Immunotherapy for TB
If adjuvant (and possibly antigen-based) immunotherapy exert their effects by stimulating the induction of inflammatory or proinflammatory cytokines, there is a certain logic to simply testing the potential of those cytokines directly. The obvious first target was IFN-γ, given its central role in immunity to M. tuberculosis. The first such attempts, against refractory nontuberculous mycobacterial infections, showed promising initial results and work on M. tuberculosis swiftly followed. In the study by Condos et al., patients with refractory MDR-TB who had remained sputum positive despite adherence to treatment, received 500 µg of aerosolized IFN-γ three-times a week for 1 month. All patients receiving treatment gained weight, converted to smear negativity, showed a small increase in time to culture positivity and showed radiological improvement. Unfortunately, in all cases, the effects seen were transient, with reversion to sputum positivity over time. In total, there have been nearly a dozen trials with IFN-γ, with consistent but disappointing data; an early improvement, followed by relapse when treatment was paused. None of these studies have shown significant effects on mortality (although, to be fair, they have been so small that they were not powered to do so). It has, however, been shown that IFN-γ used as an adjunct to chemotherapy can improve outcomes, and other groups have been able to show similar effects with IFN-α. So far, however, given the expense and side effects associated with interferon treatment, the minimal gains achieved do not seem to warrant the cost.
IL-12 – a crucial factor in the development of IFN-γ-producing CD4 T cells – is also essential for protection against M. tuberculosis infection in humans (as indicated by the susceptibility of patients with defects in the IL-12 signaling pathway), but the literature contains only a single reference to its use as an effective adjunct therapy for TB. As for IFN-γ, any enhancement of immunity generated by the treatment does not appear to persist.
In retrospect, given the discussion above on M. tuberculosis's ability to modulate the host's immune response, it is not surprising that the response to exogenous cytokine treatment is transient. Host functions dependent on IL-12 or IFN-γ may be augmented by exogenous cytokine, but the underlying mechanisms of immunity are unlikely to be changed, given that both IL-12 and IFN-γ are produced in abundance by the infected human host and are downregulated as disease becomes progressive. It appears that augmenting inflammatory responses is ineffective in the longer term, as long as the underlying defects in immunity that allowed disease to develop in the first place are still present.
IL-2 – another prototypical Th1 cytokine – is produced by activated T lymphocytes and plays a critical role in the expansion, activation and maturation of T cells. In animal models of mycobacterial infection, IL-2 has been shown to inhibit mycobacterial replication, possibly by augmenting the effect of TNF-α or simply by enhancing T-cell expansion and maturation. Animal experiments with IL-2, either alone or together with TNF-α, showed weak inhibitory effects on mycobacterial growth and the observation of decreased IL-2 expression and responsiveness in humans with TB suggested that IL-2 immunotherapy might be helpful. Initial results in patients at different stages of TB treatment (including some with MDR-TB) who received rhIL-2 for 30 consecutive days, as an adjunct to chemotherapy, indicated some improvement. The numbers of CD25 and CD56 cells increased in the peripheral blood of patients receiving rhIL-2 therapy, compared with placebo, and bacterial load in sputum decreased, as did time to sputum conversion, while radiological assessment improved in the majority of (but not all) cases. The treatment was, on the whole, well tolerated. Subsequently, a randomized, double-blinded, placebo-controlled Phase II clinical trial was conducted in 110 HIV-negative TB patients with drug-sensitive M. tuberculosis infections, with 1 year of follow-up. Although it confirmed some of the findings of the earlier studies, the study did not find any clinical improvement. The researchers noted that the increase in the percentage of CD25 T cells was specific for CD4 cells (they speculated that the inability of the treatment to activate CD8 cells might account for its failure) and they also documented increased levels of soluble IL-2 receptor and IL-2 in serum. However, the immunological effects were transient and no significant differences were seen between the groups with regard to weight gain, symptoms, relapse rates or bacillary clearance. It is possible that the difference in outcomes was due to the inclusion of MDR-TB cases in the initial studies: a poorer response to chemotherapy might have increased the window in which a positive effect of the cytokine adjunct therapy could be seen. However, the modest nature of any benefit, combined with the cost of the treatment, has meant that rhIL-2 therapy for TB has not been further pursued.
