The role of radiosurgery in the acute management of fourth ventricle compression due to brain metastases.

BACKGROUND: Approximately 20-30% of all intracranial metastases are located in the posterior fossa. The clinical evolution hinges on factors such as tumor growth dynamics, local topographic conditions, performance status, and prompt intervention. Fourth ventricle (V4) compression with secondary life-threatening obstructive hydrocephalus remains a major concern, often requiring acute surgical intervention. We have previously reported on the application of adaptive hypofractionated Gamma Knife Radiosurgery in the acute management of critically located metastases, a technique known to us as rapid rescue radiosurgery (3R). We report the results of 3R in the management of posterior fossa lesions and ensuing V4 decompression. CASE DESCRIPTIONS: Four patients with V4 compression due to posterior fossa metastases were treated with 3R by three separate gamma knife radiosurgical sessions (GKRS) over a period of seven days. Mean V4 volume was 1.02 cm3 at GKRS 1, 1.13 cm3 at GKRS 2, and 1.12 cm3 at GKRS 3. Mean tumor volume during the week of treatment was 10 cm3 at both GKRS 1 and 2 and 9 cm3 at GKRS 3. On average, we achieved a tumor volume reduction of 52% and a V4 size increase of 64% at the first follow-up (4 weeks after GKRS 3). Long-term follow-up showed continued local tumor control, stable V4 volume, and absence of hydrocephalus. CONCLUSION: For this series, 3R was effective in terms of rapid tumor ablation, V4 decompression, and limited radiation-induced toxicity. This surgical procedure may become an additional tool in the management of intractable posterior fossa metastasis with V4 compression.

The immunogenetics of narcolepsy associated with A(H1N1)pdm09 vaccination (Pandemrix) supports a potent gene-environment interaction.

The influenza A(H1N1)pdm09 vaccination campaign from 2009 to 2010 was associated with a sudden increase in the incidence of narcolepsy in several countries. Narcolepsy with cataplexy is strongly associated with the human leukocyte antigen (HLA) class II DQB1*06:02 allele, and protective associations with the DQB1*06:03 allele have been reported. Several non-HLA gene loci are also associated, such as common variants of the T-cell receptor-α (TRA), the purinergic receptor P2RY11, cathepsin H (CTSH) and TNFSF4/OX40L/CD252. In this retrospective multicenter study, we investigated if these predisposing gene loci were also involved in vaccination-associated narcolepsy. We compared HLA- along with single-nucleotide polymorphism genotypes for non-HLA regions between 42 Pandemrix-vaccinated narcolepsy cases and 1990 population-based controls. The class II gene loci associations supported previous findings. Nominal association (P-value<0.05) with TRA as well as suggestive (P-value<0.1) associations with P2RY11 and CTSH were found. These associations suggest a very strong gene-environment interaction, in which the influenza A(H1N1)pdm09 strain or Pandemrix vaccine can act as potent environmental triggers.

A coordinated cross-disciplinary research initiative to address an increased incidence of narcolepsy following the 2009-2010 Pandemrix vaccination programme in Sweden.

In response to the 2009-2010 influenza A(H1N1)pdm09 pandemic, a mass vaccination programme with the AS03-adjuvanted influenza A(H1N1) vaccine Pandemrix was initiated in Sweden. Unexpectedly, there were a number of narcolepsy cases amongst vaccinated children and adolescents reported. In this review, we summarize the results of a joint cross-disciplinary national research effort to investigate the adverse reaction signal from the spontaneous reporting system and to better understand possible causative mechanisms. A three- to fourfold increased risk of narcolepsy in vaccinated children and adolescents was verified by epidemiological studies. Of importance, no risk increase was observed for the other neurological and autoimmune diseases studied. Genetic studies confirmed the association with the allele HLA-DQB1*06:02, which is known to be related to sporadic narcolepsy. Furthermore, a number of studies using cellular and molecular experimental models investigated possible links between influenza vaccination and narcolepsy. Serum analysis, using a peptide microarray platform, showed that individuals who received Pandemrix exhibited a different epitope reactivity pattern to neuraminidase and haemagglutinin, as compared to individuals who were infected with H1N1. Patients with narcolepsy were also found to have increased levels of interferon-gamma production in response to streptococcus-associated antigens. The chain of patient-related events and the study results emerging over time were subjected to intense nationwide media attention. The importance of transparent communication and collaboration with patient representatives to maintain public trust in vaccination programmes is also discussed in the review. Organizational challenges due to this unexpected event delayed the initiation of some of the research projects, still the main objectives of this joint, cross-disciplinary research effort were reached, and important insights were acquired for future, similar situations in which a fast and effective task force may be required to evaluate vaccination-related adverse events.

