Search

Exposure to Δ9-tetrahydrocannabinol (THC) in vitro and in animal models can significantly impair the differentiation, activation and function of dendritic cells, T cells and B cells. However, studies directly assessing the impact of marijuana smoking on human immunity are lacking. A prospective study of immune responses to a standard hepatitis B vaccination was therefore carried out in a matched cohort of 9 marijuana smokers (MS) and 9 nonsmokers (NS). In addition to their regular marijuana use, MS smoked four marijuana cigarettes in a monitored setting on the day of each vaccination. Blood samples were collected over time to assess the development of hepatitis B-specific immunity. The majority of subjects from both the NS (8) and MS (6) groups developed positive hepatitis B surface antibody titers (>10 IU/L) and of these 6 NS and 5 MS were classified as high antibody (good) responders (>100 IU/L). The development of a good response correlated with the presence of hepatitis B-specific T cell proliferation and cytokine production, resulting in a clear distinction regarding the immune status of good responders versus non-responders. However, even though there were slighter more non-responders in the MS cohort, there were no significant differences between MS and NS with respect to peripheral blood cell phenotypes or vaccination-related changes in hepatitis B responses. While a larger cohort may be required to rule out a small suppressive effect, our findings do not suggest that habitual marijuana smoking exerts a major impact on the development of systemic immunity to hepatitis B vaccination.

Glioblastoma multiforme (GBM) remains the deadliest brain tumor in adults. GBM tumors are also notorious for drug and radiation resistance. To inhibit GBMs more effectively, polymalic acid-based blood-brain barrier crossing nanobioconjugates were synthesized that are delivered to the cytoplasm of cancer cells and specifically inhibit the master regulator serine/threonine protein kinase CK2 and the wild-type/mutated epidermal growth factor receptor (EGFR/EGFRvIII), which are overexpressed in gliomas according to The Cancer Genome Atlas (TCGA) GBM database. Two xenogeneic mouse models bearing intracranial human GBMs from cell lines LN229 and U87MG that expressed both CK2 and EGFR at different levels were used. Simultaneous knockdown of CK2α and EGFR/EGFRvIII suppressed their downstream prosurvival signaling. Treatment also markedly reduced the expression of programmed death-ligand 1 (PD-L1), a negative regulator of cytotoxic lymphocytes. Downregulation of CK2 and EGFR also caused deactivation of heat shock protein 90 (Hsp90) co-chaperone Cdc37, which may suppress the activity of key cellular kinases. Inhibition of either target was associated with downregulation of the other target as well, which may underlie the increased efficacy of the dual nanobioconjugate that is directed against both CK2 and EGFR. Importantly, the single nanodrugs, and especially the dual nanodrug, markedly suppressed the expression of the cancer stem cell markers c-Myc, CD133, and nestin, which could contribute to the efficacy of the treatments. In both tumor models, the nanobioconjugates significantly increased (up to 2-fold) animal survival compared with the PBS-treated control group. The versatile nanobioconjugates developed in this study, with the abilities of anti-cancer drug delivery across biobarriers and the inhibition of key tumor regulators, offer a promising nanotherapeutic approach to treat GBMs, and to potentially prevent drug resistance and retard the recurrence of brain tumors.

Systemic lupus erythematosus is a chronic autoimmune disease characterized by loss of tolerance to self-Ags and activation of autoreactive T cells. Regulatory T (Treg) cells play a critical role in controlling the activation of autoreactive T cells. In this study, we investigated mechanisms of potential Treg cell defects in systemic lupus erythematosus using MRL-Fas(lpr/lpr) (MRL/lpr) and MRL-Fas(+/+) mouse models. We found a significant increase in CD4(+)CD25(+)Foxp3(+) Treg cells, albeit with an altered phenotype (CD62L(-)CD69(+)) and with a reduced suppressive capacity, in the lymphoid organs of MRL strains compared with non-autoimmune C3H/HeOuj mice. A search for mechanisms underlying the altered Treg cell phenotype in MRL/lpr mice led us to find a profound reduction in Dicer expression and an altered microRNA (miRNA, miR) profile in MRL/lpr Treg cells. Despite having a reduced level of Dicer, MRL/lpr Treg cells exhibited a significant overexpression of several miRNAs, including let-7a, let-7f, miR-16, miR-23a, miR-23b, miR-27a, and miR-155. Using computational approaches, we identified one of the upregulated miRNAs, miR-155, that can target CD62L and may thus confer the altered Treg cell phenotype in MRL/lpr mice. In fact, the induced overexpression of miR-155 in otherwise normal (C3H/HeOuj) Treg cells reduced their CD62L expression, which mimics the altered Treg cell phenotype in MRL/lpr mice. These data suggest a role of Dicer and miR-155 in regulating Treg cell phenotype. Furthermore, simultaneous appearance of Dicer insufficiency and miR-155 overexpression in diseased mice suggests a Dicer-independent alternative mechanism of miRNA regulation under inflammatory conditions.

Professor Black and colleagues have been working to improve the quality and sensitivity of imaging in the early detection of conditions from brain tumors to Alzheimer's disease to enhance treatment protocols and patient management. Professor Black et al introduced nanoparticles to improve MRI imaging. These nanoparticles consist of poly (b-L- malic acid (PMLA)) conjugates with monoclonal antibodies ((mAbs)) and Gd-DOTA. These are known as MRI nano-imaging agents (NIA). Most importantly, they can penetrate the endothelial blood-brain barrier (BBB) to reach brain tumors (primary or metastasis). This is effective in cases of brain tumors or breast cancer or other cancers such as lung cancer and gastric cancer having HER2 and/or EGFR positive crossing BBB. By the covalent conjugation of MR contrast (NIA), the MRI virtual biopsy can differentiate brain tumors from infections or other brain pathological conditions. The brain's intrinsic natural fluorescence such as NADH, FAD, lipopigments and porphyrin in the brain tissue can be identified by using time resolved fluorescence spectroscopy (TRFS) which is operated through the use of ultra-short laser. TRFS produces various color bands to differentiate the tumor from normal brain tissue in real time and registers the data on a 3D map. This is significant, as this will provide a greatly improved assessment methodology of tissue type. Consequently, this will potentially result in shorter operation times as well as more satisfactory tumor removal. In the detection of Alzheimer disease, amyloid plaque is deposited in retina tissue (including the RGC, RNFL and inner plexiform layer) which can produce a fluorescence effect by using curcumin as a contrast. This is then shown by human retina amyloid imaging device. Immunotherapies with glatiramer acetate (GA) have been shown to reduce amyloid deposits in brain and retinal AB deposits in mice. The study of advanced imaging technology and techniques including NIA, TRFS and the detection of amyloid plaque in Alzheimer disease are very important approaches to create a new era for diagnostic and therapeutic management of brain tumors and other cancers (HER2 and/or EGFR positive). This pioneering work by Professor Black, and colleagues, gives rise to a new hope for cancer patients for targeted therapy and for immunotherapies in Alzheimer's disease.