TNF-α is another cytokine of undoubted importance in the control of TB and it is known to be crucial for the control of latent TB, as indicated by the increased risk of reactivation of latent TB in patients treated with TNF-α receptor antagonists. However, TNF-α is also the cytokine most consistently associated with pathology in TB, and may have been a primary factor in the Koch reaction. Perhaps in consideration of the potential risks, no clinical trials with exogenous TNF-α have been initiated. However, TNF-α is also associated with accelerated HIV disease progression in individuals coinfected with M. tuberculosis, and high levels of serum TNF-α were associated with a poorer response to treatment, so inhibiting TNF-α in association with TB treatment has been tested. In a study where HIV–M. tuberculosis coinfected patients received the soluble TNF-α receptor etanercept (a TNF-α antagonist) while receiving anti-TB therapy, significant gains were seen in body mass, radiologic scores and time to sputum culture conversion. This was accompanied by a significant increase in CD4 T-cell count, attributed to a possible decrease in TNF-α-driven apoptosis.
These findings are consistent with the knowledge that inhibiting inflammatory processes can improve TB chemotherapy. In a study from the 1950s in which prednisolone was first used as an adjunct to TB chemotherapy, a similar hastening of sputum clearance and improved radiology was seen, but it did not affect outcomes in the longer term. In addition, in these studies a 'rebound effect' on radiology was noted on cessation of prednisolone treatment, consistent with the concept that underlying pathologic mechanisms had been suppressed, not removed. Newer studies, using high-dose methylprednisolone, have linked the effect of corticosteroids to reduced TNF-α production. The most recent of these – a well-controlled Phase II study in HIV–M. tuberculosis-coinfected patients with CD4 T-cell counts above 200/µl – showed a transient but substantial decrease in median levels of TNF-α, TNF-α receptor type II and neopterin in the prednisolone-treated arm, together with an increase in CD4 T-cell counts and a more rapid clearance of M. tuberculosis from the sputum. Unfortunately, in a pattern which is all too familiar in TB immunotherapy, these benefits were transient, suggesting again that the treatment ameliorated overproduction of inflammatory mediators that might be driving pathology (and symptoms) in the patients, but that treatment did not address the underlying defect in immunity that had allowed TB pathology to develop in the first place.
Thus, despite trials stretching back over half a century, we remain unclear on precisely what mechanisms are involved in these interventions. The improvements observed in these studies, in which TNF-α and inflammatory pathways are inhibited, can be ascribed to a reduction in tissue destruction and bacterial escape mediated by TNF-α as easily as to improved control of the disease. It should be noted that early studies with corticosteroids in TB – without concurrent chemotherapy to kill the pathogen – demonstrated that they worsened TB (as etanercept does in latently infected TB patients), illustrating the double role that TNF-α and inflammatory processes play in TB.
Cytokine Immunotherapy
Interferons & IL-12
If adjuvant (and possibly antigen-based) immunotherapy exert their effects by stimulating the induction of inflammatory or proinflammatory cytokines, there is a certain logic to simply testing the potential of those cytokines directly. The obvious first target was IFN-γ, given its central role in immunity to M. tuberculosis. The first such attempts, against refractory nontuberculous mycobacterial infections, showed promising initial results and work on M. tuberculosis swiftly followed. In the study by Condos et al., patients with refractory MDR-TB who had remained sputum positive despite adherence to treatment, received 500 µg of aerosolized IFN-γ three-times a week for 1 month. All patients receiving treatment gained weight, converted to smear negativity, showed a small increase in time to culture positivity and showed radiological improvement. Unfortunately, in all cases, the effects seen were transient, with reversion to sputum positivity over time. In total, there have been nearly a dozen trials with IFN-γ, with consistent but disappointing data; an early improvement, followed by relapse when treatment was paused. None of these studies have shown significant effects on mortality (although, to be fair, they have been so small that they were not powered to do so). It has, however, been shown that IFN-γ used as an adjunct to chemotherapy can improve outcomes, and other groups have been able to show similar effects with IFN-α. So far, however, given the expense and side effects associated with interferon treatment, the minimal gains achieved do not seem to warrant the cost.
IL-12 – a crucial factor in the development of IFN-γ-producing CD4 T cells – is also essential for protection against M. tuberculosis infection in humans (as indicated by the susceptibility of patients with defects in the IL-12 signaling pathway), but the literature contains only a single reference to its use as an effective adjunct therapy for TB. As for IFN-γ, any enhancement of immunity generated by the treatment does not appear to persist.
In retrospect, given the discussion above on M. tuberculosis's ability to modulate the host's immune response, it is not surprising that the response to exogenous cytokine treatment is transient. Host functions dependent on IL-12 or IFN-γ may be augmented by exogenous cytokine, but the underlying mechanisms of immunity are unlikely to be changed, given that both IL-12 and IFN-γ are produced in abundance by the infected human host and are downregulated as disease becomes progressive. It appears that augmenting inflammatory responses is ineffective in the longer term, as long as the underlying defects in immunity that allowed disease to develop in the first place are still present.