Immunogenicity of virosomal adjuvanted trivalent influenza vaccination in allogeneic stem cell transplant recipients.

BACKGROUND: Influenza vaccination is generally recommended to hematopoietic stem cell transplant (HSCT) recipients. However, the seasonal subunit vaccination response is frequently suboptimal, and alternate more efficient vaccination systems must be examined. We compared the immunogenicity of an adjuvanted virosomal influenza and subunit vaccine in HSCT recipients. METHODS: The immunogenicity after a single dose (0.5 mL) of adjuvanted trivalent virosomal vaccination was evaluated in a study cohort of 21 HSCT recipients and compared to a control cohort of 30 HSCT recipients who received a single dose (0.5 mL) of non-adjuvanted seasonal trivalent subunit vaccination over 4 seasons from 2010 to 2014. Whole blood interferon-gamma (IFN-γ) release assays were tested, both before and 30 days after vaccination, in response to influenza pandemic (pdm) H1N1, H3N2, and B antigens. HLA-A*02 dextramers, to gauge for the absolute number of antigen-specific CD8(+) T-cells, and pdm 2009 hemagglutinin inhibition (HI) assays, to test for neutralizing antibodies, were used as immunological readouts. RESULTS: The pdm HI titers were poor in both cohorts with only 23% (5/21) after virosomal vaccination and 13.3% (4/30) in the seasonal vaccine cohort having protective titers (≥40). The delta change of IFN-γ production in response to influenza pdm H1N1 (P = 0.005) and influenza B antigens (P = 0.01) were significantly elevated in blood from individuals who received the virosomal as compared to the seasonal vaccine. The IFN-γ response to pdm H1N1 was stronger (P < 0.001), as compared to seasonal vaccination, in patients vaccinated >6 month post HSCT. We detected a significant increase in the frequency of matrix 1 (GILGFVTL) dextramer-specific CD8(+) T-cells after the virosomal vaccine (P = 0.01). No differences were seen in the hemagglutinin-specific CD8(+) T-cells between the 2 cohorts. CONCLUSION: Vaccination using a virosomal delivery system is beneficial in eliciting robust cellular immune responses to pdm H1N1 influenza in SCT recipients.

Evaluation of pretransplant influenza vaccination in hematopoietic SCT: a randomized prospective study.

Pretransplant influenza vaccination of the donor or allogeneic hematopoietic SCT (HSCT) candidate was evaluated in a randomized study. One hundred and twenty-two HSCT recipients and their donors were assigned to three randomization groups: no pretransplant vaccination (n=38), donor pretransplant vaccination (n=44) or recipient pretransplant vaccination (n=40). Specific IgG was assessed by both hemagglutinin inhibition (HI) and, in 57 patients, by an indirect influenza-specific ELISA at specified times after HSCT. Vaccinated donors had seroprotective HI titers for Ags H1 and H3 (P<0.001) compared with the other groups at the time of donation. The titers against H1 (P=0.028) and H3 (P<0.001) were highest in the pretransplant recipient vaccination group until day 180 after transplantation. A significant difference was found in the specific Ig levels against pandemic H1N1 at 6 months after SCT (P=0.02). The mean IgG levels against pandemic H1N1 and generic H1N1 and H3N2 were highest in the pretransplant recipient vaccination group. We conclude that pretransplant recipient vaccination improved the influenza-specific seroprotection rates.

Increased ß-haemolytic group A streptococcal M6 serotype and streptodornase B-specific cellular immune responses in Swedish narcolepsy cases.

