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Immune approaches in tuberculosis therapy: a brief overview

Expert Rev. Anti Infect. Ther. 10(3), 1–xxx  (2012)
Aldar S Bourinbaiar*1, Marina V Mezentseva 2, Dmitry A Butov 3, Peter S Nyasulu 4, Yuri V Efremenko 5, Vichai Jirathitikal 1, Vladimir V Mishchenko6 and Galyna A Kutsyna 7
1Immunitor Inc., Vancouver, BC, Canada, 2 Gamaleya Institute for Epidemiology & Microbiology, Moscow, Russia, 3 Department of Phtysiatry and Pulmonology, Kharkov National Medical University, Kharkov, Ukraine, 4 Faculty of Health Sciences, Witwatersrand University, Johannesburg, South Africa,  5 Lisichansk Regional Tuberculosis Dispensary, Lisichansk, Ukraine,  6 Central Institute for Tuberculosis, Moscow, Russia, 7 Luhansk State Medical University, Luhansk, Ukraine.
*Author for correspondence:

TB is typically caused by Mycobacterium tuberculosis, a symbiotic bacterium present in one-third of the world’s population. There any many factors triggering overt clinical disease in a small proportion of humans. In our view the major role in the process is played by the host’s immune response, especially self-directed, destructive inflammation. Conventional chemotherapy produces bactericidal or bacteriostatic effects, but immunopathological changes can only be corrected by immunotherapy. Various attempts have been made to identify the optimal immune intervention. Some have shown promising effects, but many have failed. It is commonly believed that the field started in 1890: the year Robert Koch announced his tuberculin therapy. In the Pên Ts’ao Kang Mu, classical Chinese materia medica, published during Ming dynasty, Li Shi Chen (1518–1593) recommended, as a remedy for hemoptysis, to collect from the sputum “… blood lumps, roast them till they are black, and take then them as a powder”. In retrospect, this is perhaps the earliest recorded reference relating to immunotherapy of TB with heat-killed mycobacteria. Modern science is obviously geared toward more palatable approach, but without hindsight from often disdained empirical evidence no progress can be made. The clinical experience from various trial and error processes is briefly discussed in this review.

Keywords: AIDS • antibody • autoimmune • cytokine • HIV • immunomodulator • inflammation • lung •multidrug-resistant TB • mycobacterial • pulmonary • therapeutic vaccine • tubercle bacillus • tuberculin 

Abundant literature exists concerning immune factors contributing to the development of TB. As Mycobacterium tuberculosis is an intracellular parasite the role of humoral, that is antibody- mediated immunity, is far less important than that of cell-mediated immunity. The survey of published studies concerning immunol- ogy of TB reveals a great deal of confusion. Contradicting opinions coexist even today and this perhaps is one of the main reasons why we still have no unanimous consensus with regard to the immunotherapy of TB. What is  worse is that prevailing opinion is bent towards the incorrect concept, which postulate that TB arises from an insufficient immune response. This concept lacks logic; two main diagnos- tic tools for identifying active TB, tuberculin test and IFN-g release assay, are based on the contrary principle. Indeed, individuals with TB do mount a vigorous immune response against tubercle bacilli [1]. Progressive pulmonary TB is caused by a continuous host response to myco- bacterial products and is not due to increasing numbers of viable bacilli in a host [2]. The goal for immunotherapy is to prevent a self-damaging  inflammatory response, instead of instigating more of the same. This goal is closely related to figuring out the immune response that correlates with protective immunity. Over the past 90 years, this gap in our understanding of TB immunology has been responsible for the failure of developing a safe and effective vaccine, since introduction of BCG in   1921. Recently, the research efforts in TB have intensified. However, it is difficult to appreciate the difference or distinguish immunopathologies that are associated with, and those that are causing TB. Without this there is an impression that we are ‘flying without a compass’ a term that Gene Shearer used in his comment with regard to the effort of developing AIDS vaccines. Conventional chemotherapy approaches are straightforward with clear goals of suppressing mycobacterial replication. Bacteriostatic or bactericidal agents seldom restore the immune status. This task cannot be achieved without proper immune intervention. The emergence of multidrug-resistant TB and TB–HIV coinfection, together with advances in immunology, has led to renewed interest of exploiting the immune response against M. tuberculosis. This review is intended to provide a short excurse into the history of TB immunotherapy and analysis of the current state-of-the-art. We hope that understanding the past and present experiences will provide valuable insight and may result in a better grasp of the problem. As Kaufmann quoted in one of his articles on immunol- ogy of TB “those who don’t remember the past are condemned to repeat it” [3].

Early days of immunotherapy
Robert Koch, discoverer of M. tuberculosis, can be considered as the first modern TB immunotherapist when in 1890 he announced his tuberculin therapy. Koch’s original preparation of tuberculin was a crude extract from heat-killed cultures of M. tuberculosis. Koch’s idea was based on the assumption that the reaction of the organism to tuberculin would cause the elimination of bacilli-infected tissue. It must be said that 300 years earlier, renowned Chinese scholar, Li Shi Chen (Figure 1) in his encyclopedical treatise Pên Ts’ao Kang Mu (1595) described methods of treating TB, which were not too far from Koch’s principle. Koch’s initial results of treating skin and lymphatic forms of TB were encouraging. Unfortunately, the massive trial that followed shortly after his announcement had produced disastrous results and the hopes he raised were not fulfilled.

