SUMMARY The kinetics of in vitro cellular proliferation against a PPD of Mycobacterium tuberculos... more SUMMARY The kinetics of in vitro cellular proliferation against a PPD of Mycobacterium tuberculosis or streptococcal antigen (streptokinase-streptodornase) was evaluated in pleural fluid and peripheral blood mononuclear cells (PBMC) from patients with tuberculous and non-tuberculous pleuritis. The peak proliferative response to PPD by mononuclear cells from pleural fluid occurred earlier (day 3) in 65% of patients with tuberculosis, a finding not seen in non-tuberculous effusions. Spontaneous lymphocyte proliferation of both peripheral blood lymphocytes and pleural effusion lymphocytes was frequently observed, irrespective of etiology. However, 20 of 21 tuberculous patients manifesting spontaneous lymphocyte proliferation had accelerated kinetics of proliferation to PPD, which was antigen-specific. These results suggest that spontaneous lymphocyte proliferation occurs as a response to antigen stimulation at the site of disease, and is not a non-specific response to inflammation. Fur...
ABSTRACT The PANORAMA study was designed to collect concurrent data on subjects from different wo... more ABSTRACT The PANORAMA study was designed to collect concurrent data on subjects from different worldwide regions implanted with CRM devices.
The immune response to infection with M. tuberculosis depends on cytokine activation of effector ... more The immune response to infection with M. tuberculosis depends on cytokine activation of effector cells. We therefore conducted a pilot study of recombinant human interleukin-2 (rhuIL-2) as an adjunct to multidrug therapy (MDT) to evaluate the safety of this approach and to determine whether IL-2 can enhance the cellular immune response in patients with pulmonary tuberculosis (TB). Patients included in this study presented with a wide range of extent and duration of infection, and were grouped into three categories for data analysis: (1) patients with newly diagnosed, acute-stage TB who were just beginning MDT; (2) patients who had received a minimum of 45 days MDT before the start of the study and who had responded to treatment; and (3) patients with multidrug-resistant (MDR) TB who had been on MDT for at least seven months without apparent beneficial clinical response. Twenty patients received 30 days of twice-daily intradermal injections of 12.5 micrograms of IL-2. Patients from all three groups showed improvement of clinical symptoms over the 30-day period of treatment with IL-2 and MDT. Results of direct smear for acid fast bacilli (AFB) demonstrated conversion to sputum-negative following IL-2 and MDT treatment in all newly diagnosed patients and in 5/7 MDR TB patients. (The size of the skin test response to purified protein derivative (PPD) of tuberculin increased during the 30-day IL-2 adjunctive therapy in newly diagnosed patients, but decreased or disappeared in the other two groups of treated patients.) Assays in vitro for phenotype distribution, natural killer (NK) cell activity, frequency of cells proliferating in response to exogenous IL-2, and antigen-induced blastogenesis demonstrated systemic responses to intradermally administered rhuIL-2. Levels of interferon-gamma (IFN-gamma) in plasma, peripheral blood mononuclear cell (PBMC) IFN-gamma mRNA and IFN-gamma mRNA in biopsy of site of skin test response to purified protein derivative (PPD) were highest in those patients with the most acute symptoms at the beginning of the study, and decreased during rhuIL-2 and MDT. IL-2 immunotherapy did not modify levels of mRNA expression for other cytokines. Patients receiving IL-2 did not experience clinical deterioration or significant side effects. These results suggest that IL-2 administration in combination with conventional MDT is safe and may potentiate the antimicrobial cellular immune response to TB.
The recombinant 65 kDa mycobacterial protein of M. bovis BCG has been shown to be immunodominant ... more The recombinant 65 kDa mycobacterial protein of M. bovis BCG has been shown to be immunodominant in mice immunized with M. tuberculosis. Little is known about reactivity to this antigen in patients with tuberculous pleuritis. In this study therefore, pleural effusion and autologous peripheral blood lymphocytes obtained from patients with tuberculous and nontuberculous pleuritis were stimulated in-vitro with the recombinant 65 kDa antigen. Proliferation was assessed by 3[H] thymidine incorporation. In addition, pleural effusion lymphocytes were activated in vitro with the 65 kDa antigen and tested for cytotoxic activity in 15-hr chromium-release assays. Pleural effusion lymphocytes obtained from a high percentage (56%) of patients with tuberculous pleuritis showed significant proliferative responses to the 65 kDa antigen, while the response in autologous peripheral blood lymphocytes was significantly lower. By contrast, pleural effusion lymphocytes obtained from patients with nontube...
