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Stress proteins (SPs) from the heat shock and glucose-regulated protein families are abundant intracellular molecules that have powerful extracellular roles as immune modulators. Mammalian immune cells encounter both identical (self) SPs and non-identical SPs derived from invading pathogens. Although such extracellular SPs can function as powerful immunological adjuvants, SPs, including Hsp60 and Hsp70, can also attenuate inflammatory disease via apparent effects on immunoregulatory T cell populations. It therefore seems that the immunostimulatory and immunosuppressive potential of extracellular SPs depends on the context in which they are encountered by the cellular immuneresponse network. Conclusions regarding the immunobiology of these powerful immunomodulatory molecules must therefore take into account their dichotomous properties and their physiological role and importance must be interpreted in the context of the complex in vivo microenvironments in which these proteins exist.

Simple Summary: Treatments for castrate (hormone)-resistant prostate cancer (CRPC) remain limited and are not curative. Although the first (and only) FDA-approved vaccine for CRPC (PROVENGE®, Sipuleucel-T) has been shown to improve the overall survival of patients, it is not curative and its cost prevents its widespread use. PROVENGE® induces immunity to prostatic acid phosphatase (PAP), a protein which is highly expressed in prostate cancer (PCa). Herein, we have developed a new PAP-based vaccine for PCa and demonstrated the presence of circulating PAP-specific CD8+ T cells that are responsive to this vaccine in patients with PCa. We have also shown that this new PAP sequence-derived peptide containing a modified amino sequence, in association with a strong adjuvant called CAF®09, induces strong immune responses and cytotoxic potential in a murine HHDII/DR1 transgenic model. Background: Current treatments for castrate (hormone)-resistant prostate cancer (CRPC) remain limited and are not curative, with a median survival from diagnosis of 23 months. The PAP-specific Sipuleucel-T vaccine, which was approved by the FDA in 2010, increases the Overall Survival (OS) by 4 months, but is extremely expensive. We have previously shown that a 15 amino accid (AA) PAP sequence-derived peptide could induce strong immune responses and delay the growth of murine TRAMP-C1 prostate tumors. We have now substituted one amino acid and elongated the sequence to include epitopes predicted to bind to several additional HLA haplotypes. Herein, we present the immunological properties of this 42mer-mutated PAP-derived sequence (MutPAP42mer). Methods: The presence of PAP-135-143 epitope-specific CD8+ T cells in the blood of patients with prostate cancer (PCa) was assessed by flow cytometry using Dextramer™ technology. HHDII/DR1 transgenic mice were immunized with mutated and non-mutated PAP-derived 42mer peptides in the presence of CAF®09 or CpG ODN1826 (TLR-9 agonist) adjuvants. Vaccine-induced immune responses were measured by assessing the proportion and functionality of splenic PAP-specific T cells in vitro. Results: PAP-135-143 epitope-specific CD8+ T cells were detected in the blood of patients with PCa and stimulation of PBMCs from patients with PCa with mutPAP42mer enhanced their capacity to kill human LNCaP PCa target cells expressing PAP. The MutPAP42mer peptide was significantly more immunogenic in HHDII/DR1 mice than the wild type sequence, and immunogenicity was further enhanced when combined with the CAF®09 adjuvant. The vaccine induced secretory (IFNγ and TNFα) and cytotoxic CD8+ T cells and effector memory splenic T cells. Conclusions: The periphery of patients with PCa exhibits immune responsiveness to the MutPAP42mer peptide and immunization of mice induces/expands T cell-driven, wild-type PAP immunity, and therefore, has the potential to drive protective anti-tumor immunity in patients with PCa. [ABSTRACT FROM AUTHOR]

The role of physical activity in determining the metabolic health of adolescents is poorly understood, particularly concerning the effect on low-grade chronic inflammation (chronic elevation of pro-inflammatory cytokines IL-1β, IL-6, TNF-α and acute phase protein CRP, which is implicated in the etiology of atherosclerosis) and anti-inflammatory mediators such as IL-10. Furthermore, there is limited information on the mediating effects of performance on the multi-stage fitness test (MSFT), V ˙ O 2 peak and adiposity on risk factors for cardio-metabolic disease in adolescents. Purpose: To examine the effect of performance on the MSFT, V ˙ O 2 peak and adiposity on risk factors for cardio-metabolic diseases in adolescents. Methods: Following ethical approval, 121 adolescents (11.3 ± 0.8 year) completed the study. Risk factors for cardio-metabolic disease (circulating inflammatory cytokines, blood glucose and plasma insulin concentrations) was assessed using a fasted capillary blood sample. Participants were separated into quartiles based upon distance ran during the MSFT, the blood lactate response to submaximal exercise, V ˙ O 2 peak (determined during an uphill graded treadmill test), and adiposity (determined as the sum of four skinfolds). The blood lactate response to submaximal exercise and V0 2 peak were measured in a sub-group of participants. Data were analyzed using two-way between-subjects ANCOVA and multiple linear regression. Results: Participants with the lowest performance on the MSFT had higher blood concentrations of IL-6 (3.25 ± 0.25 pg mL -1 ) and IL-1β (4.78 ± 0.54 pg mL -1 ) and lower concentrations of IL-10 (1.80 ± 0.27 pg mL -1 ) when compared with all other quartiles (all p < 0.05). Yet, when categorized into V ˙ O 2 peak quartiles, no differences existed in any of the inflammatory mediators (all p > 0.05). Performance on the MSFT was the only predictor of IL-6 (β = -0.291, p = 0.031), IL-1β (β = -0.405, p = 0.005), IL-10 (β = 0.325, p = 0.021) and fasted blood glucose (β = -0.545, p < 0.001) concentrations. Adiposity was the only predictor of plasma insulin concentration (β = 0.515, p < 0.001) and blood pressure (diastolic: β = 0.259, p = 0.042; mean arterial pressure: β = 0.322, p = 0.011). Conclusion: Enhanced performance on the MSFT, but not V ˙ O 2 peak, was associated with a favorable inflammatory profile in adolescents; whilst adiposity adversely affected plasma insulin, diastolic and mean arterial blood pressure. These findings demonstrate that enhancing performance on the MSFT and maintaining a healthy body composition are a potential therapeutic intervention for the attenuation of risk factors for cardio-metabolic diseases in adolescents.

Heat shock proteins (Hsps) are ubiquitously expressed and highly conserved families of molecules, immune reactivity to which has been implicated in the pathogenesis of inflammatory conditions such as autoimmune and cardiovascular disease. The observations that Hsp expression is induced by ischemia-reperfusion injury and is elevated in transplanted organs, and that rejecting allografts are infiltrated by Hsp-specific lymphocyte populations have prompted the suggestions that Hsps and the development of anti-Hsp immune reactivity drive transplant rejection responses. However, although these proteins can activate innate immune cells such as monocytes, macrophages and dendritic cells and can promote the development of proinflammatory immune responses, they are also cytoprotective and have been shown to improve organ viability and function after ischemia-reperfusion injury in a number of experimental models. In addition, the induction of immunity to Hsp60, Hsp70 and Grp78 attenuates experimental autoimmune disease and the induction of immunity to Hsp60 prolongs murine skin allograft survival. It would, therefore, appear that the expression of Hsps and the presence of Hsp-specific lymphocyte populations are not necessarily indicative of a deleterious response; indeed they might reflect an anti-inflammatory, protective response. This chapter reviews current knowledge in the area of Hsps, anti-Hsp reactivity and allograft rejection.