A friendly foe: Bacteria residing in the gut boost immune response to tumors
One potent, immune-based treatment for cancer is total body irradiation (TBI). This approach first depletes the body of the population of immune cells known as lymphocytes and then involves the adoptive transfer of tumor-specific T cells to the patient. Lymphodepletion has previously been shown to improve the ability of tumor-specific T cells to cause tumor regression. In a study appearing online on July 26 in advance of publication in the August print issue of the Journal of Clinical Investigation, Nicholas Restifo and colleagues from the National Cancer Institute show that, in mice, lymphodepletion does not fully account for the tumor regression observed following TBI. They show that a disruption of the population of bacteria that normally reside in the gut without causing disease also plays a role in the effectiveness of this therapeutic approach for cancer.
A specific population of bacteria present in our gut is crucial to our health. However, some treatments for cancer, particularly those that deplete the body’s immune cells, have high potential to disrupt the natural balance between our bodies and these commensal microorganisms, causing disease. Restifo and colleagues subjected mice genetically deficient in lymphocytes to TBI and found that, like TBI-treated mice with intact lymphocytes, TBI was still able to positively augment the function of adoptively transferred tumor-specific CD8+ T cells and cause tumor regression. This surprising result indicated that another mechanism for the efficacy of TBI also exists. They found that in these mutant, irradiated mice the lining of their gut was injured, allowing the passage of commensal bacteria from the gut to the lymph nodes, where the immune response to their presence increased the activation of tumor-specific CD8+ T cells and resulted in tumor regression. This effect was found to involve toll-like receptor 4. Conversely, a reduction in the number of host microorganisms by the use of antibiotics reduced the beneficial effects of TBI on tumor regression in these animals. In summary, the results of the study demonstrate that the disruption of the host/microorganism balance by TBI and the resulting transient bacterial infection is a key mechanism driving the increased reactivity of tumor-specific CD8+ T cells and subsequent tumor regression in mice.
TITLE: Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling
Nicholas P. Restifo or Chrystal M. Paulos
National Cancer Institute, Bethesda, Maryland, USA.
Phone : (301) 496-4904; Fax : (310) 496-0011; E-mail: email@example.com or firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=32205
A step forward in our understanding of tissue damage after spinal cord injury
Acute spinal cord injury can damage spinal cord tissue and result in loss of functions such as mobility or feeling. In a study appearing online on July 26 in advance of publication in the August print issue of the Journal of Clinical Investigation, J. Marc Simard and colleagues from the University of Maryland at Baltimore show that calcium-activated cation channels in capillaries surrounding spinal cord tissue are critical to the process that causes spinal cord tissue loss after acute cord injury, and as such are a potential target in the therapy of spinal cord injuries.
The authors showed that spinal cord injury in otherwise healthy rats caused a lesion in spinal cord tissue that progressively expanded in size and was accompanied by a fragmentation of surrounding capillaries, resulting in hemorrhage, tissue necrosis, and neurological dysfunction. The expression of sulfonylurea receptor 1 (SUR1) was increased in the capillaries and neurons surrounding the lesion and also associated with expression of SUR1-regulated, calcium-activated cation channels known as NC[Ca-ATP] channels. The authors went on to show that suppression or blockade of SUR1 activity following spinal cord injury essentially eliminated capillary fragmentation and hemorrhage, reduced spinal cord tissue damage 3-fold, and resulted in marked improvement in mobility in treated versus untreated animals. The results of the study suggest that SUR1-regulated NC[Ca-ATP] channels in the lining of capillaries are critical to the development of progressive hemorrhagic necrosis following spinal cord injury, and as such may constitute a target for therapy in spinal cord injury.
TITLE: Endothelial sulfonylurea receptor1–regulated NC[Ca-ATP] channels mediate progressive hemorrhagic necrosis following spinal cord injury
J. Marc Simard
University of Maryland at Baltimore, Maryland, USA.
Phone : (410) 328-0850; Fax: (410) 328-0756; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=32041
The ABCs of getting rid of excess cholesterol
Excess free cholesterol that accumulates along the walls of blood vessels is transported to the liver for excretion via a process known as reverse cholesterol transport. Three proteins, known as ABCA1, SR-BI, and ABCG1, have been shown to promote cholesterol efflux and protect against atherosclerosis in mice, but their roles in mediating reverse cholesterol transport from macrophages remains unclear. In a study appearing online on July 26 in advance of publication in the August print issue of the Journal of Clinical Investigation, Daniel Rader and colleagues from the University of Pennsylvania studied macrophage reverse cholesterol transport in mice and found that ABCA1 and ABCG1, but not SR-BI, promote reverse cholesterol transport in macrophages and that ABCA1 and ABCG1 have additive effects on this process. The data suggest that ABCA1 and ABCG1 cooperatively contribute to macrophage reverse cholesterol transport and that therapeutic intervention to increase macrophage ABCA1 and ABCG1 expression may be an effective strategy to inhibit the development of, or reduce, atherosclerosis.
