Animal models and clinical studies have linked the innate and adaptive immune system to the pathology of Parkinson’s disease (PD). Despite such progress, the specific immune responses that influence disease progression have eluded investigators. Herein, we assessed relationships between T cell phenotype and function with PD progression. Peripheral blood lymphocytes from two separate cohorts, a discovery cohort and a validation cohort, totaling 113 PD patients and 96 age- and environment-matched caregivers were examined by flow cytometric analysis and T cell proliferation assays. Increased effector/memory T cells (Tem), defined as CD45RO+ and FAS+ CD4+ T cells and decreased CD31+ and α4β7+ CD4+ T cells were associated with progressive Unified Parkinson’s Disease Rating Scale III scores. However, no associations were seen between immune biomarkers and increased age or disease duration. Impaired abilities of regulatory T cells (Treg) from PD patients to suppress effector T cell function was observed. These data support the concept that chronic immune stimulation, notably Tem activation and Treg dysfunction is linked to PD pathobiology and disease severity, but not disease duration. The association of T cell phenotypes with motor symptoms provides fresh avenues for novel biomarkers and therapeutic designs.Electronic supplementary materialThe online version of this article (doi:10.1007/s11481-012-9402-z) contains supplementary material, which is available to authorized users.

Recognition of the advantages of recombinant Listeria monocytogenes-based vaccines compared to those of other recombinant-vaccine platforms has facilitated the ongoing development and current evaluation of the former in early-phase clinical trials. These advantages include practical considerations, such as straightforward fermentation methods for manufacturing, and other desirable features, such as the ability to repeat administer even in the presence of protective L. monocytogenes-specific immunity (6,40,41). One compelling rationale for this vaccine platform is based on the well-known correlates of protection in the mouse listeriosis model: longlived functional CD4 ϩ and CD8 ϩ memory T cells induced in response to a single immunization with L. monocytogenes (19,28). There are now numerous publications that demonstrate the striking efficacy of recombinant L. monocytogenes vaccines in several animal models due to robust innate and adaptive cellular immunity (9,10,29). Recombinant L. monocytogenesbased vaccines represent an emerging approach to addressing an acute global need for effective vaccines that elicit functional cellular immunity to prevent or treat infections such as human immunodeficiency virus infection, hepatitis C virus infection, tuberculosis, and malaria as well as cancer.As L. monocytogenes is a food-borne pathogen having increased virulence among immunocompromised individuals, attenuated vaccine platforms are a prerequisite for advancement to evaluation with humans (23). We have previously described both live-attenuated and photochemically inactivated vaccine platforms derived from the wild-type (WT) strain 10403S (8, 9). The live-attenuated vaccine strain is deleted of both the actA and the inlB virulence genes (L. monocytogenes ⌬actA ⌬inlB vaccine strain), which in combination limit growth in the liver, a principal target organ of infection by the WT organism. Liver toxicity in mice, as measured by serum liver function tests for alanine transaminase and aspartate transaminase, is dramatically lower in mice injected intravenously (i.v.) with the L. monocytogenes ⌬actA ⌬inlB strain than in those injected i.v. with WT L. monocytogenes. Furthermore, liver toxicity was minimal and not dose limiting in two toxicology studies performed under good laboratory practice guidelines with cynomolgus monkeys given escalating doses of L. monocytogenes ⌬actA ⌬inlB-based strains (unpublished data). The L. monocytogenes ⌬actA ⌬inlB vaccine strain forms the basis for two ongoing FDA-approved phase 1 clinical trials being conducted with adult subjects with advanced cancers. The second vaccine platform, termed "killed but metabolically active" (KBMA), is derived from the L. monocytogenes ⌬actA ⌬inlB vaccine strain and is deleted of both uvrA and uvrB, genes encoding the DNA

The majority of colorectal cancers have lost/inactivated the p53 tumor suppressor gene. Using isogenic human colon cancer cells that differ only in their p53 status, we demonstrate that loss of p53 renders tumor cells relatively resistant to the topoisomerase I inhibitor, irinotecan. Whereas irinotecan-induced up-regulation of the proapoptotic proteins PUMA and Noxa requires p53, we find that irinotecan inhibits Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 and 5 (STAT3/5) signaling in both p53-proficient and p53-deficient tumor cells. We show that irinotecan inhibits JAK2-STAT3/5-dependent expression of survival proteins (Bcl-x L and XIAP) and cooperates with Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) to facilitate p53-independent apoptosis of colon cancer cells. Whereas xenografts of p53-deficient colon cancer cells are relatively resistant to irinotecan compared with their p53-proficient counterparts, combined treatment with irinotecan and Apo2L/TRAIL eliminates hepatic metastases of both p53-proficient and p53-deficient cancer cells in vivo and significantly improves the survival of animals relative to treatment with either agent alone. Although the synergy between chemotherapy and Apo2L/TRAIL has been ascribed to p53, our data demonstrate that irinotecan enhances Apo2L/TRAILinduced apoptosis of tumor cells via a distinct p53-independent mechanism involving inhibition of JAK2-STAT3/5 signaling. These findings identify a novel p53-independent channel of cross-talk between topoisomerase I inhibitors and Apo2L/TRAIL and suggest that the addition of Apo2L/TRAIL can improve the therapeutic index of irinotecan against both p53-proficient and p53-deficient colorectal cancers, including those that have metastasized to the liver.

Improved immunization and ex vivo T-cell culture strategies can generate larger numbers and more potent tumor-specific effector cells than previously possible. Nonetheless, the capacity of these cells to eliminate established tumors is limited by their ability to efficiently enter tumor-bearing organs and mediate their effector function. In the current study, we show that the administration of an engineered organ-homing microbe selectively targets tumor-specific immune responses to metastases within that organ. Specifically, an attenuated Listeria monocytogenes strain, which preferentially infects the liver following systemic administration, dramatically enhances the activity of a cancer vaccine against liver metastases but not metastases in the lung. This enhanced activity results from both local recruitment of innate immune effectors as well as concentration and increased activation of vaccine-induced antitumor T cells within the liver. These findings show a general approach to focus systemic cancer immunotherapies to specific organs bearing tumor metastases by taking advantage of differential tropisms and the proinflammatory nature of microbes.