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Cholesterol deposits and pro-inflammatory cytokines play an essential role in the pathogenesis of atherosclerosis, a predominant cause of cardiovascular disease (CVD). Epidemiological evidence has linked periodontal disease (PD) with atherosclerotic CVD. Accordingly, viable periodontal pathogens, including Porphyromonas gingivalis, have been found in atherosclerotic plaques in humans and mice. We aimed to determine whether cholesterol crystals (CHCs) and oral bacteria synergize in the stimulation of human monocytes. Incubation of human monocytes with CHCs induced secretion of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, and IL-8. Moreover, CHCs markedly enhanced secretion of IL-1β by monocytes stimulated with the toll-like receptor (TLR) 4 agonist Escherichia coli lipopolysaccharide (LPS), and the TLR2 agonist Staphylococcus aureus lipoteichoic acid. Notably, CHCs also enhanced IL-1β secretion induced by P. gingivalis LPS and IL-1β secretion induced by whole P. gingivalis bacteria. This enhancement was abrogated by the NLRP3 inflammasome inhibitors Z-YVAD-FMK and glibenclamide. CHCs had no effect on cytokine production induced by P. gingivalis gingipains. Taken together, our findings support that CHCs, via stimulation of NLRP3 inflammasomes, act in synergy with the periodontal pathogen P. gingivalis to promote monocyte secretion of pro-atherogenic cytokines.

Allogeneic hematopoietic cell transplantation (HCT) is a treatment for various hematologic diseases where efficacy of treatment is in part based on the graft versus tumour (GVT) activity of cells in the transplant. The cytoprotective enzyme heme oxygenase-1 (HO-1) is a ratelimiting enzyme in heme degradation and it has been shown to exert anti-inflammatory functions. In humans a (GT)n repeat polymorphism regulates the expression of HO-1. We conducted fragment length analyses of the (GT)n repeat in the promotor region of the gene for HO-1 in DNA from donors and recipients receiving allogeneic myeloablative- (MA) (n = 110) or nonmyeloablative- (NMA-) (n = 250) HCT. Subsequently, we compared the length of the (GT)n repeat with clinical outcome after HCT. We demonstrated that transplants from a HO- 1high donor after MA-conditioning (n = 13) is associated with higher relapse incidence at 3 years (p = 0.01, n = 110). In the NMA-conditioning setting transplantation of HO-1low donor cells into HO-1low recipients correlated significantly with decreased relapse related mortality (RRM) and longer progression free survival (PFS) (p = 0.03 and p = 0.008, respectively). Overall, our findings suggest that HO-1 may play a role for the induction of GVT effect after allogeneic HCT.

Periodontitis is a prevalent chronic inflammatory disease induced by bacterial biofilm in the dental pocket resulting in destruction of the periodontal tissues. Periodontitis is associated with ischaemic heart disease and we here provide a summary of the current evidence linking these two disorders.

Ex vivo expanded tumor infiltrating lymphocytes (TILs) from malignant melanoma (MM) and head & neck squamous cell carcinoma (HNSCC) share a similar oligoclonal composition of T effector memory cells, with HLA class I restricted lysis of tumor cell lines. In this study we show that ex vivo expanded TILs from MM and HNSCC demonstrate a heterogeneous composition in frequency and magnitude of tumor associated antigen specific populations by Elispot IFN¿ quantitation. TILs from MM and HNSCC shared reactivity towards NY ESO-1, cyclin B1 and Bcl-x derived peptides. Additionally we show that dominating T-cell clones and functionality persists through out expansion among an oligoclonal composition of T-cells. Our findings mirror prior results on the oligoclonal composition of TIL cultures, further indicating a potential for a broader repertoire of specific effector cells recognizing the heterogeneous tumors upon adoptive transfer; increasing the probability of tumor control by minimizing immune evasion by tumor cell escape variants.

Several lines of data have suggested a possible link between the indoleamine 2,3-dioxygenase (IDO)-like protein IDO2 and cancer. First, IDO2 expression has been described in human tumors, including renal, gastric, colon, and pancreatic tumors. Second, the apparent selective inhibition of IDO2 by the D stereoisomer of the IDO blocker 1-methyl-tryptophan (1MT), which tends to be more active than the L-isomer in a variety of biological assays for IDO function, suggests that IDO2 may be important to sustain immune escape and growth of tumors. Especially, D-1MT heightens chemotherapeutic efficacy in mouse models of cancer in a nontoxic fashion. Here, we describe the immunogenicity of IDO2 by showing the presence of spontaneous cytotoxic T-cell reactivity against IDO2 in peripheral blood of both healthy donors and cancer patients. Furthermore, we show that these IDO2-specific T cells are cytotoxic effector cells that recognize and kill tumor cells. Our data suggest that IDO2 might be a useful target for anticancer immunotherapeutic strategies.

Udgivelsesdato: 2007-Mar-15, RhoH is a small GTPase expressed only in the hematopoietic system. With the use of mice with targeted disruption of the RhoH gene, we demonstrated that RhoH is crucial for thymocyte maturation during DN3 to DN4 transition and during positive selection. Furthermore, the differentiation and expansion of DN3 and DN4 thymocytes in vitro were severely impaired. These defects corresponded to defective TCR signaling. Although RhoH is not required for TCR-induced activation of ZAP70 and ZAP70-mediated activation of p38, it is crucial for the tyrosine phosphorylation of LAT, PLCgamma1, and Vav1 and for the activation of Erk and calcium influx. These data suggest that RhoH is important for pre-TCR and TCR signaling because it allows the efficient interaction of ZAP70 with the LAT signalosome, thus regulating thymocyte development.