M. bovis

Vaccination of neonates with Mycobacterium bovis bacillus Calmette-Guerin (BCG) may be a strategy that overcomes reduced vaccine efficacy associated with exposure to environmental mycobacteria in humans and cattle. Preliminary comparisons indicated that 2-week-old calves produced an immune response to vaccination at least as intense as that observed in adults. Subsequently, five gnotobiotic hysterotomy derived calves aged 1 day were inoculated with BCG and 3 months later were challenged intranasally with virulent M. bovis. The number of tissues with lesions and the pathological extent of these lesions was reduced significantly in vaccinates. Furthermore, lesions were evident in the lung or associated chest lymph nodes of four of five controls but none of five vaccinates. BCG vaccination reduced significantly the level of bacterial colonization. However, lesions in the head associated lymph nodes were observed in three of five BCG-vaccinated cattle. Levels of interferon gamma (IFN-gamma) detected by enzyme-linked immunosorbent assay (ELISA) or enzyme-linked immunospot (ELISPOT) in individual vaccinated animals at challenge did not correlate with subsequent resistance and in general immune responses post-challenge were lower in vaccinated calves. Low IL-10 responses were evident but IL-4 was not detected. Responses to ESAT-6 and/or CFP-10 were evident in four of four control calves that had lesions. Two of the BCG vaccinates with lesions did not produce a response to ESAT-6 and CFP-10, indicating that these antigens did not distinguish vaccinated immune animals from vaccinated animals with lesions. Overall, vaccination of neonatal calves with BCG induced significant protection against disease and has potential as a strategy for the reduction of the incidence of bovine tuberculosis.     

Environmental strains of Mycobacterium avium interfere with immune responses associated with Mycobacterium bovis BCG vaccination

Prior exposure of a vaccinee to certain species of environmental mycobacteria can prime the immune system against common mycobacterial antigens, which can in turn reduce the subsequent efficacy of live attenuated mycobacterial vaccines (such as Mycobacterium bovis BCG), in both human and livestock vaccination programs. In this study, two strains of Mycobacterium avium, both isolated from New Zealand livestock, were investigated to determine their growth characteristics and effects on the immune system in murine models. Markedly different effects on the immune system were observed; an IS901-negative strain (WAg 207) induced significant up-regulation of cell surface activation markers (major histocompatibility complex II, CD80, and CD86) on in vitro-derived dendritic cells and induced the release of proinflammatory monokines (interleukin-1beta [IL-1beta], IL-6, and tumor necrosis factor alpha) in dendritic cell-macrophage cocultures following direct in vitro contact of cells with bacteria. In contrast, an IS901-positive strain (WAg 206) had none of these effects. When mice were exposed to M. avium via oral infection prior to BCG parenteral immunization, both strains were shown to be capable of decreasing subsequent antigen-stimulated gamma interferon secretion by splenic lymphocytes, although this effect was more significant for strain WAg 206. Both strains also induced a mycobacterial antigen-specific serological response in M. avium-sensitized and BCG-immunized mice; this response was greater in WAg 206-sensitized mice, and there was a predominance of immunoglobulin G1 antibody. The down-regulation of IFN-gamma responses and the up-regulation of antibody responses are characteristic of a switch to a type 2 immune response. The different results may be linked to the inherent growth characteristics of the two strains, since WAg 206 was shown to grow slowly in murine macrophages in vitro and to cause a persistent systemic infection following infection in vivo, while WAg 207 grew fast and did not persist in mice. The implications of these findings for BCG vaccination protocols are discussed.     

Enhanced secretion of interferon-gamma by bovine gammadelta T cells induced by coculture with Mycobacterium bovis-infected dendritic cells: evidence for reciprocal activating signals

Evidence suggests that gammadelta T cells form part of the innate immune response to Mycobacterium bovis infection. Dendritic cells (DCs) are capable of secreting high levels of interleukin-12 (IL-12) following infection with mycobacteria and can induce interferon-gamma (IFN-gamma) secretion by natural killer and gammadelta T cells We investigated the innate interactions occurring between WC1(+)gammadelta T cells and M. bovis-infected DCs. Following coculture with M. bovis-infected DCs, secretion of IFN-gamma and expression of CD25 and major histocompatibility complex class II on WC1(+)gammadelta T cells were significantly enhanced. Reciprocal enhancement of IL-12 secretion by the DCs was also observed and this interaction was found to be contact dependent. We hypothesize that there is an early, transient signal between the WC1(+)gammadelta T cells and the DCs, which promotes the synthesis of biologically active IL-12, and which is dependent upon cell-cell contact. Reciprocal signals including IL-12 are then delivered to WC1(+)gammadelta cells, which leads to the enhanced secretion of IFN-gamma, and the up-regulation of activation markers and antigen presentation molecules by the WC1(+)gammadelta T cells. These interactions are likely to form a critical part of the T helper type 1-conditioning response of DCs to M. bovis.     