BACKGROUND: Type 1 narcolepsy is a neurological disorder characterized by excessive daytime sleepiness and cataplexy associated with the HLA allele DQB1*06:02. Genetic predisposition along with external triggering factors may drive autoimmune responses, ultimately leading to the selective loss of hypocretin-positive neurons. OBJECTIVE: The aim of this study was to investigate potential aetiological factors in Swedish cases of postvaccination (Pandemrix) narcolepsy defined by interferon-gamma (IFNγ) production from immune cells in response to molecularly defined targets. METHODS: Cellular reactivity defined by IFNγ production was examined in blood from 38 (HLA-DQB1*06:02(+) ) Pandemrix-vaccinated narcolepsy cases and 76 (23 HLA-DQB1*06:02(+) and 53 HLA-DQB1*06:02(-) ) control subjects, matched for age, sex and exposure, using a variety of different antigens: ß-haemolytic group A streptococcal (GAS) antigens (M5, M6 and streptodornase B), influenza (the pandemic A/H1N1/California/7/09 NYMC X-179A and A/H1N1/California/7/09 NYMC X-181 vaccine antigens, previous Flu-A and -B vaccine targets, A/H1N1/Brisbane/59/2007, A/H1N1/Solomon Islands/3/2006, A/H3N2/Uruguay/716/2007, A/H3N2/Wisconsin/67/2005, A/H5N1/Vietnam/1203/2004 and B/Malaysia/2506/2004), noninfluenza viral targets (CMVpp65, EBNA-1 and EBNA-3) and auto-antigens (hypocretin peptide, Tribbles homolog 2 peptide cocktail and extract from rat hypothalamus tissue). RESULTS: IFN-γ production was significantly increased in whole blood from narcolepsy cases in response to streptococcus serotype M6 (P = 0.0065) and streptodornase B protein (P = 0.0050). T-cell recognition of M6 and streptodornase B was confirmed at the single-cell level by intracellular cytokine (IL-2, IFNγ, tumour necrosis factor-alpha and IL-17) production after stimulation with synthetic M6 or streptodornase B peptides. Significantly, higher (P = 0.02) titres of serum antistreptolysin O were observed in narcolepsy cases, compared to vaccinated controls. CONCLUSION: ß-haemolytic GAS may be involved in triggering autoimmune responses in patients who developed narcolepsy symptoms after vaccination with Pandemrix in Sweden, characterized by a Streptococcus pyogenes M-type-specific IFN-γ cellular immune response.

Totally drug-resistant tuberculosis and adjunct therapies.

The first cases of totally drug-resistant (TDR) tuberculosis (TB) were reported in Italy 10 years ago; more recently, cases have also been reported in Iran, India and South Africa. Although there is no consensus on terminology, it is most commonly described as 'resistance to all first- and second-line drugs used to treat TB'. Mycobacterium tuberculosis (M.tb) acquires drug resistance mutations in a sequential fashion under suboptimal drug pressure due to monotherapy, inadequate dosing, treatment interruptions and drug interactions. The treatment of TDR-TB includes antibiotics with disputed or minimal effectiveness against M.tb, and the fatality rate is high. Comorbidities such as diabetes and infection with human immunodeficiency virus further impact on TB treatment options and survival rates. Several new drug candidates with novel modes of action are under late-stage clinical evaluation (e.g., delamanid, bedaquiline, SQ109 and sutezolid). 'Repurposed' antibiotics have also recently been included in the treatment of extensively drug resistant TB. However, because of mutations in M.tb, drugs will not provide a cure for TB in the long term. Adjunct TB therapies, including therapeutic vaccines, vitamin supplementation and/or repurposing of drugs targeting biologically and clinically relevant molecular pathways, may achieve better clinical outcomes in combination with standard chemotherapy. Here, we review broader perspectives of drug resistance in TB and potential adjunct treatment options.

Inflammation and tuberculosis: host-directed therapies.

Tuberculosis (TB) is an airborne infectious disease that kills almost two million individuals every year. Multidrug-resistant (MDR) TB is caused by strains of Mycobacterium tuberculosis (M. tb) resistant to isoniazid and rifampin, the backbone of first-line antitubercular treatment. MDR TB affects an estimated 500,000 new patients annually. Genetic analysis of drug-resistant MDR-TB showed that airborne transmission of undetected and untreated strains played a major role in disease outbreaks. The need for new TB vaccines and faster diagnostics, as well as the development of new drugs, has recently been highlighted. The major problem in terms of current TB research and clinical demands is the increasing number of cases of extensively drug-resistant and 'treatment-refractory' TB. An emerging scenario of adjunct host-directed therapies is intended to target pulmonary TB where inflammatory processes can be deleterious and lead to immune exhaustion. 'Target-organ-saving' strategies may be warranted to prevent damage to infected tissues and achieve focused, clinically relevant and long-lasting anti-M. tb cellular immune responses. Candidates for such interventions may be biological agents or already approved drugs that can be 're-purposed' to interfere with biologically relevant cellular checkpoints. Here, we review current concepts of inflammation in TB disease and discuss candidate pathways for host-directed therapies to achieve better clinical outcomes.

