The Yin-Yang of tumor-associated macrophages in neoplastic progression and immune surveillance

Summary: An intrinsic (oncogene-driven) pathway and an extrinsic (microenvironment-driven) pathway connect inflammatory reactions and cancer. M2-polarized tumor-associated macrophages and the related myeloid-derived suppressor cells are key prototypic components of smoldering inflammation driving neoplastic progression. However, mononuclear phagocytes can exert anti-tumor activity by killing tumor cells and eliciting tissue disruptive reactions (M1), a likely scenario in the early phases of carcinogenesis of immunogenic tumors and following therapeutic intervention. Shifting the macrophage balance represents a viable therapeutic target. Herein, the 'macrophage balance' is discussed in the context of the apparent paradox of tumor promotion by innate immunity-driven inflammation and the seemingly opposed tumor surveillance by adaptive immune responses.     

Non-muscarinic effects of atropine on calcium conductances in cultured mouse spinal cord neurons

Cultured neurons derived from mouse spinal cord were studied using intracellular recording techniques. Effects of muscarinic cholinergic antagonists (atropine) on voltage-dependent membrane events, which could not be related to muscarinic receptors are described. Atropine (in nanomolar to micromolar concentrations) blocks calcium conductances in a manner which is not blocked by carbachol (100 microM). A direct effect of atropine on membrane Ca2+ conductances is suggested.     

Deletion of the mental retardation gene Gdi1 impairs associative memory and alters social behavior in mice

Non-specific mental retardation (NSMR) is a common human disorder characterized by mental handicap as the only clinical symptom. Among the recently identified MR genes is GDI1, which encodes alpha Gdi, one of the proteins controlling the activity of the small GTPases of the Rab family in vesicle fusion and intracellular trafficking. We report the cognitive and behavioral characterization of mice carrying a deletion of Gdi1. The Gdi1-deficient mice are fertile and anatomically normal. They appear normal also in many tasks to assess spatial and episodic memory and emotional behavior. Gdi1-deficient mice are impaired in tasks requiring formation of short-term temporal associations, suggesting a defect in short-term memory. In addition, they show lowered aggression and altered social behavior. In mice, as in humans, lack of Gdi1 spares most central nervous system functions and preferentially impairs only a few forebrain functions required to form temporal associations. The general similarity to human mental retardation is striking, and suggests that the Gdi1 mutants may provide insights into the human defect and into the molecular mechanisms important for development of cognitive functions.     

Lack of association between angiotensin converting enzyme polymorphism and sporadic Alzheimer's disease

Epidemiological and pathogenetic evidences suggest a strong association between vascular risk factors and sporadic Alzheimer's disease (sAD). In agreement with the vascular hypothesis of AD, the role of various candidate genes for atherosclerosis has been investigated, leading to conflicting results. In order to clarify the significance of angiotensin-converting enzyme (ACE) gene insertion (I)/deletion (D) polymorphism in a group of patients with sAD, we conducted a case-control study including 149 cases and 149 age and sex matched controls. All subjects were genotyped for ACE and Apolipoprotein E (APOE). There were no significant differences in ACE genotype or allele frequencies between cases and controls, even after stratification for APOE4 carrier status. Our data suggest that the ACE I/D polymorphism is not associated to genetic susceptibility in sAD patients.     

Immune regulatory mechanisms influence early pathology in spinal cord injury and in spontaneous autoimmune encephalomyelitis

Injuries to the central nervous system (CNS) trigger an inflammatory reaction with potentially devastating consequences. In this report we compared the characteristics of the inflammatory response on spinal cord injury (SCI) caused by a stab wound between the T7 and T9 vertebrae and spontaneous experimental autoimmune encephalomyelitis (EAE). SCI and EAE were compared in two types of myelin basic protein Ac1-11-specific T-cell receptor transgenic mice: T/R+ mice harbor regulatory T cells, and T/R- mice lack regulatory T cells. Our results show that 8 days after SCI, T/R- mice developed a strong T-cell infiltrate in the spinal cord, with remarkable down-modulation of CD4 expression that was accompanied by a local increase in Mac-3+ and F4/80+ reactivity and diffuse local and distal astrogliosis. In contrast, T/R+ mice exhibited a modest increase in CD4+ cells localized to the site of injury, without CD4 down-modulation; focal astrogliosis was restricted to the site of the lesion, although Mac-3+ and F4/80+ cells were also present. Similarly to T/R- mice that underwent SCI, T cells displaying down-modulated CD4 expression were found in the CNS of older T/R- mice afflicted by spontaneous EAE. Overall, our results suggest that common mechanisms regulate T-cell accumulation in CNS lesions of different causes, such as mechanic lesion or autoimmune-mediated damage.     

