rhulL-2 adjunctive therapy in multidrug resistant tuberculosis: A comparison of two treatment regimens and placebo

doi:10.1016/S0962-8479(97)90026-5

Tubercle and Lung Disease

Volume 78, Issues 3–4, 1997, Pages 195-203

Tubercle and Lung Di...

https://doi.org/10.1016/S0962-8479(97)90026-5 Get rights and content

Abstract

Setting: Low-dose recombinant human interleukin 2 (rhulL-2) adjunctive immunotherapy in multidrug resistant tuberculosis (MDR-TB) patients.

Objective: Evaluation of the effects of daily versus pulse-administered rhulL-2 compared to placebo.

Design: MDR-TB patients on best available antituberculous chemotherapy received rhulL-2 for 30 consecutive days (daily therapy), or for 5 days followed by a 9-day ‘rest’, for three cycles (pulse therapy). Placebo control patients received diluent. The cumulative total dose of rhulL-2 given to each patient in either rhulL-2 treatment group was the same. Patient immunologic, microbiologic, and radiologic responses were compared.

Results: The three treatment schedules induced different results. Immune activation was documented in patients receiving daily rhulL-2 therapy. Numbers of CD25⁺ and CD56⁺ cells in the peripheral blood were increased in these patients, but not in patients receiving pulse rhulL-2 or placebo. In addition, $58$ (62%) patients receiving daily rhulL-2 demonstrated reduced or cleared sputum bacterial load while only $27$ (28%) pulse rhulL-2 treated and $28$ (25%) controls showed bacillary clearance. Chest radiographs of $712$ (58%) patients receiving daily rhulL-2 indicated significant improvement over 6 weeks. Only $29$ (22%) pulse rhulL-2-treated patients and $512$ (42%) placebo controls showed radiologic improvement.

Conclusion: Daily low dose rhulL-2 adjunctive treatment stimulates immune activation and may enhance the antimicrobial response in MDR-TB.

References (14)

ST Cole
Drug resistance in Mycobacterium tuberculosis
Eur Resp J
(1995)
MM Park et al.
Outcome of MDR-TB patients, 1983–1993
KA Smith
Interleukin-2
Ann Rev Immunol
(1984)
G Kaplan et al.
The systemic influence of recombinant interleukin 2 on the manifestations of lepromatous leprosy
J Exp Med
(1991)
H Teppler et al.
Prolonged immunostimulatory effect of low-dose polyethylene glycol interleukin 2 in patients with human immunodeficiency virus type 1 infection
J Exp Med
(1993)
A Jeevan et al.
Recombinant interleukin-2 limits the replication of Mycobacterium lepraemurium and Mycobacterium bovis BCG in mice
Lymphokine Research
(1988)
BJ Johnson et al.
Clinical and immune responses of tuberculosis patients treated with low-dose IL-2 and multidrug therapy
Cytokines and Molecular Therapy
(1995)

There are more references available in the full text version of this article.

Cited by (75)