Increased (6 exon) interleukin-7 production after M. tuberculosis infection and soluble interleukin-7 receptor expression in lung tissue.

Interleukin-7 (IL-7) and the IL-7 receptor (IL-7R) have been shown to be alternatively spliced in infectious diseases. We tested IL-7 and IL-7R splicing in a tuberculosis (TB)-vaccine/Mycobacterium tuberculosis (Mtb)-challenge model in non-human primates (NHPs). Differential IL-7 splicing was detected in peripheral blood mononuclear cells (PBMCs) from 15/15 NHPs showing 6 different IL-7 spliced isoforms. This pattern did not change after infection with virulent Mtb. We demonstrated increased IL-7 (6 exon) and IL-17 protein production in lung tissue along with concomitant decreased transforming growth factor-ß (TGF-ß) from NHPs (vaccinated with a recombinant BCG (rBCG)) who showed increased survival after Mtb challenge. IL-7 increased IL-17 and interferon-γ (IFN-γ) gene and protein expression in PBMCs. Mtb-infected NHPs showed differential IL-7R splicing associated with the anatomical location and tissue origin, that is, in lung tissue, hilus, axillary lymph nodes (LNs) and spleen. Differential splicing of the IL-7R was typical for healthy (non-Mtb infected) and for Mtb-infected lung tissue with a dominant expression of soluble IL-7R (sIL-7R) receptor lacking exon 6 (9:1 ratio of sIL-7R/cell-bound IL-7R). Differential ratios of cell-bound vs sIL-7R could be observed in hilus and axillary LNs from Mtb-infected NHPs with an inversed ratio of 1:9 (sIL-7R/cell-bound IL-7R) in spleen and PBMCs. Soluble IL-7R is exclusively present in lung tissue.

Risk of tuberculosis in a large sample of patients with coeliac disease--a nationwide cohort study.

BACKGROUND: Research suggests a positive association between coeliac disease and tuberculosis (TB), but that research has often been limited to in-patients and small sample size. We examined the relationship between TB and coeliac disease. AIM: To examine the association of TB and coeliac disease. METHODS: We collected biopsy data from all pathology departments in Sweden (n=28) to identify individuals who were diagnosed with coeliac disease between 1969 and 2007 (Marsh 3: villous atrophy; n=29,026 unique individuals). Population-based sex- and age-matched controls were selected from the Total Population Register. Using Cox regression, we calculated hazard ratios (HRs) for TB from data in the Swedish national health registers. RESULTS: Individuals with coeliac disease were at increased risk of TB (HR=2.0; 95% CI=1.3-3.0) (during follow-up, 31 individuals with coeliac disease and 74 reference individuals had a diagnosis of TB). The absolute risk of TB in patients with coeliac disease was 10/100,000 person-years with an excess risk of 5/100,000. Risk estimates were the highest in the first year. Restricting our outcome to a diagnosis of TB confirmed by (I) a record of TB medication (HR=2.9; 95% CI=1.0-8.3), (II) data in the National Surveillance System for Infectious Diseases in Sweden (HR=2.6; 95% CI=1.3-5.2) or (III) positive TB cultivation (HR=3.3; 95% CI=1.6-6.8) increased risk estimates. The positive association between coeliac disease and TB was also observed before the coeliac disease diagnosis (odds ratio=1.6; 95% CI=1.2-2.1). CONCLUSION: We found a moderately increased risk of tuberculosis in patients with coeliac disease.

Alternative splicing of interleukin-7 (IL-7) and interleukin-7 receptor alpha (IL-7Ralpha) in peripheral blood from patients with multiple sclerosis (MS).

IL-7 and IL-7Ralpha (IL-7R) form a non-redundant ligand receptor system which plays a crucial role in human T cell immunity. Both IL-7 and IL-7R are multi-exonal genes and exhibit alternative splicing. We measured the relative distribution of IL-7 and IL-7R spliced mRNA from patients with MS and healthy individuals and observed extensive alternative splicing of both genes with marked differences in proportional transcript expression levels. We report here for the first time that the IL-7 transcript, lacking exon 4, and not the full length IL-7 represents the dominant IL-7 RNA transcript in human PBMCs and a novel IL-7R splice variant lacking exons 5, 6 and 7.