 Figure 1. The portrait rendition of Li Shi Chen (1518-1593). Li Shi Chen is the author of most comprehensive Chinese pharmacopoeia Pên Ts’ao Kang Mu, describing the earliest recorded TB immunotherapy based on ingestion of heat- inactivated tubercle bacilli derived from sputum. Taken from [101].

The medical opinion settled firmly against immunotherapy and against the founder of modern microbiology. The implications stemming from this trial, which was clearly indicative of exaggerated and deleterious immune reaction, known today as Koch reac- tion, have been ignored. It is clear that Koch knew of this and he was calling for caution, pointing out that tuberculin should not be used in patients with virulent or acute forms of TB and he argued against high starting doses (Figure 2). Despite negative attitudes prevailing in the medical establishment, Koch’s approach has not been totally ignored. The late 19th and early 20th centuries were replete with success and failure. Several dozen tuberculin-based approaches were promoted by their proponents [4]. A wide range of ingenious modifications of tubercle bacillus were made including passage through refractory animals, attenuation and killing by various methods. Furthermore, inoculation of nonpathogenic or atypical mycobacteria came into wide use. Names of many physicians in Europe and the USA, practicing various tuberculin- derived therapies, are commonly found in the medical literature and lay media of those days. Among them were Lichtheim (1891), Hunter (1892), Klebs (1892), Trudeau (1893), Viquerat (1894), Maragliano (1895), Paquin (1895), Fisch (1897), De Scweinitz and Dorset (1897), Smith and Baldwin (1898), Murphy (1898), Cantacuzino (1901), Goetsch (1901), Armand-Delille  (1902), Marmorek (1903), Wright (1903), Behring (1905),   Calmette (1906), Matthew (1908), Hunter (1908), von Ruck (1908), Leber and Steinharter (1908), Vallée (1909), Webb (1911), Wolff-Eisner (1912), Sahli (1912), Friedmann (1914), Wyeth (1914),   Dreyer (1919), Spahlinger (1922), Josset (1924), Dryer (1924), Reenstierna (1934) and many others. This highly active period in the history of immunotherapy had dwindled down by 1940s when first, streptomycin, and then para-aminosalicylic acid and isoniazid, were introduced as TB drugs and chemotherapy research became the next trend.

Nevertheless, Koch’s idea has greatly influenced the field. The tuberculin skin test (TST) became a critically important diagnos- tic tool in the management of TB. Von Pirquet and Schick (1907) developed a method of cutaneous scratch, Moro and Doganoff (1907) made percutaneous patch, and Calmette and Wolff-Eisner (1907) a conjunctival probe. Intracutaneous injection of tubercu- lin was refined by Mendel and Mantoux (1908) and this method became widespread because of the reproducibility of the results. In the 1930s Florence Seibert prepared purified protein derivative from ‘old tuberculin’, which now serves as a standard reference material. Jules Freund’s emulsified suspension of killed M. tuberculosis cells in mineral oil is nothing more than a super-tuberculin and most potent experimental vaccine adjuvant known, which is not used in humans owing to an extreme reactogenicity. Another outcome that remains as a tribute to Koch’s greatness is BCG vaccine, the only prophylactic TB vaccine available today. At the International Congress on TB, held in Washington, USA, in 1908, Albert Calmette stated that, “he had prepared for thera-peutic use [sic] a particularly active and relatively pure tuberculin called Tuberculin CL, which could be introduced intravenously into the body of a healthy animal…which evidently delayed   the  progress of the disease, and endowed the organism with resistance to the infection.” The fact that Calmette was inspired by Koch and started initially developing BCG as a therapy, which ended up as a preventive vaccine for cattle and was then applied in people is seldom known or is ignored by most TB  vaccinologists. 

It should be remembered that even though BCG is used widely with a relatively good safety record, it does not provoke the immune reaction that one would expect from a classical vaccine. As TB is a disease of mucosal origin, the route of administration of BCG makes a critical difference [5]. The massive transition from Calmette’s oral version to parenteral BCG may have been respon- sible for what is now blamed as a loss of vaccine’s effectiveness. It is also usually ignored that BCG is seldom administered alone as most children receive a vaccine after having been tested with the TST, which in vaccine terminology equals to priming with tuberculin. Thus, in this setting BCG is used as a booster vaccine. In neonatal direct BCG vaccination the efficacy of a vaccine is tested by TST – a situation where the prime–boost sequence is reversed. One needs to closely evaluate failed and successful BCG trials to determine whether the outcomes were influenced by these ignored but important factors. Aronson’s study in children in Indian reservations, which had shown one of the best known success rate for BCG vaccination, offers clues to that. Furthermore, depending on particular species of environmental mycobacteria, the BCG vaccination can be more efficacious or not effective at all in certain endemic areas [6,7]. The combination of BCG with tuberculin has been used with success in the treatment of TB [8]. The combination of BCG priming with heat inactivated M. vaccae therapeutic vaccine was reported to prevent TB incidence [9]. These examples imply that vaccines for therapeutic and prophylactic purposes have a common mechanism. Successes with both types of vaccines were usually associated with the lack of or lower delayed-type hypersensitivity, that is, tuberculin reactogenicity, either pre- or post-vaccination.