IL-2
IL-2 – another prototypical Th1 cytokine – is produced by activated T lymphocytes and plays a critical role in the expansion, activation and maturation of T cells. In animal models of mycobacterial infection, IL-2 has been shown to inhibit mycobacterial replication, possibly by augmenting the effect of TNF-α or simply by enhancing T-cell expansion and maturation. Animal experiments with IL-2, either alone or together with TNF-α, showed weak inhibitory effects on mycobacterial growth and the observation of decreased IL-2 expression and responsiveness in humans with TB suggested that IL-2 immunotherapy might be helpful. Initial results in patients at different stages of TB treatment (including some with MDR-TB) who received rhIL-2 for 30 consecutive days, as an adjunct to chemotherapy, indicated some improvement. The numbers of CD25 and CD56 cells increased in the peripheral blood of patients receiving rhIL-2 therapy, compared with placebo, and bacterial load in sputum decreased, as did time to sputum conversion, while radiological assessment improved in the majority of (but not all) cases. The treatment was, on the whole, well tolerated. Subsequently, a randomized, double-blinded, placebo-controlled Phase II clinical trial was conducted in 110 HIV-negative TB patients with drug-sensitive M. tuberculosis infections, with 1 year of follow-up. Although it confirmed some of the findings of the earlier studies, the study did not find any clinical improvement. The researchers noted that the increase in the percentage of CD25 T cells was specific for CD4 cells (they speculated that the inability of the treatment to activate CD8 cells might account for its failure) and they also documented increased levels of soluble IL-2 receptor and IL-2 in serum. However, the immunological effects were transient and no significant differences were seen between the groups with regard to weight gain, symptoms, relapse rates or bacillary clearance. It is possible that the difference in outcomes was due to the inclusion of MDR-TB cases in the initial studies: a poorer response to chemotherapy might have increased the window in which a positive effect of the cytokine adjunct therapy could be seen. However, the modest nature of any benefit, combined with the cost of the treatment, has meant that rhIL-2 therapy for TB has not been further pursued.
TNF-α & Steroid Therapy
TNF-α is another cytokine of undoubted importance in the control of TB and it is known to be crucial for the control of latent TB, as indicated by the increased risk of reactivation of latent TB in patients treated with TNF-α receptor antagonists. However, TNF-α is also the cytokine most consistently associated with pathology in TB, and may have been a primary factor in the Koch reaction. Perhaps in consideration of the potential risks, no clinical trials with exogenous TNF-α have been initiated. However, TNF-α is also associated with accelerated HIV disease progression in individuals coinfected with M. tuberculosis, and high levels of serum TNF-α were associated with a poorer response to treatment, so inhibiting TNF-α in association with TB treatment has been tested. In a study where HIV–M. tuberculosis coinfected patients received the soluble TNF-α receptor etanercept (a TNF-α antagonist) while receiving anti-TB therapy, significant gains were seen in body mass, radiologic scores and time to sputum culture conversion. This was accompanied by a significant increase in CD4 T-cell count, attributed to a possible decrease in TNF-α-driven apoptosis.
These findings are consistent with the knowledge that inhibiting inflammatory processes can improve TB chemotherapy. In a study from the 1950s in which prednisolone was first used as an adjunct to TB chemotherapy, a similar hastening of sputum clearance and improved radiology was seen, but it did not affect outcomes in the longer term. In addition, in these studies a 'rebound effect' on radiology was noted on cessation of prednisolone treatment, consistent with the concept that underlying pathologic mechanisms had been suppressed, not removed. Newer studies, using high-dose methylprednisolone, have linked the effect of corticosteroids to reduced TNF-α production. The most recent of these – a well-controlled Phase II study in HIV–M. tuberculosis-coinfected patients with CD4 T-cell counts above 200/µl – showed a transient but substantial decrease in median levels of TNF-α, TNF-α receptor type II and neopterin in the prednisolone-treated arm, together with an increase in CD4 T-cell counts and a more rapid clearance of M. tuberculosis from the sputum. Unfortunately, in a pattern which is all too familiar in TB immunotherapy, these benefits were transient, suggesting again that the treatment ameliorated overproduction of inflammatory mediators that might be driving pathology (and symptoms) in the patients, but that treatment did not address the underlying defect in immunity that had allowed TB pathology to develop in the first place.
Thus, despite trials stretching back over half a century, we remain unclear on precisely what mechanisms are involved in these interventions. The improvements observed in these studies, in which TNF-α and inflammatory pathways are inhibited, can be ascribed to a reduction in tissue destruction and bacterial escape mediated by TNF-α as easily as to improved control of the disease. It should be noted that early studies with corticosteroids in TB – without concurrent chemotherapy to kill the pathogen – demonstrated that they worsened TB (as etanercept does in latently infected TB patients), illustrating the double role that TNF-α and inflammatory processes play in TB.
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