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Role of Immunotherapy in the Treatment of Tuberculosis

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Role of Immunotherapy in the Treatment of Tuberculosis ROLE OF IMMUNOTHERAPY IN THE TREATMENT OF TUBERCULOSIS MURTHY, K.J.R. VIJAYA LAKSHMI, V. and Singh, S. Bhagwan Mahavir Medical Research Centre, 10-1-1, Mahavir Marg, Hyderabad - 500 029. India. ABSTRACT Tuberculosis is caused by Mycobacterium tuberculosis, an intracellular pathogen residing in macrophages. Cell mediated immune (CMI) and delayed type of hypersensitive (DTH) responses play a pivotal role in providing protection to the host. The most important cell is the CD4 T lymphocyte, which is divided into TH1 and TH2 subsets depending on the type of cytokines produced. TH1 cells produce the cytokines interferon-gamma and interleukin-2, which are important for activa- tion of antimycobacterial activities and essential for the DTH response. Grange opines that the immune response in an individual with tuberculous infection gets locked in' to one or other pattern of response viz. TH1 or TH2 response, the latter response leading to tissue damage and progression of disease. Stanford and co-workers conducted several studies on the effectiveness of Mycobacterium vaccae, as an immunotherapeutic agent for tuberculosis. It is non-pathogenic in humans and is thought to be a powerful TH1 adjuvant. A series of small studies pointed that M. vaccae has a beneficial effect and there is enough evidence now to show that its use as an immunotherapeutic agent, as an adjunct to chemotherapy in the treatment of tuberculosis especially at a time when drug resistance is rampant, appears promising. KEY WORDS : Tuberculosis, Drug-Resistance, Immunotherapy, T Cell Responses. ROLE OF IMMUNOTHERAPY IN THE cytokines secreted by the TH1 cell are interferon- TREATMENT OF TUBERCULOSIS gamma (IFN-~,) and interleukin-2 (IL-2). The protection provided by CD4+ cells is well M.tuberculosis is an intracellular pathogen, appreciated in the individuals affected with AIDS, residing in macrophages, which when activated since depletion of this cell results in the loss of DTH display microbicidal activity and kill the bacilli. and low levels of IL-2 and IFN-?. M.tuberculosis is Macrophages are also stimulated by T lympho- one of the most common oppurtunistic pathogens cytes, which secrete cytokines. T lymphocytes, infecting patients with AIDS. specific for M.tuberculosis are of paramount im- Defective cell mediated immunity in tubercu- portance in both cell mediated immune (CMI) and losis could be attributed to multiple defects in delayed type of hypersensitive (DTH) responses. macrophages or monocytes in patients, such as DTH response provides some protection, although low phagocytosis or low bacteriocidal properties; it results in Iocalised inflammatory responses defective chemotaxis (attraction of cells to the site causing tissue damage. of action); presence of suppressor mononuclear T cells are important since in addition to cells and/or depletion of CD4+ T lymphocytes macrophages, they also recruit and activate other resulting in decreased secretion of IFN-? and IL-2. non-specific inflammatory cells, by the secretion In a small study conducted at our centre on of cytokines. Generally CD4+ T cells are involved, the specific cell mediated immune response in while few CD8 cells participate in the response. children, the results suggested that those with TH1 and TH2 are subsets of CD4 lymphocytes, tuberculosis (meningitis, lymphadenitis and mili- the former playing a pivotal role in providing pro- ary forms) had significantly low CD4 to CD8 cell tection against the infection (1). The important ratio, low levels of IFN-~, and IL-2, when compared to normal, age and sex-matched group of children Address for correspondence : (unpublished data). Dr. K.J.R. Murthy at above address Indian Journal of Clinical Biochemistry, 1997, 12 (Suppl), 76-79 76 Murthy, Lakshmi and Singh Immunotherapy in tuberculosis treatment Augmentation of depressed cell mediated resolution of generalised lymphadenopathy asso- immune response particularly of the beneficial ciated with HIV infection Two patients who re- type (such as TH1 cell) in immunocompromised ceived a placebo were still positive for HIV an- individuals like a tuberculosis patient, could go a tibody, one year later, whereas, two others who long way in the treatment of tuberculosis, thereby received immunotherapy with M.vaccae, tested reducing spread of the disease. Appropriate cel- negative, after one year. The results suggested lular immune response could perhaps be modu- that M.vaccae evokes the beneficial type of re- lated or stimulated by the use of immunothera- sponse. peutic agents. The mode of action of M.vaccae, according The concept of immunotherapy for tubercu- to Stanford and group is on the pathway of T losis was first exploited by Robert Koch about a helper cell maturation, production of type 1 100 years ago (1). He administered repeated cytokines and regulation of immunopathology (2). injections of old tuberculin. In the 1930's, Grange proposed the theory that the immune Spahlinger attempted the use of a slightly