Tuberculin continued It is commonly held that the reputation of tuberculin therapy has been deeply affected by a large TB trial held at the Charité hos- pital in Berlin. Robert Koch’s tuberculin trial, which included 1010 patients with pulmonary TB, resulted in 1.3% cured, 36.1% improved, 4.6% dead, and the rest without apparent clinical benefit. Among 707 patients with extrapulmonary TB, including skin, bone and lymphatic forms, the outcomes were 2.1, 54.5, 1.3 and 42.1% for cured, improved, dead and without clinical benefit patients, respectively [10]. The way these finding are usually interpreted is that therapeutic vaccination against TB is ineffective and even harmful [11]. Considering that the mortality among untreated TB cases in 19th century Berlin was approximately 25%, this is clearly not an example of a failed treatment, but rather a case of misin- terpreted results, which was orchestrated by Koch’s rival, Rudolf Virchow. Today, in the 21st century, the global TB death rate has not greatly improved, even though chemotherapy is widely avail- able. Thus, even by today’s standards, if one looks at mortality as an unequivocal clinical end point, since cure and improvement end points were subject to arbitrary bias, then Koch’s trial had an outstanding outcome.

Figure 2. Robert Koch (1843–1910), discoverer of Mycobacterium  tuberculosis  and tuberculin immunotherapy. A portrait by unknown artist (most likely German portraitist Gustav Graef – mentor of Hedwig Freiberg – Koch’s second wife) made from the original photograph taken in 1890 [102] – the year he announced tuberculin remedy. The hastened clinical trial at Charité and misplaced interpretation of the results had tarnished his reputation. His later method of making pure tuberculin, as opposed to the original crude reactogenic tuberculin, was based on washing out the  lipid fraction with ethanol and salt-precipitating proteinaceous  content, which resulted in apparently safe and effective preparation. Normal healthy volunteers, including his students  von Behring and Kitasato, without signs of TB, had only transient mild increase in temperature and malaise. However, one volunteer with suspected TB, had more pronounced adverse reaction and Koch had overcome this by reducing further the starting dose of tuberculin. Unfortunately, his ingenious foresight of decreasing undesirable reactogenicity by removing lipids and using small initial doses, which were gradually increased, was somehow forgotten and lost to the TB vaccinologists of today. Image courtesy of Vera Seehausen of the Institute of History of the Medicine, Centre for Human and Health Sciences, at Charité University of Medicine, Berlin, Germany. Taken from [102].

Note that Calmette’s preventive BCG trial in children resulted in an almost identical mortality rate and yet his results were hailed as a pioneering breakthrough. However, owing to Virchow’s domineering influence on medical establishment in Germany at the time, his negative opinion perpetuated and carried over to modern day. Judging from various contemporary  sources, Virchow did not seem to be overly preoccupied with praising clini- cal benefits of tuberculin, in fact he did not discuss it at all – he was primarily concerned with fatal ‘injection pneumonias’ – found in approximately half of the deceased patients and attributed to Koch reaction.

Nevertheless, the renewed interest in this approach became apparent by the 1950s, perhaps due to the realization that chemo- therapy was not a panacea and doctors started seeing drug-resist- ant cases. By then most of the work had been carried out in the Soviet Union. The important clues to successfully managing tuberculin therapy outcome were revealed by several groups of Soviet phthysiatists who started using immune intervention in combination with chemotherapy. Most prominent among them was Edvard Mirzoian whose deductive work in the 1960s has laid basis to the currently used tuberculin treatment scheme common in Russia [12]. The main message resulting from their extensive work spanning over decades was simple: dilute! This concept was not entirely new, heated debates were raging in the early part of 20th century as to which dose was most optimal. Koch himself noted that smaller doses were producing tolerizing effects that could eventually heal guinea pigs and high doses were caus- ing massive, occasionally lethal, immune reactions, which have become known as the ‘Koch phenomenon’.

The Soviet school has adopted an approach consisting of a series of increasing doses of subcutaneous or intradermal tuberculin starting with initial dilutions as low as 1:10,000,000. The initial dose was one that produced minimal induration and this was incrementally scaled-up by injecting a tenfold higher dose twice every week until it reached a 1:10 dilution after a 2–3-month treatment course. The typical results were quite convincing. In a large-scale trial involving 1380 patients, sputum clearance at the end of 3 months stood at 82 versus 61.9% of those who received chemotherapy alone (Table 1). Clinical symptoms, healing of cavities were clearly better in the tuberculin group. The healing of cavities was observed in 73.7% (n = 752) as opposed to 49% (n = 422) patients in the control group. This and other trials spanning over the five decades (beginning in 1950) have been, unfortunately, totally ignored in the west.

