Pathogenesis and treatment of oral submucous fibrosis.

The aim of this thesis was to investigate the pathogenesis of oral submucous fibrosis (OSF), a chronic inflammatory condition of oral mucosa restricted to certain racial and behavioural groups. Specifically, the objectives were to investigate (a) the HLA antigen frequencies in OSF patients in order to determine whether any genetic predisposition is related to this condition, (b) the systemic inflammatory and antifibrotic cytokines synthesised by peripheral blood mononuclear cells (PBMC) of OSF patients by an ELISA method (c) to observe the effect of IFN-γ on collagen synthesis by OSF fibroblasts in vitro and (d) to determine the effect of IFN-γ on OSF in vivo by observing improvements in the clinical symptoms of OSF, after they had received fifteen intra-lesional injections of 50μg rhlFN-γ. Finally, tissue alterations in OSF were compared by characterising (e) the inflammatory cell infiltrate and (f) the cellular source of cytokines and growth factors in lesional tissue immunohistochemically. The results showed that (a) the HLA antigen frequencies HLA-A24, Bw6, DRB1 11 and DRB3 0202/3 are significantly higher in OSF patients compared to the Caucasians; (b) the levels of cytokines IL-1β, IL-6, IL-8 and TNF-α synthesised by PBMC are significantly higher, and IFN-γ lower, in OSF patients compared to healthy controls; (c) rhIFN-γ shows a dose dependent inhibition of collagen synthesis by OSF fibroblasts in vitro; (d) there is a significant improvement in mouth opening and other oral symptoms after intra-lesional injection of rhIFN-γ in vivo, without any major side effects; (e) the predominant chronic inflammatory cells express CD4 and HLA-DR, with higher CD4 to CDS ratios in OSF compared to normal oral mucosa, and (f) the levels of cytokines and growth factors IL-1β, IL-6, IFN-β, FGFb and PDGF appear to be higher in OSF, but IFN-γ to be lower, in OSF compared to normal. In conclusion, the results suggest that OSF is a chronic fibrotic lesion as a result of a local immune reaction in a group of areca nut chewers who are genetically vulnerable. The signs and symptoms are attributable at least in part to a deficiency of IFN-γ. Local injections of rhIFN-γ have a beneficial effect and may offer a novel means of therapy for this condition