modi- response in an individual with tuberculous infec- fied Koch's therapy. Later, M.chelonae was used tion gets locked in' to one or other pattern of as a therapeutic agent but was found to be ben- response, viz. TH1 or TH2 response (3). The eficial only in some cases, particularly in non- latter is an inappropriate response leading to tis- pulmonary form~ where the bacillary load was sue damage and progression of disease. M. vaccae small. is a powerful TH1 adjuvant, perhaps supressing In the recent years, Stanford and co-workers TH2 mediated responses (1). conducted several studies on the usefulness of Improvement of immunity and stimulation of Mycobacterium vaccae as an immunotherapeutic the relevant responses in patients with tubercu- agent for tuberculosis. The main reason be~Jnd losis by immunotherapy, is not only encouraging, the choice of this species, was that it is non- but raises hopes in the treatment of drug-resistant pathogenicto humans. The other reasons include tuberculosis, where chemotherapy alone is not its association with protection because of the effective in the elimination of bacteria. presence of group i common mycobacterial an- Drug-resistant tuberculosis is a cause for tigens, lack of pathogenic significance due to the concern as its incidence is now on the rise. Re- presence of species specific group iv antigens sistance to one, two or more drugs is becoming and its antagonistic features to tissue necrotic more common. The problems, present in the pre- elements of Koch phenomenon. M.vaccae is a antibiotic era of tuberculosis, have surfaced once scotochromogen and a rapidly growing species. again. Studies with M.vaccae as an immunothera- In India, an increase in acquired rifampicin- peutic agent in the treatment of tuberculosis by resistance was reported by ICMR in 1968 after a Stanford and co-workers suggested that immune surveillance. In Gujarat, a rise from 2.8% in 1980 recognition of common mycobacterial antigens to 37.3% in 1986 was observed (4). Local sta- was restored in patients who were previously tistics reveal that 16.1% of patients with tubercu- anergic to the same in skin test. M.vaccae also losis are resistant to more than two drugs (Goud regulated tissue necrotising immune reactions. In & Chandrasekhar, 1997, personal communica- general, the cure rate in newly diagnosed patients tion). Infection with MDR-strains and outbreak of was improved. such bacilli, may become a common phenom- A higher number i.e. 86% of patients in the enon in patients with AIDS. Some strains of immunotherapy group, compared to 58% of the tubercle bacilli are resistant to seven or more placebo group, showed progressive resolution of antibiotics. cavities. This improved radiological appearance In a small study conducted in Iran (5), clini- associated with immunotherapy was noted in an cal cure and bacteriological resolution was ob- early study of M.vaccae in Kuwait (1). Similar served in 27% of multi-drug resistant tuberculous results were observed in pilot studies in Argen- patients, whilst only 1% were cured with chemo- tina, Romania and Vietnam (1). In Nigeria, in therapy alone (5). In a recent report, 13 out of 14 patients with HIV related tuberctilosis, increased patients, seven with MDR-TB, were cured. A pre- survival and sputum clearance was attributed to liminary study conducted at our centre, on the use immunotherapy with M.vaccae. Also there was of M.vaccae as an adjunct to chemotherapy, in Indian Journal of Clinical Biochemtstry, 1997, 12 (SuppL), 76-79 77 Murthy, Lakshmi and Singh Immunotherapy in tuberculosis treatment patients with MDR-TB, showed clearance of ba- conducted at Durban, M.vaccae is injected on the cilli, increase in body weight and CMI response day 8 of treatment and in a study in London it is in almost all the patients. being injected during the first thr~e days of treat- Observations from several studies indicated ment. The authors feel that further benefit from that M.vaccae had beneficial effects when used immunotherapy could be obtained by even ad- as an adjunct to chemotherapy. However, the ministering it on the first day of chemotherapy (6). ideal time and number of times it has to be Thus, in tuberculous infection, elimination of administered for the patients to obtain optimum bacilli, eventually leading to cure depends largely benefit, is yet to be established. While a single on the immune response of the individual, par- injection was sufficient in patients with a short ticularly the cell mediated. The disease manifests history of less than two years of chemotherapy, in a host who is immunocompromised. Interven- repeated injections were required for chronic pa- tion by chemotherapy further assists in the elimi- tients with longer treatment history. Thus 86% nation of the pathogen, especially the persistors. patients with primary resistance were cured after The idea of enhancing the relevant immune re- a single injection, while 22% with chronic disease sponses by immunotherapy is, appealing. There and acquired resistance were cured only after is enough evidence now to show that immuno- multiple (2-4) injections of M.vaccae (6).
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