Interleukin-7 (IL-7) and IL-7 splice variants affect differentiation of human neural progenitor cells.

Alternative splicing of pre-mRNA increases proteomic diversity, a crucial mechanism in defining tissue identity. We demonstrate differentially spliced interleukin (IL)-7 in distinct anatomic areas in the adult, in developing human brains and in normal human neuronal progenitor (NHNP) cells. IL-7c (c, the canonical form spanning all six exons) or its variants IL-7 delta 5, delta 4 or delta 4/5 were cloned and expressed as recombinant proteins. IL-7 and splice variants were able to shift the differentiation of NHNP cells as compared with the diluent control (P<0.01) defined by anti-beta (III)-tubulin and glial fibrillary acidic protein expression, with different degrees (IL-7c>delta 4/5>IL-7 delta 5); IL-7 delta 4 exhibited a significantly weaker potency. Differentiation was confirmed by transcriptome analysis of IL-7c-stimulated neural NHNP cells, resulting in 58 differentially expressed genes; some of these are involved in neural differentiation, for example, the developmentally regulated transcription factor krüppel-like factor 12, musashi 2, a translational regulator of cell fate or the sonic hedgehog receptor patch 1. This suggests that IL-7 influences neural development at a molecular level by participating in human brain architecture through glia cell formation: a paradigm that alternative splicing in cytokines, for example, for IL-7, has a physiological role in human organ development and progenitor cell differentiation.

Expression analysis and functional activity of interleukin-7 splice variants.

Alternative splicing results in multiple protein isoforms derived from a single gene. The magnitude of this process ranges from a complete loss of function to gain of new function. We examined, as a paradigm, alternative splicing of the non-redundant human cytokine, interleukin-7 (IL-7). We show that extensive IL-7 splicing in human tissues of different histology, including MTB+ granuloma lesions, transformed tissue and tumor cell lines. IL-7 splice variants were expressed as recombinant proteins. A differentially spliced IL-7 isoform, lacking exon 5, leads to STAT-5 phosphorylation in CD4+ and CD8+ T cells, promotes thymocyte maturation and T-cell survival. Human tumor lesions show aberrant IL-7 isoform expression, as compared with the autologous, non-transformed tissue. Alternatively spliced cytokines, such as IL-7, represent candidates for diagnostics and therapeutic interventions.

Clinical and microbiological efficacy of moxifloxacin versus amoxicillin/clavulanic acid in severe odontogenic abscesses: a pilot study.

The aim of this study targeted the evaluation of the in vivo effect of moxifloxacin in the treatment of patients with severe odontogenic abscesses. This was a prospective, two-armed, randomised, unblinded, monocentric pilot study, which enrolled 21 hospitalized patients with severe odontogenic abscesses. After extraoral incision, patients were either treated with moxifloxacin 400 mg i.v. once daily or amoxicillin/clavulanic acid 2.2 g i.v. three times daily. Primary clinical endpoint was the time until clinical remission, represented by simultaneous assertion of the following criteria: body temperature <38.5 degrees C, no pain at palpation, and mouth opening similar or better than preoperatively. White blood cell count, C-reactive protein, pain, health related quality of life (HR-QoL) and length of hospital stay were recorded as secondary outcome criteria. The mean duration until reaching the primary end point was 6.6 (range, 4.3-8.8) days in the moxifloxacin group and 6.0 (range, 3.8-8.2) days in the amoxicillin/clavulanic acid group. Median days of in-house treatment ranged between five and six days for both groups. HR-QoL was highly impaired in both groups preoperatively and reached near normal on days three and four in both samples. In this pilot investigation, moxifloxacin showed promising results as compared to amoxicillin/clavulanic acid. Therefore, a larger prospective clinical trial using moxifloxacin in severe odontogenic abscesses appears encouraging. We suggest a combination of body temperature, palpatory pain, and subjective pain as a parameter for successful intervention; however, both findings need prospective validation by means of a phase III evaluation.

Severe versus local odontogenic bacterial infections: comparison of microbial isolates.