Mycobacterium tuberculosis is a bacterial pathogen capable of survival and replication within hum... more Mycobacterium tuberculosis is a bacterial pathogen capable of survival and replication within human macrophages. Cytotoxic T cells are thought to be important for the eradication of infected macrophages. To test this hypothesis, pleural effusion lymphocytes from patients with tuberculous pleuritis were stimulated in vitro with PPD, and proliferation and cytotoxicity were assessed by thymidine incorporation and chromium release, respectively. The level and kinetics of generation of antigen-specific cytotoxicity were measured and compared with those in autologous peripheral blood, control peripheral blood, and nontuberculous effusions. Both proliferation and cytotoxicity in tuberculous pleural effusions were augmented and accelerated in comparison to autologous or control peripheral blood. By contrast, low levels of cytotoxicity were observed in nontuberculous effusions, without evidence of accelerated kinetics. Cell subset fractionation by panning indicated that the cytotoxicity was mediated by CD4+ cells. The accelerated kinetics of induction of PPD-specific cytotoxic T cells demonstrated here suggests reactivation of in vivo generated cytotoxic T cells. These findings provide evidence that cytotoxic T cells are induced at the site of pathology in vivo and suggest that these cells play an important role in protection in vivo against infection with tuberculosis.
Catheter ablation of ventricular tachycardia (VT) is demanding and time consuming. Robotically co... more Catheter ablation of ventricular tachycardia (VT) is demanding and time consuming. Robotically controlled catheter ablation reduces operator fatigue and exposure to X-rays, and provides greater precision and stability of the catheter. A new flexible, integrated robotic sheath and ablation catheter has recently been introduced (Lynx(TM)) and used in atrial ablation procedures. We describe the first VT substrate modification ablation in the world with the Lynx(TM) robotic radio frequency ablation catheter.
The immune response to infection with M. tuberculosis depends on cytokine activation of effector ... more The immune response to infection with M. tuberculosis depends on cytokine activation of effector cells. We therefore conducted a pilot study of recombinant human interleukin-2 (rhuIL-2) as an adjunct to multidrug therapy (MDT) to evaluate the safety of this approach and to determine whether IL-2 can enhance the cellular immune response in patients with pulmonary tuberculosis (TB). Patients included in this study presented with a wide range of extent and duration of infection, and were grouped into three categories for data analysis: (1) patients with newly diagnosed, acute-stage TB who were just beginning MDT; (2) patients who had received a minimum of 45 days MDT before the start of the study and who had responded to treatment; and (3) patients with multidrug-resistant (MDR) TB who had been on MDT for at least seven months without apparent beneficial clinical response. Twenty patients received 30 days of twice-daily intradermal injections of 12.5 micrograms of IL-2. Patients from all three groups showed improvement of clinical symptoms over the 30-day period of treatment with IL-2 and MDT. Results of direct smear for acid fast bacilli (AFB) demonstrated conversion to sputum-negative following IL-2 and MDT treatment in all newly diagnosed patients and in 5/7 MDR TB patients. (The size of the skin test response to purified protein derivative (PPD) of tuberculin increased during the 30-day IL-2 adjunctive therapy in newly diagnosed patients, but decreased or disappeared in the other two groups of treated patients.) Assays in vitro for phenotype distribution, natural killer (NK) cell activity, frequency of cells proliferating in response to exogenous IL-2, and antigen-induced blastogenesis demonstrated systemic responses to intradermally administered rhuIL-2. Levels of interferon-gamma (IFN-gamma) in plasma, peripheral blood mononuclear cell (PBMC) IFN-gamma mRNA and IFN-gamma mRNA in biopsy of site of skin test response to purified protein derivative (PPD) were highest in those patients with the most acute symptoms at the beginning of the study, and decreased during rhuIL-2 and MDT. IL-2 immunotherapy did not modify levels of mRNA expression for other cytokines. Patients receiving IL-2 did not experience clinical deterioration or significant side effects. These results suggest that IL-2 administration in combination with conventional MDT is safe and may potentiate the antimicrobial cellular immune response to TB.