A key role for lung‐resident memory lymphocytes in protective immune responses after BCG vaccination

The immune mechanisms that orchestrate protection against tuberculosis as a result of BCG vaccination are not fully understood. We used the immunomodulatory properties of fingolimod (FTY720) treatment to test whether the lung‐resident memory T lymphocytes generated by BCG vaccination were sufficient to maintain immunity against challenge infection with mycobacteria (BCG). Mice were given daily fingolimod treatment, starting either immediately before s.c. BCG vaccination or during subsequent BCG i.n. challenge, to prevent LN effector and memory lymphocytes from entering the periphery either during priming or challenge, respectively. Treatment with fingolimod during vaccination reduced vaccine‐mediated protection against subsequent infection. By contrast, BCG‐vaccinated mice were protected when fingolimod was given during the infectious challenge, suggesting that memory lymphocytes that migrate to the lung following vaccination are sufficient for protection. Notably, the antigen‐reactive IFN‐γ or multicytokine‐producing CD4⁺ T cells present in the lung when fingolimod was given during BCG challenge did not correlate with protection; however, expression of MHC class II on macrophages isolated from the lungs post BCG challenge was increased in the protected mice. We conclude that protection conferred by BCG vaccination is dependent on memory lymphocytes retained in the lung, although IFN‐γ production by this population is not correlated with vaccine‐mediated protection.     

Interferon-gamma and skin test responses of schoolchildren in southeast England to purified protein derivatives from Mycobacterium tuberculosis and other species of mycobacteria

The immune responses of schoolchildren in southeast England to Mycobacterium tuberculosis and other species of mycobacteria were studied prior to vaccination with bacille Calmette-Guérin (BCG). Data are presented for tuberculin (Heaf) skin test and interferon-gamma (IFN-gamma) responses to M. tuberculosis purified protein derivative (PPD), and IFN-gamma responses to PPDs from eight other environmental mycobacteria, measured in 424 schoolchildren (13-15 years of age). Responses to M. tuberculosis PPD were detected in 27% of schoolchildren by in vitro IFN-gamma response and in 20% by the Heaf test. IFN-gamma responses were more prevalent to PPDs from species of mycobacteria other than M. tuberculosis, predominantly those of the MAIS complex and M. marinum (45-60% responders). Heaf test and IFN-gamma responses were associated (P<0.001) for M. tuberculosis, MAIS and M. marinum. These findings have implications for appropriate implementation of vaccination against tuberculosis.     

Recombinant Mycobacterium bovis BCG vector system expressing SIV Gag protein stably and persistently induces antigen-specific humoral immune response concomitant with IFN gamma response, even at three years after immunization

