With this strong case for type I IFN’s important role as a heritable risk factor, a correlate of disease activity and a global immune response modifier central to the pathogenesis of SLE (and some other systemic autoimmune diseases), many groups have concluded that this cytokine is an appropriate target for therapeutic modulation. Current efforts are directed at understanding the impact of currently available therapies on IFN pathway activation and development of new agents to inhibit the pathway, directly or indirectly.
Arguably the most effective approach to inhibiting production of IFNα is administration of intravenous high dose methylprednisolone. This treatment virtually ablates the IFN signature based on microarray or real-time PCR data from patient PBMC before and after pulse steroid treatment.3
The presumed basis of this effect is death of the major producers of IFNα, pDCs, by the high dose steroids. Recent data suggest that additional mechanisms that modulate the capacity of IRFs to regulate gene transcription might also contribute to reduced IFN pathway activation by high dose steroids.57–59
Although the mechanism by which other frequently used therapeutic agents, such as mycophenolate mofetil (MMF), might inhibit IFN production are only recently coming under study, our preliminary data suggest that MMF treatment is associated with reduction of the IFN score derived from lupus patient PBMC.58
A recent study implicates a possible effect of MMF on autophagy and the TLR-independent innate immune system pathway, but additional investigation will be required to pursue that suggestion.59
As described, hydroxychloroquine inhibits acidification of intracellular vesicles, and in vitro studies clearly document the inhibition of IFN production induced by nucleic acid-containing immune complexes by chloroquine. It is likely that additional mechanisms account for the positive impact of hydroxychloroquine therapy on reduction of lupus flares, but the strong rationale for its use based on the recent IFN pathway data have suggested that additional approaches to inhibition of TLR activation might be even more productive in SLE. Among the approaches under investigation are inhibition of nucleic acid-mediated TLR activation by oligonucleotide inhibitors of TLR7, TLR8 and TLR9. This approach is quite attractive if the oligonucleotide inhibitors can be modified to assure adequate delivery to target cells.
The most active area of clinical development of therapeutics targeting the IFN pathway involves current clinical trials of monoclonal antibodies specific for numerous IFNα isoforms. At least three of these monoclonal agents are in clinical development, each presumably slightly different from the others in the range of isoforms targeted. Very promising pharmacodynamic data from MedImmune have demonstrated inhibition of the IFN signature in PBMC and in skin biopsies from at least some lupus patients treated with Medi-545.60
At this time the blockade of interaction of IFNα with IFNAR by monoclonal anti-IFNα antibodies appears to be the most feasible and likely to be effective approach to controlling this important innate immune system pathway.
Additional antibodies are available that block the IFN receptor. As the receptor not only binds IFNα but is also activated by the other type I IFNs, including IFNβ, IFNθ and others, it would seem that receptor blockade might produce a more complete blockade of downstream gene expression than the anti-IFNα antibodies, for better or worse.
The essential role of type I IFN in host defense against virus infection is clearly evident from the obvious effort expended by the collective human genome over evolutionary time to generate a variety of similar but non-identical type I IFN isoforms. Of those, IFNα has the most variants (thirteen different isoforms). The high impact of this system on generating effective and comprehensive immune responses triggered by virus infection is emphasized when considering the numerous approaches used by viruses to hijack the normal host response.61
Virus-encoded proteins have been shown to block induction of type I IFN and response to that cytokine. In fact, study of the mechanisms used by viruses to paralyze the host IFN response has provided important insights into the essential components of that response. Blockade of any system that holds such responsibility for maintaining the intactness of the host in the setting of a viral assault should only be modulated with great care. Development of any of the therapeutic approaches described will be accompanied by careful monitoring for viral infection. Considering the different options, it would seem that blockade of IFNAR might be most risky, while TLR blockade or inhibition of selective type I IFNs (such as inhibition of IFNα with monoclonal antibodies) would allow some other routes for production of IFN or response to other isoforms to be available. Although the role of type I IFN in viral host defense has garnered the most extensive investigation, IFNα is also active in modulating certain hematologic malignancies such as hairy cell leukemia, and the role of the type I IFNs in regulating myeloid differentiation is not fully understood, suggesting a further need for caution as therapeutic trials move forward.