SUMMARY The kinetics of in vitro cellular proliferation against a PPD of Mycobacterium tuberculos... more SUMMARY The kinetics of in vitro cellular proliferation against a PPD of Mycobacterium tuberculosis or streptococcal antigen (streptokinase-streptodornase) was evaluated in pleural fluid and peripheral blood mononuclear cells (PBMC) from patients with tuberculous and non-tuberculous pleuritis. The peak proliferative response to PPD by mononuclear cells from pleural fluid occurred earlier (day 3) in 65% of patients with tuberculosis, a finding not seen in non-tuberculous effusions. Spontaneous lymphocyte proliferation of both peripheral blood lymphocytes and pleural effusion lymphocytes was frequently observed, irrespective of etiology. However, 20 of 21 tuberculous patients manifesting spontaneous lymphocyte proliferation had accelerated kinetics of proliferation to PPD, which was antigen-specific. These results suggest that spontaneous lymphocyte proliferation occurs as a response to antigen stimulation at the site of disease, and is not a non-specific response to inflammation. Fur...
ABSTRACT The PANORAMA study was designed to collect concurrent data on subjects from different wo... more ABSTRACT The PANORAMA study was designed to collect concurrent data on subjects from different worldwide regions implanted with CRM devices.
The immune response to infection with M. tuberculosis depends on cytokine activation of effector ... more The immune response to infection with M. tuberculosis depends on cytokine activation of effector cells. We therefore conducted a pilot study of recombinant human interleukin-2 (rhuIL-2) as an adjunct to multidrug therapy (MDT) to evaluate the safety of this approach and to determine whether IL-2 can enhance the cellular immune response in patients with pulmonary tuberculosis (TB). Patients included in this study presented with a wide range of extent and duration of infection, and were grouped into three categories for data analysis: (1) patients with newly diagnosed, acute-stage TB who were just beginning MDT; (2) patients who had received a minimum of 45 days MDT before the start of the study and who had responded to treatment; and (3) patients with multidrug-resistant (MDR) TB who had been on MDT for at least seven months without apparent beneficial clinical response. Twenty patients received 30 days of twice-daily intradermal injections of 12.5 micrograms of IL-2. Patients from all three groups showed improvement of clinical symptoms over the 30-day period of treatment with IL-2 and MDT. Results of direct smear for acid fast bacilli (AFB) demonstrated conversion to sputum-negative following IL-2 and MDT treatment in all newly diagnosed patients and in 5/7 MDR TB patients. (The size of the skin test response to purified protein derivative (PPD) of tuberculin increased during the 30-day IL-2 adjunctive therapy in newly diagnosed patients, but decreased or disappeared in the other two groups of treated patients.) Assays in vitro for phenotype distribution, natural killer (NK) cell activity, frequency of cells proliferating in response to exogenous IL-2, and antigen-induced blastogenesis demonstrated systemic responses to intradermally administered rhuIL-2. Levels of interferon-gamma (IFN-gamma) in plasma, peripheral blood mononuclear cell (PBMC) IFN-gamma mRNA and IFN-gamma mRNA in biopsy of site of skin test response to purified protein derivative (PPD) were highest in those patients with the most acute symptoms at the beginning of the study, and decreased during rhuIL-2 and MDT. IL-2 immunotherapy did not modify levels of mRNA expression for other cytokines. Patients receiving IL-2 did not experience clinical deterioration or significant side effects. These results suggest that IL-2 administration in combination with conventional MDT is safe and may potentiate the antimicrobial cellular immune response to TB.
The recombinant 65 kDa mycobacterial protein of M. bovis BCG has been shown to be immunodominant ... more The recombinant 65 kDa mycobacterial protein of M. bovis BCG has been shown to be immunodominant in mice immunized with M. tuberculosis. Little is known about reactivity to this antigen in patients with tuberculous pleuritis. In this study therefore, pleural effusion and autologous peripheral blood lymphocytes obtained from patients with tuberculous and nontuberculous pleuritis were stimulated in-vitro with the recombinant 65 kDa antigen. Proliferation was assessed by 3[H] thymidine incorporation. In addition, pleural effusion lymphocytes were activated in vitro with the 65 kDa antigen and tested for cytotoxic activity in 15-hr chromium-release assays. Pleural effusion lymphocytes obtained from a high percentage (56%) of patients with tuberculous pleuritis showed significant proliferative responses to the 65 kDa antigen, while the response in autologous peripheral blood lymphocytes was significantly lower. By contrast, pleural effusion lymphocytes obtained from patients with nontube...