A vaccine against HIV-1 infection absolutely needs the ability to effectively elicit virus-specific immunity over a long term; nevertheless, there have been few studies indicating that the immunoinductivity of such a candidate vaccine has been researched for several years running. In a previous report, we demonstrated that recombinant BCG (rBCG) expressing the full-length gag gene of simian immunodeficiency virus (SIV) (rBCG-SIVgag) induced Gag-specific delayed-type hypersensitivity, T cell proliferation, gamma interferon (IFN gamma), and serum IgG responses in guinea pigs immunized intradermally (i.d.) with 0.1 mg for the 1-year period of study. Especially, the production of long-lasting Gag-specific serum IgG in the vaccinated animals perhaps reflects the persistent antigenic stimulation by rBCG-SIVgag. How long, we questioned, will such immune responses to Gag engendered by the rBCG-SIVgag vaccination persist without booster immunizations? To learn this, we examined Gag-specific IgG production in sera and Gag-specific IFN gamma mRNA expression in peripheral blood mononuclear cells (PBMC) in guinea pigs vaccinated with rBCG-SIVgag i.d. (0.1 mg) or orally (80 mg x 2) during a 3-year period. As a result, Gag-specific serum IgG was highly generated for 3 years at similar levels between the i.d. and the orally immunized guinea pigs (IgG2>IgG1). The enhancement of IFN gamma mRNA expression by in vitro restimulation with Gag antigen was also detected in PBMC from the two immunization groups throughout the 3-year observation period. In guinea pigs immunized i.d. with rBCG-SIVgag, a high level of Gag-specific IFN gamma response was observed at 1 year after vaccination, whereas the response has waned gradually. The current study indicates that i.d. and oral inoculations of rBCG-SIVgag elicit stable, strong, Gag-specific serum IgG production while exhibiting the different kinetics of Gag-specific IFN gamma responses between i.d. and oral vaccination routes. This suggests that the rBCG vector system expressing an appropriate size of foreign antigen gene should be suited for the induction of the antigen-specific humoral immunity concomitant with an IFN gamma response.     

Multiple Mycobacterium antigens induce interferon-gamma production from sarcoidosis peripheral blood mononuclear cells

Studies of sarcoidosis immunology have noted oligoclonal T cell populations, suggesting cell-mediated immunity that is antigen-specific. Sarcoidosis immunology and pathology are most similar to mycobacterial infections. Mycobacterium tuberculosis infection in mice and humans reflects T helper 1 (Th1) immune responses to multiple cell wall and secreted antigens. We investigated if the oligoclonal immune response in individual sarcoidosis subjects could be elicited by multiple secreted mycobacterial antigens by performing ex vivo enzyme-linked immunospot assay (ELISPOT) on peripheral blood mononuclear cells (PBMC) from 30 sarcoidosis, 26 purified protein derivative negative (PPD-) control and 10 latent tuberculosis subjects (PPD+) to assess Th1 responses to mycobacterial superoxide dismutase A (sodA), catalase-peroxidase (katG) and early secreted antigenic target protein (ESAT-6). A significant difference was noted among the sarcoidosis and PPD- control subjects to ESAT-6 [12 of 30 versus one of 26 (P = 0.0014)], katG [nine of 30 versus none of 26 (P = 0.002)] and sodA [12 of 30 versus none of 26 (P = 0.002)]. There was no significant difference between sarcoidosis and PPD+ subjects. Twelve sarcoidosis subjects recognized two or more mycobacterial proteins, as well as multiple distinct epitopes within individual proteins. One sarcoidosis subject on whom we collected bronchoalveolar lavage (BAL) fluid and PBMC had no recognition of mycobacterial antigens using PBMC, but BAL fluid demonstrated strong Th1 immune responses to ESAT-6 and katG. Individual sarcoidosis subjects recognized not only multiple mycobacterial proteins, but multiple distinct peptides within a specific protein, thus demonstrating that multiple mycobacterial epitopes elicit the Th1 immune response observed. Immune responses by sarcoidosis T cells to mycobacterial proteins may have an important role in sarcoidosis pathogenesis.     

Primary immune response to keyhole limpet haemocyanin following trauma in relation to low plasma glutamine

Severe trauma can lead to a compromised immune response, thereby increasing susceptibility to infections. Here we will study to what extent these early changes in the immune status upon trauma affect a primary immune response to keyhole limpet haemocyanin (KLH). Because glutamine is the preferred respiratory substrate for immune competent cells and known to be depleted after trauma, we studied the immune status and the primary sensitization in relation to the glutamine plasma concentration in a group of severe trauma patients [injury severity score (ISS) >17]. Trauma patients (n = 31) were sensitized with KLH within 12 h after trauma; plasma glutamine concentrations and immune parameters were determined, after which KLH-specific immune responsiveness was evaluated on days 9 and 14. Low plasma glutamine concentrations were found after trauma. Significantly elevated numbers of granulocytes and CD14-positive leucocytes were found, whereas the HLA-DR expression on CD14-positive cells was significantly lower in trauma patients than in healthy controls. Trauma did not change the in vitro proliferative capacity of lymphocytes when cultured with glutamine; however, when lymphocytes were cultured without glutamine, trauma resulted in lower proliferation than healthy controls. Phytohaemagglutinin-(PHA)-induced interferon (IFN)-gamma and interleukin (IL)-10 production was significantly lower after trauma, whereas IL-4 production was not affected. KLH sensitization following trauma resulted in poor skin test reactivity and low in vitro KLH-induced lymphocyte proliferation compared to controls. In contrast, the development of anti-KLH IgM, IgG, IgA, IgG1, IgG2, IgG3 and IgG4 production on days 9 and 14 following trauma was not different from that in healthy controls. Major trauma was associated with a reduced cell-mediated immune response, correlating with low plasma glutamine concentrations, while no effects of trauma were found on the development of a primary humoral immune response.     