Self-MHC class Ia (RT1-A(n)) protects cells co-expressing the activatory allogeneic MHC class Ib molecule (RT1-E(u)) from NK lysis

We have previously shown activation of NK cells via recognition of an allogeneic, non-classical MHC class I molecule, RT1-E(u). In this study we investigated whether a self-MHC class I molecule could protect the allogeneic targets from being recognized and killed by the alloreactive NK (allo NK) cells. NK cells from BN (RT1 n) rats, primed in vivo by immunization with RT1(u)-expressing cells, manifested cytolytic activity against RT1(u)- as well as RT1(u/lv1)-expressing targets, but not against RT1(u/n)-expressing targets. The absence of cytolytic activity against semiallogeneic targets, i.e. targets expressing self-allotypes, was also valid for allo NK cells from alloimmunized F344 (RT1 (lv1)) rats. To analyze the ability of a distinct MHC class I molecule to protect target cells from NK lysis, Rat2 cells transfected with the activating allogeneic MHC class Ib, RT1-E(u) molecule were also transfected with the self-MHC class Ia, RT1-A1(n) molecule. The allo NK cells from BN rats immunized with RT1(u)-expressing cells were cytolytic against Rat2 transfected with the RT1-E(u) molecule. However, the allo NK cells manifested no cytolytic activity against double-transfected Rat2 cells, expressing the RT1-E(u) as well as the RT1-A1(n) molecule. We conclude that expression of a self-MHC class Ia (RT1-A) molecule protects targets from allo NK killing. Furthermore, the NK inhibition via recognition of the self-MHC class Ia molecule dominates over the activation via recognition of the allogeneic MHC class Ib molecule, RT1-E.     

Locally superantigen-activated peritoneal cytolytic T lymphocytes belong to the CD8+ CD45RC- subset and lyse MHC class II+ tumor cells.

Bacterial encoded superantigens (SA) are capable of activating and targeting cytolytic human and mouse T lymphocytes (CTL) to lyse major histocompatibility complex class II positive (MHC class II+) target cells. In this study both in vitro and in vivo activated rat CTL were directed against MHC II+ tumor targets by bacterial encoded SA. Polyclonal in vitro activation of rat peripheral blood T lymphocytes generated CTL capable of killing MHC class II+ human BSM cells coated by staphylococcal enterotoxin (SE) -A, -E, -D, and TSST-1 but not by SEB or SEC1-3. Allo selective peritoneal CTL generated by intraperitoneal stimulation with allogeneic spleen cells were directed against BSM cells by SEA, -D, and -E but not by SEB, SEC1-3 or TSST-1. Based on the above observations, and in order to locally activate CTL, SEA was chosen for in vivo priming of rats by intraperitoneal inoculation of the toxin. SEA injection generated highly cytolytic CTL, and maximum cytolytic responses were seen at 50-250 micrograms SEA per animal with a peak in response 48-72 hours after injection of the toxin. The cytolytic activity of peritoneal SEA reactive effector cells was confined to the TCR alpha beta+ CD4- CD8+ CD45RC- cell population. MHC class II- colon carcinoma cells were insensitive to lysis by SEA reactive CTL but colon carcinoma cells induced to express MHC class II by interferon-gamma (IFN-gamma) treatment were efficiently lysed in the presence of SEA. Comparison of rat and human MHC II+ colon carcinomas revealed a peak in sensitivity to lysis at 10-100 ng SEA/ml for both tumor targets. These findings suggest that superantigens can be used in local immunotherapy of peritoneal tumors such as ovarian and colorectal carcinomatosis, with inducible or constitutive expression of MHC class II.