TB and the ‘host’ immune response

 

When considering the fundamental complexities of TB and its treatment, two issues emerge:

 

Firstly, since the bacterium has a propensity to mutate, it is inevitable that resistant forms will eventually develop in response to any drug therapy used against it. 

 

Secondly, the relative health and strength of the infected patient’s immune system (the ‘host’ immune response) has an important impact at several stages of the disease progression. Firstly, not everyone who is exposed to the bacteria will develop the infection. Then, of those who do (with a primary latent infection), the vast majority never develop the active disease. Finally, while TB is unquestionably a lethal disease, normally only 50-70% of those who develop full-blown TB are expected to die if they never receive treatment. In fact, a proportion of them do recover their health.

 

So what’s stopping those primary infections in the first place? What’s then stopping the disease progressing into its active phase? And what’s allowing some of those with full active disease to survive? Ultimately it’s down to the state of the patient’s immune system or their ‘host immunity’.

 

It is very important to appreciate that the majority of TB-infected individuals by definition must generate immune responses that control their M. tuberculosis infections otherwise everyone exposed to the bacteria would develop active TB disease. In other words, active TB disease is actually the exception and not the rule and so it has to be possible that a safe technique could provide assistance at critical moments of the disease progression and thus make these exceptions less frequent. 

 

Immunotherapy for tuberculosis

 

There's surely every reason for the effort to be made to investigate this important avenue of research, and yet it’s extraordinary how little attention is currently being paid to this in the growing number of reports and research papers that are currently appearing on TB. 

 

At first, it might seem that there's a good reason for this. Robert Koch (the renowned ‘father of modern immunology’ who first identified the bacteria in 1882) tried a famous immunotherapy on his patients. In some individuals, it definitely did lead to recoveries but in others, it had severe reactions and may have even caused their deaths.

What Koch didn’t know  was that M. tuberculosis is able to interfere with the host's immune response at multiple points in the course of the disease progression, having the capacity not just to turn off the host's inflammatory immune response at critical moments, but also to turn it on when this it to its advantage. 

 

More recently there have been highly publicised problems with immunotherapy research into other diseases (e.g. the notorious 'elephant man' study at Northwick Park London in 2006, and the 2016 Juno Therapeutics trial in Seattle) resulting in researchers becoming very wary of this field (and TB research has suffered for decades from lack of interest anyway, because it's not seen as being sufficiently profitable).

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However, despite the challenges, researching an immunotherapeutic response to TB should not be ignored or neglected, because if the safety factor can be overcome, it could be an easier target for research than a new vaccine, and certainly as significant in the long term as any new drugs.

 

For immunotherapy to be effective and safe against M. tuberculosis, it needs to meet specific criteria. First, the effect needs to be appropriately balanced so as not to over-provoke an immune response which could be dangerous to the patient. Second, the immune response generated needs to either target specific molecules or be broad enough so that the bacteria can’t totally evade the immune system’s memory response. Thirdly it needs to be safe. This is a daunting challenge for a new intervention, but much less daunting from the perspective of a therapy that has been regularly used for at least two millennia for treating a wide range of health problems (i.e. moxa) and which has evidence of efficacy when used at a low dosage on a daily basis for TB. 

 

A few recent immunotherapy studies initially seemed promising, although their benefits (where reported) appear to have only been temporary. This suggests a failure to address the underlying defect in immunity mediators that might have allowed TB pathology to develop in the first place.

 

The other issue is their anticipated cost: sophisticated modern immunotherapy is likely to be expensive enough to preclude its implementation where it is most needed. And this is where we think moxa may come in.

 

Moxa as viable immunotherapy for TB

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Historically moxa has been reported as helping TB patients recover from their illness in the years before TB drugs first appeared in Japan.  Did it provoke a broad enough immune response to account for such recovery? It seems quite possible. If so, might it do the same today when the drugs are failing? 

 

How might such moxa-promoted immune responses work? This question is still unanswered; for us, the first and most important thing has been to establish evidence of effect.  If we can demonstrate this, we will know that moxa therapy can be put to work, and we already know it is safe and cheap. We envisage various ways in which moxa might be useful:

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1. Preventing the initial infection (a protective measure for family members, close contacts, or health workers who are known to be at immediate risk).
    

2. Preventing the progression from sub-clinical to active disease (used prophylactically in high-incidence environments).
    

3. Helping first-line TB drugs work faster and more effectively (thus potentially reducing the pool of infection).
    

4. Helping second-line drugs work better when periods to sputum clearance and non-infectiousness take so long (perhaps improving the poor success rates for MDR- or XDR-TB treatment).
    

5. Helping recovery (or reduce infectiousness) when all available treatment is failing and patients are ‘programmatically untreatable’.
    

6. Helping as an ongoing therapy to help reduce re-infection or relapse rates and/or extend life expectancy in TB patients who have successfully completed drug treatment.

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All of these are now on Moxafrica’s radar as we pass the first milestones of investigation: establishing moxa’s effect in terms of strengthening immunity as adjunctive therapy for treating drug-susceptible TB (even with HIV co-infections) and establishing clear indications of safety.