Innate immune responses to human rotavirus in the neonatal gnotobiotic piglet disease model

Intestinal and systemic dendritic cell (DC) frequencies, serum and small intestinal content cytokines and uptake/binding of human rotavirus (HRV) virus‐like particles (VLP) were studied in HRV acutely infected or mock‐inoculated neonatal gnotobiotic piglets. Intestinal, mesenteric lymph node (MLN) and splenic plasmacytoid DCs (pDCs), conventional DCs (cDCs) and macrophages/monocytes were assessed by flow cytometry. In infected pigs, serum and small intestinal content interferon‐α (IFN‐α) were highest, interleukin‐12 (IL‐12) was lower and IL‐10, tumour necrosis factor‐α and IL‐6 were minimal. Compared with mock‐inoculated piglets, frequencies of total intestinal DCs were higher; splenic and MLN DC frequencies were lower. Most intestinal pDCs, but few cDCs, were IFN‐α⁺ and intestinal macrophages/monocytes were negative for IFN‐α. Serum IFN‐α levels and IFN‐α⁺ intestinal pDCs were highly correlated, suggesting IFN‐α production in vivo by intestinal pDCs (r = 0·8; P < 0·01). The intestinal pDCs and cDCs, but not intestinal macrophages/monocytes, of HRV‐infected piglets showed significantly lower VLP uptake/binding compared with mock‐inoculated piglets, suggesting higher activation of pDCs and cDCs in infected piglets. Both intestinal pDCs and cDCs were activated (IFN‐α⁺ and lower VLP binding) after HRV infection, suggesting their role in induction of HRV‐specific immunity. Dose‐effects of HRV on serum IFN‐α and IFN‐α⁺ DCs were studied by infecting piglets with 100‐fold higher HRV dose. A high dose increased parameters associated with inflammation (diarrhoea, intestinal pathology) but serum IFN‐α and IFN‐α⁺ DCs were similar between both groups. The pDCs have both anti‐ and pro‐inflammatory functions. Stimulation of the anti‐inflammatory effects of pDCs after the high dose, without increasing their pro‐inflammatory impacts, may be critical to reduce further immunopathology during HRV infection.     

Intranasal IFNgamma extends passive IgA antibody protection of mice against Mycobacterium tuberculosis lung infection

Intranasal inoculation of mice with monoclonal IgA against the alpha-crystallin (acr1) antigen can diminish the tuberculous infection in the lungs. As this effect has been observed only over a short-term, we investigated if it could be extended by inoculation of IFNgamma 3 days before infection, and further co-inoculations with IgA, at 2 h before and 2 and 7 days after aerosol infection with Mycobacterium tuberculosis H37Rv. This treatment reduced the lung infection at 4 weeks more than either IgA or IFNgamma alone (i.e. 17-fold, from 4.2 x 10(7) to 2.5 x 10(6) CFU, P = 0.006), accompanied also by lower granulomatous infiltration of the lungs. IFNgamma added prior to infection of mouse peritoneal macrophages with IgA-opsonized bacilli resulted in a synergistic increase of nitric oxide and TNFalpha production and a 2-3 fold decrease in bacterial counts. Our improved results suggest, that combined treatment with IFNgamma and IgA could be developed towards prophylactic treatment of AIDS patients, or as an adjunct to chemotherapy.     