Therapeutic host-directed strategies to improve outcome in tuberculosis
2020, Mucosal Immunology
Bacille Calmette-Guérin (BCG) is the only licenced tuberculosis (TB) vaccine, but has limited efficacy against pulmonary TB disease development and modest protection against extrapulmonary TB. Preventative antibiotic treatment for Mycobacterium tuberculosis (Mtb) infections in high-prevalence settings is unfeasible due to unclear treatment durability, drug toxicity, logistical constraints related to directly observed treatment strategy (DOTS) and the lengthy treatment protocols. Together, these factors promote non-adherence, contributing to relapse and establishment of drug-resistant Mtb strains. Although antibiotic treatment of drug-susceptible Mtb is generally effective, drug-resistant TB has a treatment efficacy below 50% and can, in a proportion, develop into progressive, untreatable disease. Other immune compromising co-infections and/or co-morbidities require more complex prevention/treatment approaches, posing huge financial burdens to national health services. Novel TB treatment strategies, such as host-directed therapeutics, are required to complement pathogen-targeted approaches. Pre-clinical studies have highlighted promising candidates that enhance endogenous pathways and/or limit destructive host responses. This review discusses promising pre-clinical candidates and forerunning compounds at advanced stages of clinical investigation in TB host-directed therapeutic (HDT) efficacy trials. Such approaches are rationalized to improve outcome in TB and shorten treatment strategies.
Nanostructured drug delivery for better management of tuberculosis
2014, Journal of Controlled Release
Citation Excerpt :
While agglutinin surface modified nanoparticles needed only three doses administered every 14 days for 45 days. Passive targeting of chemotherapeutic compounds to alveolar macrophages has been studied using pulmonary administration of nanoparticles for the treatment of TB infections [121,122]. Versatility of the nanoparticle-based formulations was further established by effective subcutaneous injections to mice infected with M. tuberculosis [123].
With almost 30% of the world population suffering from tuberculosis (TB) including its resurgence in the developed world, better management of this global threat is highly desired. The emergence of multidrug-resistant TB (MDR-TB) against first-line drugs and extensively drug resistant TB (XDR-TB) due to misuse of second-line antitubercular drugs (ATDs) is a further concern. Recommended treatment involves long term and multiple drug therapy with severe side effects. In this context, nanostructured systems efficiently encapsulating considerable amounts of ATDs, eliciting controlled, sustained and more profound effect to overcome the need to administer ATDs at high and frequent doses, would assist in improving patient compliance and circumvent hepatotoxicity and/or nephrotoxicity/ocular toxicity/ototoxicity associated with the prevalent first-line chemotherapy. Nanostructured delivery systems constitute a wide range of systems varying from liposomes, micelles, micro- and nanoemulsions, to polymeric nanoparticles (PNPs) and solid lipid nanoparticles (SLNs). Improved bioavailability, solubility, stability and biocompatibility make them an ideal choice for delivery of ATDs. Present review comprehensively covers research carried out on first-line antitubercular drug therapy using these nanostructured systems.
Increasing the biological activity of IL-2 and IL-15 through complexing with anti-IL-2 mAbs and IL-15Rα-Fc chimera
2014, Immunology Letters
Citation Excerpt :
Yet, IL-2 cancer therapy is of continued interest in part because about one-third of the clinical responses are complete, durable remissions. So far, IL-2 immunotherapy has been shown to be beneficial in a variety of clinical trials [40–44]. For example, studies to identify antigen-nonspecific strategies for enhancing immune reconstitution in individuals with HIV infection include those using IL-2 [45].
IL-2 and IL-15 are structurally relative cytokines that share two receptor subunits, CD132 (γ_c chain) and CD122 (β chain). However, the expression pattern and physiological role of IL-2 and IL-15 private receptor α chains CD25 and IL-15Rα, respectively, are strikingly different. CD25, together with CD122 and CD132, forms a trimeric high affinity IL-2 receptor that is expressed and functions on cells acquiring an IL-2 signal. Conversely, IL-15Rα is expressed and binds IL-15 with high affinity per se already in the endoplasmic reticulum of the IL-15 producing cells and it presents IL-15 to cells expressing CD122/CD132 dimeric receptor in trans. Thus, while IL-2 is secreted almost exclusively by activated T cells and acts as a free molecule, IL-15 is expressed mostly by myeloid cells and works as a cell surface-associated cytokine. Interestingly, the in vivo biological activity of IL-2 can be dramatically increased through complexing with certain anti-IL-2 mAbs; such IL-2/anti-IL-2 mAbs immunocomplexes selectively stimulate the proliferation of a distinct population of immune cells, depending on the clone of the anti-IL-2 mAb used. IL-2/S4B6 mAb immunocomplexes are highly stimulatory for CD122^high populations (memory CD8⁺ T and NK cells) and intermediately also for CD25^high populations (Treg and activated T cells), while IL-2/JES6-1 mAb immunocomplexes enormously expand only CD25^high cells. Although IL-2 immunocomplexes are much more potent than IL-2 in vivo, they show comparable to slightly lower activity in vitro. The in vivo biological activity of IL-15 can be dramatically increased through complexing with recombinant IL-15Rα-Fc chimera; however, IL-15/IL-15Rα-Fc complexes are significantly more potent than IL-15 both in vivo and in vitro. In this review we summarize and discuss the features and biological relevance of IL-2/anti-IL-2 mAbs and IL-15/IL-15Rα-Fc complexes, and try to foreshadow their potential in immunological research and immunotherapy.
Progress in tuberculosis vaccine development and host-directed therapies-a state of the art review
2014, The Lancet Respiratory Medicine
Citation Excerpt :
Intradermal injection of 12·5 μg twice daily over 30 days of human recombinant interleukin 2 was safe and seemed to be effective to achieve conversion to a sputum-negative smear in an open label non-randomised trial with 20 patients, including patients with multidrug-resistant tuberculosis.63,64 Daily administration was better to achieve sputum conversion than was pulsed therapy.65 However, a randomised, placebo-controlled, double-blinded trial assessed adjuvant therapy with interferon 2 in 110 patients with sputum smear-positive, pan drug-susceptible tuberculosis, and could not confirm the results from the preliminary studies.66