It must be said that the use of gradually increasing doses has been known since Koch times. His contemporaries such as Ziegler, Pottenger, Petruschky, Römer, Pearson, Gilliland, Jurgens and Neumann were promoting this approach, but to no avail. It is perhaps worthwhile to reassess the value of ‘similia similibus curantur’, the term used in homeopathic practice that relies on tiny doses of antigen. It is well known that immune tolerance can be produced by two means; either by injecting very small doses or by oral administration of antigen. Interestingly, both of these approaches had, historically, higher success rates in TB immunotherapy than other modalities. Indeed, Koch’s tenth experiment, described in his seminal work Die Ätiologie der Tuberkulose (1882), refers to oral feeding of tubercular meat to rats, a proce- dure that completely protected them from subsequent challenge without provoking reactivity, but when feeding was stopped for several weeks animals became susceptible to repeated challenge. The famous tenth experiment was certainly a most curious one, as it almost defied Koch’s own Postulates, but it might have inspired another Nobelist, Charles Richet, of promoting zomotherapy and René Dubos’ eloquent example of lower TB incidence among meat-eating Masai than in vegetarian tribe Akikuyu.

Cytokines, Th1/Th2 & rational empiricism

With rapid advances in immunology resulting in the discovery of various humoral factors secreted by immune cells and domination of Th1/Th2 concept in cellular immunity, attempts have been made to apply this new knowledge to immunotherapeutic interventions. Without going into details of several clinical trials, employing the extensive range of cytokines and anticytokines, as reviewed elsewhere it can be said that the value of these immuno- modulatory molecules remained unclear and their clinical utility has been dismal [13]. Immune intervention such as inhaled IFN-g, corticosteroids, Type 1 interferons, IL-2 or anti-TNF regimens have all been quite disappointing and were largely responsible for the cautious attitude toward immunotherapy that prevails today in the field. In fact calls were made to abandon immunotherapy altogether. Thus, there is a significant gap between a priori (rational reasoning) and a posteriori (empirical evidence), a problem that has been plaguing not only the TB community but the philosophy in general, long before Immanuel Kant’s reconciliation attempt in his Critique of Pure Reason (1781). Despite the progress the correlates of protective immunity are still unknown and without it the rational science has to rely on evidence from empirical ‘poking’. Without mutual feedback and cooperation between bench versus bedside camps there will be no true progress.

Other mycobacterial vaccines

In addition to tuberculin, there are several preparations of mycobacterial origin, which have been or are still being used as adjunct therapy for TB. Among these are Mycobacterium chelonae or ‘turtle vaccine’ developed by Friedrich Friedmann, sold until recently under brand name Anningzochin (Laves-Arzeimittel Gmbh, Ronnenberg, Germany) [4]; Mycobacterium microti, which has been tested in UK and used widely in The Czech Republic and Slovakia, but mostly as a prophylactic vaccine [14]; Mycobacterium phlei from Sanum-Kehlbeck in Germany, also manufactured in China (Utilin S, Chengdu Jin Xing Sanum-Kehlbeck Medicine Co., Ltd, China) [15]; Mycobacterium w or Mycobacterium indicus originally developed as a leprosy vaccine (Immuvac, Cadila Pharmaceuticals, India) [16]; Mycobacterium bovis (standard BCG vaccine), which is also used as an adjunct immunotherapy [8,17]; and Mycobacterium vaccae, a therapeutic vaccine developed by Stanford et al., (Immodulon Therapeutics, London, UK) [18], approved in China under the Vaccae® brand name for adjuvant therapy of TB (Anhui Longcom, China) [19]. The oral tableted form of heat-killed of M. vaccae (V7) is now being tested in a Phase II trial by Immunitor Inc., (Canada), this trial is aimed to confirm beneficial clinical findings reported by Dlugovitzky et al., of their own oral formulation [20]. Preliminary results from the V7 trial are shown in Table 1. A therapeutic vaccine, RUTI®, containing delipidated fragments of M. tuberculosis, as a modern day Dreyer’s ‘defatted’ or diaplyte tuberculin [21] and (Figure 3),was developed by Archivel Farma (Spain), but no data regarding its efficacy in humans are yet available [22].

Figure 3. Box containing ampoules with the ‘defatted’ tuberculin vaccine of Georges Dreyer (1924).

Of special interest is the extremely small quantity of    tubercular  antigen – only 10 ng per dose. Georges Dreyer, born in Shanghai from Danish parents, was, between 1907 and 1934, the first full Professor of Pathology at Oxford University, UK. Of note is that after Dreyer’s death his place was taken by Howard Florey – who with Chain and Heatley succeeded in producing clinical quantities of penicillin from the sample of the original mold strain, which was actually given to Dreyer by none other than Alexander Fleming himself. The principle of action of Dreyer’s vaccine is similar to ‘delipidated’ or detoxified RUTI vaccine, currently being developed by Archivel Farma, Spain. This principle follows the proposal made by Auclair (1900) and Sternberg (1902) that adverse effects of tuberculin were due to the presence of the lipid fraction of the bacterial cell wall, which supports Koch’s description of the same phenomenon described in Über neue Tuberkulinpräparate  (1896). 

