Previous studies suggest that IL-12, the potent Th1-inducing cytokine, IFN-gamma, TNF-alpha and nitric oxide (NO) contribute to resistance against blood-stage malaria. Early Th1 responses correlate with resistance, whereas predominantly Th2 responses are associated with susceptibility. In the present studies, the requirements for endogenous IL-12 and its role in host defense against blood-stage P. chabaudi AS malaria were investigated. Our results reveal, for the first time, significant differences in the kinetics of endogenous IL-12 p70 synthesis and splenic IL-12R beta1 and beta2 mRNA expression between resistant B6 and susceptible A/J mice that correlate with the polarization of Th responses observed in these hosts during early blood-stage malaria. The spleen was found to be the major source of systemic IL-12 in infected B6 hosts. In addition, significant differences were observed between acutely infected B6 and A/J hosts, on a per cell basis, in IL-12 p70 release by splenic macrophages in vitro. Importantly, these differences correlated with greater malaria parasite-induced IFN-gamma synthesis in vitro by spleen cells from infected B6 mice. Furthermore, systemic IL-12 production and Th1 responses were found to be unimpaired in P. chabaudi AS infected mice deficient in TNFR compared to wild type controls. However, LPS, but not PRBC, -induced NO synthesis by splenic macrophages, was significantly reduced in infected TNFR deficient hosts. Finally, compared to controls receiving chloroquine (CQ) alone, the mechanism(s) of combined low dose IL-12 and CQ therapy for malaria-infected A/J mice was found to involve increased splenocyte expression of IL-12R beta1 and beta2 and IFN-gamma mRNA, together with enhanced parasite antigen-induced synthesis of IFN-gamma by spleen cells in vitro. This novel IL-12 and CQ therapeutic strategy resulted in significantly reduced parasitemia, enhanced survival, and was effective against established blood-stage malaria. Taken together
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.35939 |
| Date | January 1998 |
| Creators | Sam, Hakeem. |
| Contributors | Stevenson, M. M. (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001650817, proquestno: NQ50255, Theses scanned by UMI/ProQuest. |
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