Short wheat challenge is a reproducible in-vivo assay to detect immune response to gluten

It has been reported that interferon (IFN)-γ-secreting T cells reactive to gluten can be detected in the peripheral blood of individuals with treated coeliac disease (CD) after a short consumption of wheat-containing food. By contrast, very little is known about the reproducibility of this in-vivo procedure in the same patient cohort which underwent two, or more, gluten consumptions. Fourteen coeliac patients in remission consumed wheat bread for 3 days; 13 underwent a second gluten challenge after a wash-out of 3-10 months on a strict gluten-free diet. Immune reactivity to gluten was analysed in peripheral blood by detecting IFN-γ before and 6 days after commencing a gluten diet. Gliadin-specific IFN-γ-secreting CD4(+) T cells increased significantly on day 6 of the first challenge. These cells resulted as prevalently human leucocyte antigen (HLA)-DQ restricted and with a phenotype of gut homing, as suggested by the expression of β7-integrin. Similarly, reactiveness to gliadin was observed after the second wheat consumption, although with an individual variability of responses at each challenge. Our findings confirmed that the short wheat challenge is a non-invasive approach to investigate the gluten-related immune response in peripheral blood of subjects intolerant to gluten. Furthermore, we demonstrated that the in-vivo procedure can be reproduced in the same subject cohort after a gluten wash-out of at least 3 months. Our study has important implications for the application of this procedure to clinical practice.     

A role for CD4+CD25+ T cells in regulation of the immune response during human tuberculosis

Active tuberculosis (TB) is associated with prolonged suppression of Mycobacterium tuberculosis (MTB)-specific immune responses, but mechanisms involved are understood incompletely. We investigated a potential role for CD4+CD25+ regulatory T cells in depressed anti-MTB immunity by evaluating serially CD4 cell phenotype and interferon (IFN)-gamma production by mononuclear cells from patients with TB. At diagnosis, frequencies of CD4+CD25+ T cells were increased in blood from TB patients compared to healthy purified protein derivative (PPD)-positive controls (with a history of prior TB exposure), and remained elevated at completion of therapy (6 months). By contrast, expression of another activation marker, CD69, by CD4 T cells was increased at diagnosis, but declined rapidly to control levels with treatment. Among CD4+CD25+ T cells from TB patients at diagnosis those expressing high levels of CD25, probably representing regulatory T cells, were increased 2.9-fold when compared to control subjects, while MTB-stimulated IFN-gamma levels in whole blood supernatants were depressed. A role for CD4+CD25+ T cells in depressed IFN-gamma production during TB was substantiated in depletion experiments, where CD25+-depleted CD4 T cells produced increased amounts of IFN-gamma upon MTB stimulation compared to unseparated T cells. At follow-up, IFN-gamma production improved most significantly in blood from TB patients with high baseline frequencies of CD4+CD25+ T cells (more than threefold higher than controls for both total and CD25hi+ CD4 T cells), who also had a significant drop in frequencies of both total and 'regulatory' CD4+CD25+ T cells in response to treatment. Expansion of CD4+CD25+ regulatory T cells during active TB may play a role in depressed T cell IFN-gamma production.     

Immunization of mice with the antigen A60 of Mycobacterium bovis BCG.

Antigen 60 (A60) is a thermostable component of the cytoplasm of Mycobacterium tuberculosis and BCG which can be fractionated into at least 15 protein bands when analysed by Western blot. Normal B6D2 mice were immunized subcutaneously with 20 micrograms of the A60 protein suspended in Freund's incomplete adjuvant (FIA) or in saline. Three weeks later the mice received a second dose of vaccine followed 2 weeks later by an aerogenic challenge with approximately 10(3) CFU of M. tuberculosis Erdman. The mice receiving the adjuvanted A60 showed a significant reduction (P less than 0.05) in the number of viable organisms recovered from the lungs and the spleen 3 weeks after challenge. However, this response was less than that seen in BCG vaccinated controls.     

Synergistic antiviral effect of a combination of mouse interferon-alpha and interferon-gamma on mouse hepatitis virus