Image courtesy of Lorenzo Iozzi (History and Technology  Department, Museum Victoria, Victoria, Australia).

Last year, Immunitor made a similar vaccine, V5; containing circulating M. tuberculosis antigens derived from heat and chemically inactivated blood of donors, which has already been through several Phase II trials [23–26]. Finally, the National Institute for the Control of Pharmaceutical and Biological Products (Beijing, China) reported therapeutic vaccine based on acellular Mycobacterium smegmatis that appeared to be safe in patients with TB  [27]. The efficacy of the above vaccines is variable, ranging from unknown to excellent, but what is important is that all of them reported to be safe. Furthermore, these vaccines appeared to be equally effective against drug-resistant TB and TB with HIV, the major challenge for current chemotherapeutic interventions. Curiously, most of these vaccines, some of which have been in commercial use for decades, are known to only small number of TB researchers. Nevertheless, they exist and resources need to be devoted to investigate them further, since ignoring or dismissing them a priori will be a disservice to patients, especially to those who have no treatment options left.

Other immunotherapeutics  This section summarizes TB trials in which various immuno- modulators from Russia and other former Soviet republics were used as an adjunct therapy to conventional chemotherapy. Russia has an exceptionally diverse repertoire of immunomodulating agents, with over 130 unique chemical entities currently sold for a wide range of clinical indications. We have previously published a review on many of these agents and refer to it for the detailed description of composition and putative mechanisms of action [28]. Most studies relating to their use against TB are either published in the Russian language or exist as a technical information sheet or treatment recommendations from the manufacturers [29–32]. A review article that summarizes TB trials with select immuno modulators was recently published by Mezentseva et al. [33]. See also Table 1 for the outcome of some of these immune interventions. It can be seen that in all cases the immunomodulators enhance the efficacy of TB drugs and in less time than the mandatory 6 months required for chemotherapy. Admittedly, many of them are inconvenient in terms of administration, or have potential side effects, but one thing is clear there is plenty of choice. This is in stark contrast to the situation in western countries, there are no immunomodulators to choose from, since none exist.

We and our clinical collaborators in the Ukraine have worked on the immunotherapy of TB over the past 10 years resulting in nearly 20 published clinical trials involving close to 1500 indi- viduals. Initially, we have used locally-produced, herbal immu- nomodulator Dzherelo or Immunoxel [34–36]. Sputum conversion among multidrug-resistant-TB, extremely drug-resistant-TB and TB–HIV patients after 2–4 months of treatment were approximately 85–100%, while in controls on TB drugs alone it took 6–24 months to reach the 48–85% range. However, what was of interest to us is that inflammation and other TB symptoms were improved by Dzherelo in a manner that was strikingly similar to V5 [23–26]. Similar anti-inflammatory properties were reported by our colleagues in Russia in investigations of their own immuno modulators [29–33]. This suggests that an effective immunotherapy ought to have a beneficial effect on inflammation, which can be, for example, measured by two unsophisticated tests, that is, eryth- rocyte sedimentation rate and leukocyte counts. Measuring fever reduction or bodyweight gain are even more simple tests. These simple biomarkers combined with immunological tests evaluating cytokine profile and Th1/Th2 balance can provide reliable correlates of immune protection [37]. The effective immune intervention must possess similar if not identical properties in terms of anti-inflam matory effects and other clinical improvements we have observed in our trials.

Conclusion  The emergence of TB, especially drug-resistant TB and TB–HIV is of great concern to global public health. As new prophylactic vaccines, currently under investigation, are not expected before 2020, the elimination of TB must rely on existing immune inter- ventions to be used together with currently available TB drugs. In recent times, the immunotherapy of TB has been mostly a disappointing experience with high rates of failure, and it is not surprising that many physicians are skeptical about this concept. We have been working with various immune therapies during the past 10 years and can attest that this approach merits more atten- tion than it has previously received. However, caution is required so that protective and not harmful traits of immunity are induced [11,38]. TB is a classic example of chronic infectious disease char acterized by persistent inflammation with autoimmune features. This simple concept is still struggling to gain wider acceptance [1–2,38–40]. Conventional chemotherapy cannot correct protective immunity. Without adjunct immunotherapy one cannot speed up bacterial clearance and the healing process. Without immuno therapy one cannot overcome drug resistance and HIV coinfec tion. Clinical experience with various immunomodulators has not always been encouraging, but those that have shown clinical benefit must be urgently adopted and more resources must be allocated to understand their mechanism and introduce existing immunomodulators into wider clinical use.