Mycobacterium tuberculosis is a bacterial pathogen capable of survival and replication within hum... more Mycobacterium tuberculosis is a bacterial pathogen capable of survival and replication within human macrophages. Cytotoxic T cells are thought to be important for the eradication of infected macrophages. To test this hypothesis, pleural effusion lymphocytes from patients with tuberculous pleuritis were stimulated in vitro with PPD, and proliferation and cytotoxicity were assessed by thymidine incorporation and chromium release, respectively. The level and kinetics of generation of antigen-specific cytotoxicity were measured and compared with those in autologous peripheral blood, control peripheral blood, and nontuberculous effusions. Both proliferation and cytotoxicity in tuberculous pleural effusions were augmented and accelerated in comparison to autologous or control peripheral blood. By contrast, low levels of cytotoxicity were observed in nontuberculous effusions, without evidence of accelerated kinetics. Cell subset fractionation by panning indicated that the cytotoxicity was mediated by CD4+ cells. The accelerated kinetics of induction of PPD-specific cytotoxic T cells demonstrated here suggests reactivation of in vivo generated cytotoxic T cells. These findings provide evidence that cytotoxic T cells are induced at the site of pathology in vivo and suggest that these cells play an important role in protection in vivo against infection with tuberculosis.
Catheter ablation of ventricular tachycardia (VT) is demanding and time consuming. Robotically co... more Catheter ablation of ventricular tachycardia (VT) is demanding and time consuming. Robotically controlled catheter ablation reduces operator fatigue and exposure to X-rays, and provides greater precision and stability of the catheter. A new flexible, integrated robotic sheath and ablation catheter has recently been introduced (Lynx(TM)) and used in atrial ablation procedures. We describe the first VT substrate modification ablation in the world with the Lynx(TM) robotic radio frequency ablation catheter.
The immune response to infection with M. tuberculosis depends on cytokine activation of effector ... more The immune response to infection with M. tuberculosis depends on cytokine activation of effector cells. We therefore conducted a pilot study of recombinant human interleukin-2 (rhuIL-2) as an adjunct to multidrug therapy (MDT) to evaluate the safety of this approach and to determine whether IL-2 can enhance the cellular immune response in patients with pulmonary tuberculosis (TB). Patients included in this study presented with a wide range of extent and duration of infection, and were grouped into three categories for data analysis: (1) patients with newly diagnosed, acute-stage TB who were just beginning MDT; (2) patients who had received a minimum of 45 days MDT before the start of the study and who had responded to treatment; and (3) patients with multidrug-resistant (MDR) TB who had been on MDT for at least seven months without apparent beneficial clinical response. Twenty patients received 30 days of twice-daily intradermal injections of 12.5 micrograms of IL-2. Patients from all three groups showed improvement of clinical symptoms over the 30-day period of treatment with IL-2 and MDT. Results of direct smear for acid fast bacilli (AFB) demonstrated conversion to sputum-negative following IL-2 and MDT treatment in all newly diagnosed patients and in 5/7 MDR TB patients. (The size of the skin test response to purified protein derivative (PPD) of tuberculin increased during the 30-day IL-2 adjunctive therapy in newly diagnosed patients, but decreased or disappeared in the other two groups of treated patients.) Assays in vitro for phenotype distribution, natural killer (NK) cell activity, frequency of cells proliferating in response to exogenous IL-2, and antigen-induced blastogenesis demonstrated systemic responses to intradermally administered rhuIL-2. Levels of interferon-gamma (IFN-gamma) in plasma, peripheral blood mononuclear cell (PBMC) IFN-gamma mRNA and IFN-gamma mRNA in biopsy of site of skin test response to purified protein derivative (PPD) were highest in those patients with the most acute symptoms at the beginning of the study, and decreased during rhuIL-2 and MDT. IL-2 immunotherapy did not modify levels of mRNA expression for other cytokines. Patients receiving IL-2 did not experience clinical deterioration or significant side effects. These results suggest that IL-2 administration in combination with conventional MDT is safe and may potentiate the antimicrobial cellular immune response to TB.
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Papers by Faizel Lorgat