Tuberculosis continues to kill 1·4 million people annually. During the past 5 years, an alarming increase in the number of patients with multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis has been noted, particularly in eastern Europe, Asia, and southern Africa. Treatment outcomes with available treatment regimens for drug-resistant tuberculosis are poor. Although substantial progress in drug development for tuberculosis has been made, scientific progress towards development of interventions for prevention and improvement of drug treatment outcomes have lagged behind. Innovative interventions are therefore needed to combat the growing pandemic of multidrug-resistant and extensively drug-resistant tuberculosis. Novel adjunct treatments are needed to accomplish improved cure rates for multidrug-resistant and extensively drug-resistant tuberculosis. A novel, safe, widely applicable, and more effective vaccine against tuberculosis is also desperately sought to achieve disease control. The quest to develop a universally protective vaccine for tuberculosis continues. So far, research and development of tuberculosis vaccines has resulted in almost 20 candidates at different stages of the clinical trial pipeline. Host-directed therapies are now being developed to refocus the anti-Mycobacterium tuberculosis-directed immune responses towards the host; a strategy that could be especially beneficial for patients with multidrug-resistant tuberculosis or extensively drug-resistant tuberculosis. As we are running short of canonical tuberculosis drugs, more attention should be given to host-directed preventive and therapeutic intervention measures.
Autologous mesenchymal stromal cell infusion as adjunct treatment in patients with multidrug and extensively drug-resistant tuberculosis: An open-label phase 1 safety trial
2014, The Lancet Respiratory Medicine
Citation Excerpt :
13% of patients with MDR or XDR tuberculosis exhibited worsening of chest radiographs, an outcome which is expected in this patient cohort on the basis of earlier studies.4,5,26 Other adjunct immune-based therapies such as intradermal interleukin 252 or interferon γ via aerosol have shown limited results in improving tuberculosis-treatment outcomes or shortening the duration of therapy.53 Our findings show that MSC infusion was safe and well tolerated in all included patients.
Novel treatment options are urgently needed for multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis, which are associated with immune dysfunction and poor treatment outcomes. Mesenchymal stromal cells (MSCs) are immunomodulatory and adjunct autologous treatment with bone marrow-derived MSCs might improve clinical outcome by transforming chronic inflammation into productive immune responses. Our aim was to assess the safety of infusion of autologous MSCs as an adjunct treatment in patients with tuberculosis.
30 patients with microbiologically confirmed MDR or XDR tuberculosis were treated with single-dose autologous bone marrow-derived MSCs (aimed for 1×10⁶ cells per kg), within 4 weeks of the start of antituberculosis-drug treatment in a specialist centre in Minsk, Belarus. Inclusion patients were those with pulmonary tuberculosis confirmed by sputum smear microscopy, culture, or both; MDR or XDR tuberculosis confirmed by drug-susceptibility testing to first-line and second-line drugs; age older than 21 years to 65 years or younger; and absence of lesion compatible with a malignant process or ongoing tuberculosis in organs other than the lungs and pleura. In addition to the inclusion criteria, patients were excluded if they were pregnant, coinfected with HIV, or infected with hepatitis B, C, or both. The primary endpoint was safety measured by MSC-infusion related events; any tuberculosis-related event within the 6 month observation period that related to a worsening of the underlying infectious disease, measured by conversion of Mycobacterium tuberculosis culture or microscopic examination; or any adverse event defined clinically or by changes in blood haematology and biochemistry variables, measured monthly for 6 months after MSC infusion per protocol. This study is registered with the German Clinical Trials Registry, number DRKS00000763.
The most common (grade 1 or 2) adverse events were high cholesterol levels (14 of 30 patients), nausea (11 of 30 patients), and lymphopenia or diarrhoea (ten of 30 patients). There were no serious adverse events reported. We recorded two grade 3 events that were transitory—ie, increased plasma potassium ion concentrations in one patient and a transitory grade 3 γ-glutamyltransferase elevation in another patient.
MSCs as an adjunct therapy are safe and can now be explored further for the treatment of patients with MDR or XDR tuberculosis in combination with standard drug regimens. Adjunct treatment with MSCs needs to be evaluated in controlled phase 2 trials to assess effects on immune responses and clinical and microbiological outcomes.
Heart and Lung foundation, Vinnova, SIDA, Söderberg Foundation, Swedish Research Council.
Changes in cell-mediated immune response after lung resection surgery for MDR-TB patients
2011, Tuberculosis
Citation Excerpt :
However, the prolonged exposure to high amounts of various types of Mtb derived antigens, due to the persistent infection, may induce strong immune suppression in several levels in MDR-TB patients. The results of the present study support previous reports showing that recombinant IL-2 or plasmid DNA encoding mycobacterial hsp6549–51 was effective in immunotherapy for the treatment of MDR-TB. The recovery of the suppressed immune mechanisms by the removal of diseased lung sections from TB patients may suggest that enhancing CMI responses should be added to the chemotherapeutic treatment regimen in order to increase the efficiency of MDR-TB treatment.
The immune responses of multidrug-resistant tuberculosis (MDR-TB) patients undergoing lung resection surgery were investigated in order to understand the mechanism of strong immune suppression in MDR-TB. We examined changes in cell-mediated immune response (CMI) of a total of sixteen MDR-TB patients, three of them extensively drug-resistant tuberculosis (XDR-TB) patients, after the removal of the heavily diseased lung section. The IFN-γ response to Mycobacterium tuberculosis culture filtrate proteins (Mtb-CFP), one of the most important CMI to defend TB, showed a statistically significant elevation in 2–4 months after operation when compared to the preoperative CMI in patients who were converted into AFB negative and cured in two years’ follow-up, suggesting that the recovery of CMI may be one of the key factors in the successful treatment of MDR-TB. Interestingly, IL-10 response to Mtb-CFP was also elevated in 2–4 months after surgery in cured patients although both proliferative response and PBMC composition were not significantly changed. Infection with first- or second-line drugs resistant Mtb reduces the efficiency of chemotherapeutic treatment of MDR-TB to about 50%. Thus, this study suggests that chemotherapeutic treatment of MDR-TB may be more effective when combined with accompanying therapy that increases CMI, includes lung resection surgery.