Expert commentary  Medical practitioners have a set of 40-year-old antibiotics which they use according to outdated regimens and they seldom venture outside indoctrinated confines. With expansion of drug resistant strains and HIV the therapeutic choices are becoming even more limited. It is thus imperative that basic science, especially immuno logy, is brought back to iatrochemist masses. Phtysiatrists must understand that their enemy is not tubercle bacilli only, but misdirected immune response. They often hear and read that a third of the population carries M. tuberculosis, but they seldom question why 95% of them never get sick. They know well that every 25 seconds a person dies from TB, but they never question what the real cause of death was. Everyone has been taught in their medical school to equate mycobacterium with death. In our opinion this is wrong. The death results from self-destructive inflammatory responses triggered by mycobacterial infection. The division of TB bacilli into virulent and avirulent types is based on in vivo assays, which is clearly dependent from the host immune response, since in vitro assays based on measurement of cell death in infected macrophages or dendritic cells, the virulent TB strains are usually less cytotoxic than avirulent ones [41,42]. To the best of our knowledge there is only one reference
in the literature, which implies M. tuberculosis being directly cytopathic to human epithelial cells and even then this might have been an artifact due to HIV coinfection [43]. Furthermore, the symbiotic relationship between mycobacteria and host is not necessarily harmful, one can find in the literature examples of beneficial coexistence [44]. In order to increase our ability to control infectious diseases and prevent epidemics, it is vital that doctors are properly educated. It is important to allocate more resources toward existing immune interventions so that clinical outcomes are improved. The current gaps in our knowledge must be identified and explored according to their relevance not paradigmatic convenience.
Five-year view  Basic TB research has intensified in the last decade. The TB pandemic that started in early 1990s has shown that even the most developed countries are vulnerable. TB will continue to be a threat to the global community as it has been for mil- lennia. Every country should take measures by implementing a national preparedness and response plan, by empowering the local community, by training the medical personnel and out- reach health staff in the identification and management of TB, and by creating new tools for diagnosis and treatment. The estab lishment of truly novel protocols for management of TB needs to be implemented. If the scarcely populated field of immune interventions is invigorated with renewed enthusiasm then in the next 5 years we may witness the renaissance of the immune therapy that was dominating TB research prior to introduction of the chemotherapy.

Acknowledgements  We would like to thank many experts who have contributed their comments and critiques. In particular, we are indebtful to John Stanford, Graham Rook, John Grange, Ali Zumla, Gene Shearer, Feng-li Tao, Shilong Yang, Jiang Pu, Chuanyou Li, Wing-wai Yew, CC Leung, Ying Zhang, Satoshi Makino, Ray Spier, Nataliya Kozhan, Vasilyi Petrenko, Elena Rekalova, Irina Il’ inskaya, Petr Rytik, Felix Ershov, Volodymyr Pylypchuk, Pere-Joan Cardona, Jim Johnston, Carl Feng, Christoph Lange, Bob Wallis, Keertan Dheda, Gavin Churchyard, Tony Hawkridge, Tom Evans, Robert Loddenkemper, Stefan Kaufmann and Mel Spigelman for sharing with us their views on TB issues. The authors are also grateful to patients who participated in trials of immunotherapeutics discussed in this review.  

Key issues 

•   The immune approach in TB therapy has been promoted since 1890, starting with Robert Koch himself, but there are even earlier empirical precedents such as those found in Li Shi Chen’s Pên Ts’ao Kang Mu. 

•   Immunotherapy is still skeptically viewed due to the failure of various approaches, especially involving cytokines. 

•   Failures are linked to the belief that TB arises as a result of a ‘weakened’ immune response. 

•   We believe that TB, as a disease, occurs when the immune tolerance to mycobacterium is replaced by an exaggerated immune response, characterized by inflammatory reaction against own tissues harboring the tubercle bacilli. 

•   By consequence, TB is an autoimmune disease triggered by mycobacterial infection. 

•   In order to produce a favorable clinical outcome one needs to manage immunity with the aim of restoring immune tolerance. 

•   Immune tolerance does not mean immune suppression or anergy, it’s an active process, which is as potent as classical immune activation. 

•   If this concept is true, then immune correlates of protective immunity have to be searched for in places that were overlooked by current dogmas. 

•   There are many immunotherapeutics that have been successful and they need to be investigated so that clues emerge, which could help not only the therapy but also prophylaxis of TB.

Financial & competing interests disclosure 

AS Bourinbaiar and V Jirathitikal are officers of the Immunitor company, involved in developing TB immunotherapies. Some of the trials of immuno- therapeutics described in this review were supported by Business Partnership Grant UKB1-9017-LK-09 awarded by the US Civilian Research & Development Foundation a nonprofit organization authorized by the US Congress and established in 1995 by the National Science Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.  No writing assistance was utilized in the production of this manuscript.

