HR for some time i have been confused about progression of fibrosis relating to viral stimulated immune response.
if the Th1 immune response is pro-inflammatory ( and Th2 response anti-inflammatory) how do the trial drugs that promote the Th1 response work to decrease inflamation, ALT levels, and improve histology?
does hcv cause overproduction Th2 cytokines and down regulate Th1 cytokines causing chronic inflammation the reason for fibrotic progression? are immune therapies a good adjunct to prevent worsening of fibrosis to be considered.
Activation of Th1 means that the subset of helper T lymphocytes that preferentially produce IFN gamma and Il-12 and direct the cytotoxic T cell population as their main effector cell population is in the foreground of activation. This is typically the response that allows to identify virus infected cells via the extremely sensitive class I epitope - T cell receptor system, with subsequent killing of the infected cell AND the secretion of local gamma inteferon that will inhibit and sometimes eradicate the virus in the neighborhood of the recognized cell as well.
Insofar as this reduces intrahepatic viral presence and reduces consequently the general proinflammatory reaction - " hepatitis", and therefore the collateral activation of hepatic stellate cells, that receive signals from this inflammatory process that turn them into a fiber producing myofibroblast, they indirectly reduce fibrosis in the longer run.
HCV is not intending to increase fibrosis but benefits from lesser Th1 propensity and has evolved some counteractive mechanisms in that regard. The persistence of the virus causes persistent inflammation - see above- and fosters fibrosis in this fashion.
Immune therapies like thymosin alpha are a good adjunct to IFN, since they further strengthen the T cell aspect of the multiple IFN actions. But when the response to IFN is either weak from the host side or inactivated by the virus, or if the virus has found means to inactivate by clever blocking mechanism the actual final IFN and other cytokine actions then they also will not really work.
The US Thymosin alpha trial plus SOC vs SOC in SOC nullresponders was terminated when the response ( SVR) rate was 1%! in SOC and yes three times more with the addition of Thymosin alpha , namely a very very paltry 3%.
On the other hand, in treatment naive patients the addition of Thymosin to SOC will lead to a substantial improvement of SVR rates as I was told from interim results from the large ongoing European trials for this setting.
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