TITLE: Macrophage ABCA1 and ABCG1, but not SR-BI, promote macrophage reverse cholesterol transport in vivo
Daniel J. Rader
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: (215) 573-4176; Fax: (215) 573-8606; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=32057
Activation of liver X receptor–beta lowers cholesterol and reverses atherosclerosis
In animals and humans, the proteins known as liver X receptors (LXRs) sense cholesterol levels. Upon sensing increases in cholesterol, these receptors activate signaling pathways that remove diet-derived cholesterol from the body. Two types of LXRs – LXR-alpha and LXR-beta – are therefore potential targets for the development of anti-atherosclerosis drugs. However, the effects of synthetic drugs that activate these two receptors have not been well studied. In a study appearing online on July 26 in advance of publication in the August print issue of the Journal of Clinical Investigation, Peter Tontonoz and colleagues from the University of California, Los Angeles, show that activation of LXR-beta by a synthetic compound is able to reverse atherosclerosis and cholesterol overload in mice.
The authors began by studying mice lacking apolipoprotein E (apoE; a protein that functions in cholesterol distribution among cells), which have increased cholesterol levels and are predisposed to develop atherosclerosis. They showed that the loss of LXR-alpha in these animals results in a striking body-wide accumulation of cholesterol and accelerated atherosclerosis. This observation suggests that LXR-beta alone is unable to maintain homeostasis under conditions of cholesterol overload. Surprisingly, however, administration of a synthetic compound that activates LXR-beta, was able to compensate for the loss of LXR-alpha, reduce cholesterol overload and reduce atherosclerosis. The results of the study suggests that LXR-alpha has an essential role in maintaining cholesterol homeostasis in conditions of cholesterol overload such as hypercholesterolemia and lend support to the notion that future drug development studies should examine targeting LXR-beta.
TITLE: Ligand activation of LXR-beta reverses atherosclerosis and cellular cholesterol overload in mice lacking LXR-alpha and apoE
University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California, USA.
Phone : (310) 206-4546; Fax: (310) 267-0382; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=31909
SLAT protein is involved in T cell development and function
The protein known as SLAT (SWAP-70–like adaptor of T cells) was recently identified, however it’s physiological function remained unclear. In a study appearing online on July 26 in advance of publication in the August print issue of the Journal of Clinical Investigation, Amnon Altman and colleagues from the La Jolla Institute for Allergy and Immunology studied SLAT-/- mice and found that these animals displayed defects in the early stages of thymocyte development. Thymocytes are precursors of immune cells known as T cells, which respond to foreign pathogens and are tolerant of self-antigens. The observed defect in thymocyte development resulted in reduced numbers of peripheral T cells. In addition, the thymocytes in these animals were impaired in their ability to differentiate into Th1- or Th2-type cells, and as such Th1- and Th2-type inflammatory immune responses in the lung were also impaired. The authors went on to show that the basis for this defect is that SLAT-deficient T cells are incapable of releasing calcium in response to stimulation, which limits their ability to further differentiate. These data suggest that SLAT plays an important role in fundamental aspects of T cell development and physiology.
TITLE: SLAT regulates Th1 and Th2 inflammatory responses by controlling Ca2+/NFAT signaling
La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Phone: (858) 752-6808; Fax: (858) 752-6986; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=31640
Macrophages in the spleen regulate the immune response and immune tolerance
Autoimmune diseases such as multiple sclerosis and arthritis result from the body’s immune system attacking it’s own tissues or ‘self antigens’. Therefore, researchers have long desired to understand how a state of immune tolerance (the inability to mount an immune response against an antigen) may be forcibly induced as a therapeutic approach to treating autoimmune disease. In a study appearing online on July 26 in advance of publication in the August print issue of the Journal of Clinical Investigation, Masato Tanaka and colleagues from RIKEN Research Center for Allergy and Immunology in Japan investigated the contribution of cells in the spleen known as macrophages to the establishment of immunological tolerance.
The authors generated transgenic mice in which macrophages in an area known as the marginal zone in the spleen were transiently deleted by the administration of diphtheria toxin (DT). In healthy mice, injected, dying cells are normally selectively engulfed and destroyed by immune cells known as dendritic cells, and as such the presence of cell-associated antigens does not trigger an immune response. By contrast, in DT-treated mice that lacked macrophages in the marginal zone of the spleen, the ingestion and destruction of the dying cells by dendritic cells was irregular and the mice became susceptible to the development of a multiple sclerosis-like autoimmune response. This is the first study demonstrating that macrophages in the marginal zone of the spleen regulate not only efficient clearance of dying cells, but also the selective engulfment of dying cells by dendritic cells, and that functional failure of these macrophages impairs the induction of tolerance to cell-associated antigens.
TITLE: Critical role of macrophages in the marginal zone in the suppression of immune responses to apoptotic cell–associated antigens
RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa, Japan.
Phone: 81-45-503-9686; Fax: 81-45-503-9685; E-mail: email@example.com
RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa, Japan.
Phone: 81-45-503-9140 (ext. 6251); Fax: 81-45-503-9694; Email: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=31990
AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.