Anti-Filarial T-cell Responses in Onchocerciasis: Protective responses to recombinant Onchocerca volvulus antigens and regulatory mechanism

Thumbnail Image
Journal Title
Journal ISSN
Volume Title
Onchocerciasis or River blindness is of high prevalence in tropical Africa, however current control methods, cannot stop transmission completely. Thus complementary approaches including the role of immune mechanisms to control have been advocated. The presence of putative immune individuals and evidence from animal models suggest the existence of immunity to onchocerciasis and that a mixed Thl/Th2 may be involved. To elucidate protective human immune responses, whole blood of onchocerciasis patients were stimulated with 17 O. volvulus recombinant antigens and the cytokine profiles elicited were assessed. Stimulation with these antigens induced moderate to high levels of cell proliferation and the production of IFN-γ, IL-5, IL-13 and IL-b. Interferon-γ production was observed to be significantly higher in cultures stimulated with the recombinant antigens OvALD, RAL-2 and ASP-1. These antigens also showed enhanced production of IL-S (P< 0.05). Only ASP-1 induced significant production of IL-13 (P=0.002). Thus, OvALD, RAL-2 and ASP-i proved potent in inducing a mixed Th1 /Th2 cytokine profile, and could be further investigated for vaccine development. The phenomenon of peripheral tolerance as observed in generalized onchocerciasis, involves different mechanisms. T regulatory-1 (Tr1) cells, a subset of CD4+ T cells, are implicated in suppressor functions in vitro and in vivo. Characterized by the predominant production of IL-10 and/or TGF-3, Tr1 cells have mainly been generated experimentally in an IL- 10-rich environment and have not been characterized in infectious diseases. In this study, it is shown that in the chronic helminth infection of onchocerciasis, T cells can be obtained which bear characteristics of Tr1 cells, producing substantial amounts of IL- 10, variable amounts of IL-5, and some IFN-γ but no IL-2 or IL-4. In contrast to Thl and Th2 clones, these cells display elevated amounts of CTLA-4 after stimulation and are able to inhibit other T cells in coculture. The effect of T cells with a regulatory profile on IgG4 production was investigated using generated T cell clones (TCC) with two different cytokine profiles co-cultured with purified CD19+ B cells. The present study showed that in T-B cell co-culture, IL- 10, if induced by the TCC or added to the system, down-regulated the immune response by inducing IgG4 secretion. The correlation between IgG4 and IL-l0 (r2 = 0.352) indicates that IL-b is an important but not the only factor for IgG4 induction. This establishes a direct implication of IL-I 0 in humoral hyporesponsiveness; especially where the T-B cell interplay determines the subsequent immune response.
A thesis submitted to the Department of Theoretical and Applied Biology, Faculty of Biosciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy, 2005