AIM: It was the aim of this study to evaluate the clinical and microbiological differences between severe and local odontogenic abscesses. METHODS: Thirty patients were prospectively enrolled. Sixteen of 30 patients suffered from a severe life-threatening abscess of the head and neck, whereas 14/30 patients presented with a localized submucous abscess. Anaerobic bacteria were identified and susceptibility testing was performed using E test strips for penicillin, amoxicillin + clavulanic acid, imipenem + cilastatin, clindamycin and metronidazole. RESULTS: The mean duration until removal of all drains was 14.1 and 3.5 days, respectively. Anaerobic bacteria were found in all episodes of local abscesses, whereas 19% of the severe episodes were culture negative, and in 13%, only aerobes were identified. A total of 60 anaerobes were isolated from 27 patients (2.2 isolates/positive sample). The dominating species were Prevotella sp. (n = 17), Peptostreptococcus sp. (n = 15) and Propionibacterium sp. (n = 5). Eighty-seven percent of the isolates were susceptible to penicillin. Ninety-seven percent of the anaerobes were susceptible to amoxicillin + clavulanic acid, imipenem + cilastatin, and clindamycin. Eighty-three percent were susceptible to metronidazol. There was a tendency for a higher rate of episodes with penicillin-resistant bacteria in the patients with severe abscesses (14 vs. 31%). No difference in susceptibility regarding amoxicillin + clavulanic acid and clindamycin (7%) was observed.

Impact of MHC class I alleles on the M. tuberculosis antigen-specific CD8+ T-cell response in patients with pulmonary tuberculosis.

Challenged by scattered understanding of protective immunity to Mycobacterium tuberculosis (MTB), we have mapped peptide epitopes to human leukocyte antigen (HLA)-A*0101, A*0201, A*1101, A*2402, B*0702, B*0801 and B*1501 of the secreted mycobacterial antigen Ag85B, a vaccine candidate that may be associated with immune protection. Affinity (ED(50)) and half-life (t(1/2), off-rate) analysis for individual peptide species on HLA-A and HLA-B molecules revealed binding ranges between 10(-3) and 10(-7) M. After selection of the best matches, major histocompatibility complex class I/peptide tetramer complexes were constructed to measure the CD8+ T-cell responses directly ex vivo in peripheral blood mononuclear cells (PBMC) derived from 57 patients with acute pulmonary tuberculosis. Three patterns of (allele-) specific CD8+ recognition were identified: (a). Focus on one dominant epitope with additional recognition of several subdominant T-cell epitopes (HLA-A*0301, A*2402, B*0801 and B*1501); (b). Co-dominant recognition of two distinct groups of peptides presented by HLA-B*0702; and (c). Diverse and broad recognition of peptides presented by HLA-A*0201. Peptides that bound with slow off-rates to class I alleles, that is HLA-A*0201, were associated with low frequency of CD8+ T cells in PBMCs from patients with tuberculosis. HLA-B alleles showed fast off-rates in peptide binding and restricted high numbers (up to 6%) of antigen-specific CD8+ T cells in patients with pulmonary tuberculosis.

MHC class II tetramer guided detection of Mycobacterium tuberculosis-specific CD4+ T cells in peripheral blood from patients with pulmonary tuberculosis.

Novel diagnostic tools are needed to diagnose latent infection and to provide biologically meaningful surrogate markers to define cellular immune responses against Mycobacterium tuberculosis (MTB). Interferon gamma-based assays have recently been developed in addition to the more than 100-year-old tuberculin skin test (TST) for the immune diagnosis of MTB in blood. The advent of soluble MHC/peptide tetramer molecules allows to objectively enumerate antigen-specific T cells. We identified novel MHC class II-restricted MTB epitopes and used HLA-DR4 tetrameric complexes to visualize ex vivo CD4(+) T cells directed against the antigens Ag85B and the 19-kDa lipoprotein, shared between MTB and other Mycobacterium species, and CD4(+) T cells which recognize the MTB-associated ESAT-6 antigen. MTB-reactive CD4(+) T cells reside predominantly in the CD45RA(+) CD28(+) and CD45(-) CD28(+) T-cell subset and recognize naturally processed and presented MTB epitopes. HLA-DR4-restricted, Ag85B or ESAT-6-specific CD4(+) T cells show similar dynamics over time in peripheral blood mononuclear cells (PBMC) when compared with CD8(+) T cells directed against the corresponding HLA-A2-presented MTB epitopes in patients with pulmonary MTB infection and subsequent successful therapy. This was not found to be true for T-cell responses directed against the 19-kDa lipoprotein. The dissection of the cellular immune response in M. tuberculosis infection will enable novel strategies for monitoring MTB vaccine candidates and to gauge CD4(+) T cells directed against MTB.