Variations in exposure and treatment may contribute to heterogeneity in immunity and granuloma-induced pathology in human schistosomiasis. To examine this hypothesis, olive baboons were either repeatedly infected with Schistosoma mansoni cercariae or received an equivalent dose in a single infection. They were then cured with praziquantel and reinfected with a single exposure. Serial liver biopsies were obtained throughout the course of the experiment, and cytokine responses by peripheral blood mononuclear cells were measured every 2 to 3 weeks. Reinfection after treatment resulted in a twofold-smaller granuloma size at 6 and 9 weeks after infection compared to the size for the same period after primary infection (P < 0.001) but had no effect at 16 or 19 weeks postinfection. The pattern of exposure did not influence granuloma size. During primary infection schistosome-soluble egg antigen (SEA)-induced cytokine production correlated with granulomatous inflammation. Cytokine levels peaked during the acute infection, declined with chronic infection, and became undetectable after treatment. Reinfection after treatment stimulated a two- to three-fold increase in SEA-specific interleukin-4 (IL-4), IL-5, IL-10, IL-2, and transforming growth factor beta (TGF-beta) production and a marked rise in SEA-specific immunoglobulin E (IgE) and IgG regardless of the type of exposure. Cytokine production was significantly greater in repeatedly exposed animals (P < 0.001). SEA-induced gamma interferon production, however, did not increase with reinfection after treatment. SEA-induced TGF-beta was the only cytokine that remained elevated as the infection become chronic and correlated with diminished hepatic granuloma size, implying its participation in down-modulation. These studies demonstrate that baboons partially retain their ability to down-modulate the granulomatous response after treatment.
Purpose: We investigated serum cytokine and T-cell responses directed against tumour-associated antigens (TAAs) in association with survival of patients with glioblastoma multiforme (GBM).
Patients and methods: Peripheral blood from 205 treatment-naïve patients with glioma (GBM = 145; non-GBM = 60) was obtained on the day of surgery to measure (i) circulating T-cells reacting to viral antigens and TAAs, in the presence or absence of cytokine conditioning with IL-2/IL-15/IL-21 or IL-2/IL-7, and (ii) serum cytokine levels (IL-4, IL-5, IL-6, TNF-a, IFN-? and IL-17A). Patients were followed-up for at least 1000 days post-surgery. Survivin protein and gene expression in resected GBM tumour tissue were confirmed by immunohistochemistry and real-time polymerase chain reaction, respectively. Antigen-specific T-cell responses were gauged by ICS (intracellular cytokine production). Associations between patient survival and immunological reactivity patterns were analysed using univariate and multivariate statistics.
Results: Approximately 2% of patients with GBM and 18% of patients with non-GBM glioma, were alive beyond 1000 days of surgery. Univariate analysis indicated that the combination of three cytokines (IL-4/IL-5/IL-6, p = .0022; IFN-?/TNF-a/IL-17A, p = .0083) but not a 'partial' combination of these cytokines, the IFN-? immune response to EBV-EBNA-1 (p < .0001) as well as T-cell responses to the survivin97-111 peptide (p = .0152) correlated with longer survival among patients with GBM. Multivariate analysis identified survivin97-111-directed IFN-? production with IL-2/IL-15/IL-21 conditioning (p = .024), and the combined presence of serum IFN-?/TNF-a/IL-17a (p = .003) as independent predictors of survival.
Conclusion: Serum cytokine patterns and lymphocyte reactivity to survivin97-111, particularly with IL-2, IL-15 and IL-21 conditioning may be instrumental in predicting survival among patients with GBM. This has implications for clinical follow-up of patients with GBM and the targeted development of immunotherapy for patients with CNS tumours.