Papers of special note have been highlighted  as:
 * of interest
** of considerable interest
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** Equates TB with inflammation.
2 Dannenberg AM Jr, Collins FM. Progressive pulmonary tuberculosis is not due to increasing numbers of viable bacilli in rabbits, mice and guinea pigs, but is due to a continuous host response to mycobacterial products. Tuberculosis 81, 229–242 (2001).
** Describes the immunopathogenesis of TB from the host’s viewpoint.
3 Kaufmann SH. Introduction. Rational vaccine development against tuberculosis: “Those who don’t remember the past are condemned to repeat it”. Microbes Infect. 7, 897–898 (2005).
4 Vilaplana C, Cardona PJ. Tuberculin immunotherapy: its history and lessons to be learned. Microbes Infect. 12, 99–105 (2010)
* Most recent review of tuberculin-based therapy.
5 Hoft DF, Brown RM, Belshe RB. Mucosal Bacille Calmette-Guérin vaccination of humans inhibits delayed-type hypersensitivity to purified protein derivative but induces mycobacteria-specific interferon-g responses. Clin. Infect. Dis. 30(Suppl. 3), 217–222 (2000).
6 Brandt L, Feino Cunha J, Weinreich Olsen A et al. Failure of the Mycobacterium bovis BCG vaccine: some species of environmental mycobacteria block multiplication of BCG and induction of protective immunity to tuberculosis. Infect. Immun. 70, 672–678 (2002).
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12 Mirzoian EZ. On the method of tuberculin therapy of pulmonary tuberculosis in adults. Probl. Tuberk. 42, 33–38 (1964).
13 Churchyard GJ, Kaplan G, Fallows D, Wallis RS, Onyebujoh P, Rook GA. Advances in immunotherapy for tuberculosis treatment. Clin. Chest Med. 30, 769–782 (2009).  
• Describes the latest immunotherapeutic approaches against TB 
14 Sula L, Radkovský I. Protective effects of M. microti vaccine against tuberculosis. J. Hyg. Epidemiol. Microbiol. Immunol. 20, 16 (1976)
15 Zhao GR, Feng DH. A systematic   review  of inactivated Mycobacterium phlei injection for adjunctive treatment of drug resistant pulmonary tuberculosis. Pharm. J. Chin. PLA 25, 361–364 (2009). 
16 Nyasulu PS. Role of adjunctive Mycobacterium w immunotherapy for tuberculosis. J. Exp. Clin. Med. 2, 123–129 (2010). 
17 Lei JP, Xiong GL, Hu QF et al. Immunotherapeutic  efficacy of BCG vaccine in pulmonary tuberculosis and its preventive effect on multidrug-resistant tuberculosis. Zhonghua Yu Fang Yi Xue Za Zhi 42, 86–89 (2008). 
18  Stanford J, Stanford C, Grange  J. Immunotherapy with Mycobacterium vaccae in the treatment of tuberculosis. Front. Biosci. 9, 17011719 (2004)
19   Luo Y, Lu S, Guo S. Immunotherapeutic effect of Mycobacterium vaccae on  multi-drug  resistant  pulmonary tuberculosis. Zhonghua Jie He He Hu Xi Za Zhi 23, 85–88 (2000). 
20   Dlugovitzky D, Notario R, Martinel- Lamas D et al. Immunotherapy with oral, heat-killed, Mycobacterium vaccae in patients with moderate to advanced pulmonary tuberculosis. Immunotherapy 2, 159–169 (2010). 
21 Dryer G. Some new principles in bacterial immunity, their experimental foundation, and their application to the treatment of refractory infections, including tuberculosis. Brit. J. Exp. Pathol. 46, 146176 (1923).
22 Vilaplana C, Montané E, Pinto S et al. Double-blind, randomized, placebo-controlled Phase 1 clinical trial of the therapeutical antituberculous vaccine RUTI. Vaccine 28, 1106–1116 (2010).
23 Arjanova OV, Prihoda ND, Yurchenko LV et al. Phase 2 trial of V-5 Immunitor (V5) in patients with chronic hepatitis C co-infected with HIV and Mycobacterium tuberculosis. J. Vaccines Vaccinat. 1, 103 (2010). 
24 Arjanova OV, Prihoda ND, Yurchenko LV et al. Adjunct oral immunotherapy in patients with re-treated, multidrug-resistant or HIV-coinfected TB. Immunotherapy 3, 181–191 (2011).
25  Butov DA, Pashkov YN, Stepanenko  AL et al. Phase 2b randomized trial of adjunct immunotherapy in patients with first- diagnosed tuberculosis, relapsed and  multi-drug-resistant (MDR) TB. J. Immune Based Ther. Vaccines 9, 3 (2011).
26 Arjanova OV, Butov DA, Prihoda ND et al. One-month immunotherapy trial in treatment-failed TB patients. Open J. Immunol. 1, 5055 (2011). 
27  Xu M, Luo Y-a, Chen B-w et al. The study on preventive effect of M. smegmatis vaccine for people infected with M. tuberculosis. Drug Evaluation 2, 1–5 (2006). 
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33 Mezentseva MV, Stakhanov VA, Zakharova MV et al. Prospects for immunotherapy in adjunct treatment of infiltrating pulmonary tuberculosis. Biopreparaty 2, 20–25 (2011). 
· Describes some of the Russian immunomodulators used as adjunct therapy for TB.
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36 Prihoda ND, Arjanova OV, Yurchenko LV et al. Adjuvant immunotherapy of extensively drug-resistant tuberculosis (XDR-TB) in Ukraine. Curr. Res. TB 1, 1–6 (2009). 
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    Links TB with inflammatory reaction. 
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101Classics of traditional Chinese medicine. chinesemedicine/emperors.html 
Refers to Ch’en Hsueh-lou, Chung-kuo li tai ming i t’u chua: Biographies and Portraits of Chinese Famous Doctors in Past Dynasties, Nan-ching, 1987.
102 The natural history of pulmonary tuberculosis, facilitator guide. HARRIS+coverpage.pdf 
103 Cycloferon (Polysan) St-Peterburg, Russia. 
104 Amiksin (Pharmstandart) Tomsk, Russia. 
105 Galavit (Medicor) Moscow, Russia. 
106 Polyoxidonium (Petrovax) Moscow, Russia. 
107 Likopid (Peptec) Moscow, Russia. 
108 Glutoxim (Farma VAM) St-Peterburg,  Russia
109 Neovir (Pharmsynthez) St-Peterburg, Russia.
110 Bestim (Verta) St-Peterburg, Russia. 
111 Ronkoleukin (Biotech) St-Peterburg, Russia.
113 Tuberculin (SPbNIIVS - Institute of Vaccines and Sera) St-Peterburg, Russia.
114 V7 (Immunitor) Vancouver, Canada. 