View all citing articles on Scopus

View full text

Article preview

Tubercle and Lung Disease

Abstract

References (14)

Drug resistance in Mycobacterium tuberculosis

Eur Resp J

Outcome of MDR-TB patients, 1983–1993

Interleukin-2

Ann Rev Immunol

The systemic influence of recombinant interleukin 2 on the manifestations of lepromatous leprosy

J Exp Med

Prolonged immunostimulatory effect of low-dose polyethylene glycol interleukin 2 in patients with human immunodeficiency virus type 1 infection

J Exp Med

Recombinant interleukin-2 limits the replication of Mycobacterium lepraemurium and Mycobacterium bovis BCG in mice

Lymphokine Research

Clinical and immune responses of tuberculosis patients treated with low-dose IL-2 and multidrug therapy

Cytokines and Molecular Therapy

Cited by (75)

Therapeutic host-directed strategies to improve outcome in tuberculosis

Nanostructured drug delivery for better management of tuberculosis

Increasing the biological activity of IL-2 and IL-15 through complexing with anti-IL-2 mAbs and IL-15Rα-Fc chimera

Progress in tuberculosis vaccine development and host-directed therapies-a state of the art review

Autologous mesenchymal stromal cell infusion as adjunct treatment in patients with multidrug and extensively drug-resistant tuberculosis: An open-label phase 1 safety trial

Changes in cell-mediated immune response after lung resection surgery for MDR-TB patients

Original articlerhulL-2 adjunctive therapy in multidrug resistant tuberculosis: A comparison of two treatment regimens and placebo

Abstract

Drug resistance in Mycobacterium tuberculosis

Eur Resp J

Outcome of MDR-TB patients, 1983–1993

Interleukin-2

Ann Rev Immunol

The systemic influence of recombinant interleukin 2 on the manifestations of lepromatous leprosy

J Exp Med

Prolonged immunostimulatory effect of low-dose polyethylene glycol interleukin 2 in patients with human immunodeficiency virus type 1 infection

J Exp Med

Recombinant interleukin-2 limits the replication of Mycobacterium lepraemurium and Mycobacterium bovis BCG in mice

Lymphokine Research

Clinical and immune responses of tuberculosis patients treated with low-dose IL-2 and multidrug therapy

Cytokines and Molecular Therapy

Original article
rhulL-2 adjunctive therapy in multidrug resistant tuberculosis: A comparison of two treatment regimens and placebo