Partially circumventing peripheral tolerance for oncogene-specific prostate cancer immunotherapy

BACKGROUND: Failure of cancer immunotherapy is essentially due to immunological tolerance to tumor-associated antigens (TAAs), as these antigens are also expressed in healthy tissues. METHODS: Here, we used transgenic adenocarcinoma of mouse prostate (TRAMP) mice, which develop lethal prostate cancer due to prostate-specific expression of SV40 T antigen (Tag), to evaluate effects of prostatic transformation on oncogene TAA-specific tolerance and to test the possibility of breaking such tolerance using a modified recombinant vaccinia virus. RESULTS: We showed that Tag expression in TRAMP mice is uniquely extra-thymic, and levels of prostatic Tag expression positively correlate with malignant transformation of the prostate. Yet, young tumor-free TRAMP mice were tolerant to Tag antigen. We therefore attempted overcoming such peripheral oncogene-specific T cell tolerance through immunization with a vaccinia construct encoding Tag immunogenic epitopes. This vaccination modality showed that oncogene-specific tolerance was successfully overcome by effective in vivo priming of Tag-specific cytotoxic T cells (CTLs). However, this was restricted to young TRAMP mice. Tag-specific CTL from "tumor na?ve" young TRAMP mice showed significant anti-tumor efficacy in vivo by eliminating established heterotopic prostate tumors and prolonging survival in SCID mice harboring Tag-expressing tumors. In contrast, older TRAMP mice with established prostate tumors exhibited oncogene-specific tolerance as evidenced by failure to generate Tag-specific CTL following Tag-specific immunization. CONCLUSIONS: Peripheral tolerance can be overcome for effective anti-tumor therapy following oncogene-specific immunization. However, this ability to elicit oncogene-specific CTL is impeded in the tumor-bearing host, in the context of increased oncogene expression associated with tumor progression.     

Screening for coronary artery disease in patients with type 2 diabetes mellitus: An evidence-based review

Coronary artery disease (CAD) is the leading cause of morbidity and mortality in patients with diabetes. CAD is often asymptomatic in these patients, until the onset of myocardial infarction or sudden cardiac death. Consequently, proper screening and diagnosis of CAD is crucial for the prevention and early treatment of coronary events. This review deals with selection of the sub group of patients who have type 2 diabetes, who are at high risk for developing CAD and need to be screened for the same. The various diagnostic modalities which can be used in the screening process for enhancing risk stratification and management are also discussed.     

Role of scavenger receptor MARCO in macrophage responses to CpG oligodeoxynucleotides

The macrophage Class A scavenger receptor MARCO (macrophage receptor with a collagenous structure) functions as a pattern-recognition receptor for bacterial components, but its role in responses to CpG oligonucleotide sequences (CpG-ODN) in microbial DNA has not been characterized. Phosphorothioate (PS)-linked CpG-ODN stimulated IL-12 and NO production in wild-type but not in MARCO-deficient, thioglycollate-elicited peritoneal macrophages. MARCO and the related class A receptor SR-A belong to a redundant system of receptors for PS ODNs. The ability of MARCO to bind CpG-ODNs and conversely, to costimulate IL-12 and NO production upon specific ligation with immobilized mAb is consistent with MARCO being a signaling receptor for CpG-ODNs, costimulating TLR9-mediated NO and IL-12 production in macrophages. In contrast to MARCO, SR-A is likely to mediate negative regulation of macrophage responses to CpG-ODNs. In particular, increased affinity toward SR-A may contribute to decreased potency of oligo G-modified CpG-ODNs in stimulating IL-12 production. The results suggest that differential involvement of activating and inhibitory membrane receptors, such as SR-A and MARCO, may underlie profound differences observed in biological activities of different ODN sequences.     

Haptoglobin interacts with the human mast cell line HMC-1 and inhibits its spontaneous proliferation

Haptoglobin (Hp) is an acute phase reactant produced by hepatocytes. There is evidence for an immunomodulatory potential of Hp, though there is no clear evidence yet about the mechanisms of this action. We have previously shown that Hp interacts with the beta2-integrin CD11b/CD18. In addition, other investigators reported the binding of Hp to B lymphocytes through the CD22 receptor, and to neutrophils through two different receptors. In the present study, we investigated the interaction of haptoglobin with the human mast cell line HMC-1. We report that fluorescein isothiocyanate (FITC)-labelled haptoglobin binds to this cell line and that binding is increased by calcium in a dose- and time-dependent manner. Hp binding sites on HMC-1 were upregulated upon stimulation with phorbol myristate acetate (PMA)/A23187 and after treatment with anti-CD43 and anti-CD44 monoclonal antibodies (MoAbs). HMC-1 cells do not express either CD11b/CD18 or CD22 receptors, indicating that the haptoglobin-binding receptor on this cell line is different from the known receptors. Assessment of cell function showed that Hp inhibits the spontaneous growth of HMC-1 up till 40% at higher Hp concentrations, but it did not exhibit any effect on the expression of CD54 on the release of either tryptase or IL-1ra. In conclusion, haptoglobin binds specifically to human mast cells via a receptor different from CD11b/CD18 and CD22, and may play a role in the modulation of mast cell functions. Exploration of Hp effects in mast cell-dependent diseases such as allergic rhinitis and urticaria seems warranted.     

Aortic diameter at age 65 in men with newly diagnosed type 2 diabetes

Objectives. Type 2 diabetes mellitus has been linked to a decreased risk for abdominal aortic aneurysm (aortic diameter ≥30?mm, AAA) development in men. The aim of this study was to evaluate if such an effect is detectable already around the time of diabetes diagnosis. Design. We cross-sectionally compared aortic diameter at ultrasound screening for AAA in 691 men aged 65 years with incipient or newly diagnosed type 2 diabetes (group A) with 18,262 65-year old control men without diabetes (group B). Results. Aortic diameter did not differ between groups (18.8[17.4–20.8] vs. 19.0[17.5–28.7] mm; p?=?0.43). AAA prevalence was 2.5% in group A and 1.5% in group B (p?=?.010). In logistic regression taking group differences in body mass index (BMI), smoking, presence of atherosclerotic disease and hypertension into account, the difference in AAA prevalence was no longer significant (p?=?.15). Among men in group A, C-peptide (r?=?.093; p?=?.034), but not HbA1c (r?=?.060; p?=?.24) correlated with aortic diameter. Conclusion. Among 65 year old men aortic diameter and AAA prevalence do not differ between those with newly diagnosed type 2 diabetes and those without diabetes. Putative protective effects of type 2 diabetes mellitus against aortic dilatation and AAA development therefore probably occur later after diagnosis of diabetes.