Table 1. Summary of the outcome of TB trials in Russia and Ukraine, in which various immunotherapeutic agents were employed as an adjunct to the conventional chemotherapy. 


Manufacturer; location 

Active ingredient 

Delivery mode 

Duration (months) 

Smear conversion, % (n) 

Test group               Control group 



Polysan;  St-Peterburg, Russia 

Meglumine acridonacetate 

Oral b.i.d. for 30 days 


48 (n = 44) 

22.5 (n = 32) 



Pharmstandart; Tomsk, Russia 

Tilorone  dihydrochloride 

First 2 days 250 mg per os, then 

125 mg b.i.d. total 20  pills 


85.7 (n = 25) 

55.6 (n = 25) 



Medicor; Moscow, Russia 

Monosodium 5-amino-2–3-dihydro- 1–4-phthalazine dione 

im. once every 3 days × 15-times 


54.5 (n = 21) 

20 (n = 12) 



Petrovax; Moscow, Russia 

N-oxidized polyethylene piperazine 

im. twice/week × 10-times 


77.3 (n = 29) 

30 (n = 16) 



Peptec; Moscow, Russia 

N-acetylglucosamine-N- acetylmuramylalanine-d-isoglutamine 

Oral tablet, once per day for 10 days then TB drugs alone 


80 (n = 30) 

66.5 (n = 36) 



Farma VAM; St-Peterburg, 


Glutamyl-cysteinyl-glycine disodium 

iv. b.i.d. for 54 days 


55 (n = 46) 

44 (n = 28) 



Pharmsynthez; St-Peterburg, Russia 



im. injection 250 mg  twice-weekly 

× 10 


68 (n = 19) 

35 (n = 15) 



Verta; St-Peterburg, Russia 


im. 100 µg once-daily ×  5-times 


50 (n = 14) 

37.5 (n = 14) 



Biotech; St-Peterburg, Russia 

Recombinant IL-2 

iv. 3–7 injections, 106 units spaced by 48 h 


74 (n = 30) 

53 (n = 15) 



Ekomed; Kiev, Ukraine 

Phytoconcentrate of over 20 medicinal herbs 

Oral 30–60 drops for 2–4 months 


80 (n = 597) 

48 (n = 628) 



SPbNIIVS - Institute of Vaccines and Sera; St- Peterburg, Russia 

Killed Mycobacterium tuberculosis 

im. dilution: 1:100,000, then tenfold increased doses twice- weekly 


82 (n = 847) 

61.9 (n = 533) 



Immunitor; Vancouver, Canada 

Heat-killed Mycobacterium tuberculosis 

Oral tablet (850 mg), once per day for 30 days 


82.9 (n = 107) 

13.9 (n = 74) 



Immunitor; Vancouver, Canada 

Heat-killed Mycobacterium vaccae 

Oral tablet, (850 mg), once per day for 30 days 


78.9 (n = 20) 

19 (n = 21) 


b.i.d.:  Twice  daily;  im.:  Intramuscularly;  iv.:  Intravenously;  os:  Oral administration. 



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Treatment of cavitary and infiltrating pulmonary tuberculosis with and without the immunomodulator DzhereloClinical validation of sublingual formulations of Immunoxel (Dzherelo) as an adjuvant immunotherapy in treatment of TB patientsAdjuvant Immunotherapy of Extensively Drug-Resistant Tuberculosis (XDR-TB) in UkraineEffect of Immunomodulator Dzherelo on CD4 + T-Lymphocyte Counts and Viral Load in HIV Infected Patients Receiving Anti-Retroviral Therapy
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