Although interferon (IFN)-alpha and IFN-gamma have been reported to exhibit a synergistic antiviral effect through the different signaling pathways in vitro, their therapeutic efficacy is not well defined in vivo. The current study was carried out to investigate the combined antiviral effect in a model of mouse hepatitis virus Type 2 (MHV-2) infection, in which fulminant hepatitis is developed. MHV-2 was injected intraperitoneally into 4-week-old ICR mice, IFN or the vehicle was administered intramuscularly for 5 days, and the antiviral effect was evaluated based on survival periods, liver histology, serum alanine transaminase (ALT) levels, and MHV-2 virus titers in the liver tissues. The animals in the group treated with a combination of IFN-alpha and IFN-gamma survived for longer periods than the groups treated with IFN-alpha alone and IFN-gamma alone (IFN-alpha 10(3) (IU/mouse)/-gamma 10(3) vs. IFN-alpha 10(3), P < 0.005; IFN-alpha 10(3)/-gamma 10(3) vs. IFN-gamma 10(3), P < 0.001). This is consistent with the lower levels of hepatocellular necrosis and serum ALT and the decreased titers of MHV-2 virus in the liver tissues (48 hr, P < 0.001; 72 hr, P < 0.001). These findings indicate that a combination of IFN-alpha and IFN-gamma exhibits a synergistic antiviral effect on MHV-2 infection. The biology of MHV-2 is quite different from that of human hepatitis viruses; however, these results suggest the beneficial combined therapy of IFN-alpha and IFN-gamma for the treatment of human viral hepatitis.     

Mendelian susceptibility to mycobacterial disease

Cottle LE. Mendelian susceptibility to mycobacterial disease. The host response to mycobacterial infection is mediated by the type I cytokine pathway (cell‐mediated immunity). Deficiencies in this response result in susceptibility to poorly pathogenic mycobacterial species such as bacille Calmette‐Guérin and environmental mycobacteria. In recent years a number of mutations in the genes encoding major components in the type I cytokine axis have been described which predispose to disseminated infection with these weakly virulent mycobacterial species. Affected individuals are also prone to extra‐intestinal disease caused by non‐typhoidal Salmonella. The genes involved display a high level of allelic heterogeneity, accounting for a number of distinct genetic disorders which vary in their mode of inheritance and clinical presentation. These disorders have been termed Mendelian susceptibility to mycobacterial disease and are discussed in this review article.     

Detection of in vitro interferon-gamma and serum tumour necrosis factor-alpha in multidrug-resistant tuberculosis patients

Multidrug-resistant tuberculosis (MDR-TB) is known as having a poor prognosis with a weak response to therapy and very high death rates. The aim of this work was to assess the immune response to the RD1-encoded antigen ESAT-6 of Mycobacterium tuberculosis in MDR-TB patients and compare to non-resistant (NR) TB patients and healthy controls (HC). Evaluation of interferon (IFN)-gamma production showed that, although 55% of the MDR patients were responsive to ESAT-6, they produced lower IFN-gamma levels (553 +/- 11 pg/ml) when compared to NR-TB (1179 +/- 163 pg/ml; P < 0.05) but not to controls (412 +/- 65.7 pg/ml). Differences in the response to ESAT-6 and to its overlapping peptides mixture were also significant between MDR versus treated pulmonary NR-TB. Furthermore, a very low rate of response to PPD (23.5%) and to Ag85B (33.3%) was noted in MDR-TB patients as compared to the other groups. To determine the inflammatory response in patients' groups, detection of tumour necrosis factor (TNF)-alpha was assessed in their sera before and during chemotherapy. Mean TNF-alpha levels in MDR-TB (43.8 +/- 9 pg/ml) paralleled those found in treated pulmonary, and it was significantly different (P < 0.05) from the values found in untreated NR and HC. Interestingly, secretion of IFN-gamma and TNF-alpha were predominant in MDR patients who presented with bilateral pulmonary lesions and lung cavitation. The present data indicate that the overall immune response to mycobacterial antigens is decreased in resistant TB and the major role inflammatory cytokines may play in perpetuating pulmonary tissue damage.     

Ginseng modulates the immune response by induction of interleukin-12 production

In infections with intracellular microorganisms such as mycobacteria and Leishmania parasites as well as certain extracellular chronic infections such as Pseudomonas aeruginosa a Th1 response with activation of macrophages is desirable. Several studies indicate that such a response is associated with better recovery from infection, improved course of the chronic infection, and higher survival rate. In Th1 responses there is increased interferon-gamma (IFN-gamma) and interleukin-12 (IL-12) production, whereas that of interleukin-10 (IL-10) is decreased. The present study indicated that Ginseng modulation of stimulated peripheral blood mononuclear cells (PBMC) results in a higher IL-12 production. The enhanced IL-12 production could induce a stronger Th1 response, resulting in better protection against infection with a variety of pathogens.