JCI table of contents: March 15, 2007

New antibacterial strategies are needed because more and more bacteria are antibiotic resistant and because antibiotics are not effective at eradicating chronic bacterial infections. One approach to developing new antibacterial strategies, taken by researchers from the University of Washington, Seattle, is to limit the amount of iron (Fe), which is critical for bacterial growth, to which bacteria have access.

In the study, which appears online on March 15 in advance of publication in the April print issue of the Journal of Clinical Investigation, Pradeep Singh and colleagues show that Gallium (Ga), which is chemically similar to Fe and can disrupt biological systems by substituting for Fe, inhibits the in vitro growth of Pseudomonas aeruginonsa; even multidrug resistant strains of P. aeruginonsa isolated from individuals with cystic fibrosis. Ga also prevented P. aeruginonsa forming biofilms, the multi-cellular bacterial communities responsible for chronic bacterial infections, and killed both free-living bacteria and bacteria in biofilms. Furthermore, inhalation of Ga protected mice from both acute and chronic P. aeruginonsa lung infections. As Ga is already FDA approved for the treatment of hypercalcemia of malignancy, these data suggest that Ga might be a promising new therapeutic for the treatment of infection with P. aeruginonsa, a major cause of infection in individuals with cystic fibrosis and of infection acquired in hospital.

TITLE: The transition metal gallium disrupts Pseudomonas aeruginonsa iron metabolism and has antimicrobial and antibiofilm activity

AUTHOR CONTACT:
Pradeep K. Singh
University of Washington School of Medicine, Seattle, Washington, USA.
Phone: (206) 221-7151; Fax: (206) 543-8297; E-mail: singhpr@u.washington.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30783

Infection with Kaposi's sarcoma virus (KSHV) can cause 3 types of tumor, including primary effusion lymphoma (PEL). Although KSHV has been known to cause tumors for many years, there are no effective therapies for the treatment of KSHV-induced tumors. Now, researchers from the University of Helsinki, Finland, have found that the small-molecule inhibitor Nutlin-3a has antitumor effects in a mouse xenograft model of PEL.

In the study, which appears online on March 15 in advance of publication in the April print issue of the Journal of Clinical Investigation, Päivi Ojala and colleagues show that Nutlin-3a induces human PEL cell lines to undergo cell death by a process known as apoptosis. Nutlin-3a was found to disrupt an interaction between the KSHV protein LANA and the human proteins p53 and MDM2, releasing p53 to mediate apoptosis. As treatment with Nutlin-3a induced substantial tumor regression in mice with established human PEL, reactivation of p53 using Nutlin-3a might provide a viable therapeutic for the treatment of individuals with PEL.

TITLE: Reactivation of the p53 pathway as a treatment modality for KSHV-induced lymphomas

AUTHOR CONTACT:
Päivi M. Ojala
University of Helsinki, Helsinki, Finland.
Phone: +358-9-191-25548; Fax: +358-9-191-25554; E-mail: Paivi.Ojala@helsinki.fi.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30945

Many researchers are developing ways in which to harness the immune response to treat patients with cancer. However, many results have not been as successful as hoped, largely because tumors develop ways in which to suppress the immune system. For example, before immune cells known as CD8+ T cells can destroy tumors cells they must receive signals through 2 receptors on their cell surface and many tumors do not express the molecules that trigger the second signal, through CD28.

In a study that appears online on March 15 in advance of publication in the April print issue of the Journal of Clinical Investigation, Hua Gu and colleagues show that mouse CD8+ T cells lacking a protein known as Cbl-b can respond in vitro without receiving a signal through CD28. In vivo, when mice lacking Cbl-b were transplanted with tumors they rejected the tumors rapidly, whereas normal mice did not. In addition, if mice that spontaneously develop tumors were engineered to lack Cbl-b the incidence of spontaneous tumor development was markedly decreased. Although these data indicate that ablation of Cbl-b can enhance antitumor immune responses, further studies are needed to determine the short- and long-term impact of Cbl-b ablation before these observations can be translated into the clinic for the treatment of individuals with cancer.

TITLE: Ablation of Cbl-b provides protection against transplanted and spontaneous tumors

AUTHOR CONTACT:
Hua Gu
Columbia University College of Physicians and Surgeons, New York, New York, USA.
Phone: (212) 342-1398; Fax: (212) 342-1677; E-mail: hg2065@columbia.edu.

Richard Hodes
National Institutes of Health, Bethesda, Maryland, USA
Phone: (301) 496-9265; Fax: (301) 496-2525; E-mail: richard.hodes@nih.hhs.gov

View the PDF of this article at: https://www.the-jci.org/article.php?id=29472

Immune cells known as monocytes are recruited to sites of inflammation, such as sites where microbes have invaded the body. Recruitment is mediated by soluble factors known as chemokines, but the precise identity of the chemokines that mediate the movement of monocytes from the bone marrow to the blood and then from the blood to the site of inflammation have not been well defined.

In a study that appears online on March 15 in advance of publication in the April print issue of the Journal of Clinical Investigation, Israel Charo and colleagues from the Gladstone Institute of Cardiovascular Disease in San Francisco show that the chemokines MCP1 and MCP3 are crucial for monocyte movement from the bone marrow to the blood. Compared with normal mice, mice lacking either MCP1 or MCP3 had reduced numbers of monocytes in their blood and increased numbers of monocytes in their bone marrow. Similar observations were made in mice lacking the protein CCR2, which is the receptor to which MCP1 and MCP3 bind. The interaction of MCP1 and MCP3 with CCR2 was also shown to be required for the early recruitment of monocytes from the blood to sites of inflammation. This study indicates that MCP1/MCP3 and CCR2 are essential for the maintenance of a normal number of monocytes in the blood and for the early recruitment of monocytes from the blood to sites of inflammation.

TITLE: Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites

AUTHOR CONTACT:
Israel F. Charo
Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA
Phone: (415) 734-2000; Fax: (415) 355-0960; E-mail: icharo@gladstone.ucsf.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=29919

Immune responses are initiated in highly organized structures known as lymph nodes, making these structures almost indispensable in the fight against infectious microbes. Previous studies by Watanabe and colleagues have established that structures resembling lymph nodes (artificial lymph nodes; aLNs) can be generated in mice by implanting in them a biocompatible scaffold containing both stromal cells and dendritic cells.

In a study that appears online on March 15 in advance of publication in the April print issue of the Journal of Clinical Investigation Watanabe and colleagues from the RIKEN Institute, Japan, now show that aLNs support the same immune responses as normal lymph nodes. If the mice in which the aLNs were generated had been immunized with a specific protein, the aLNs contained immune cells known as T cells and B cells able to respond to the immunizing protein. Upon transplantation into mice lacking their own T and B cells, the T and B cells in the aLNs responded to further immunization with the specific protein, known as a secondary immune response. Importantly, the cells in the aLNs making this secondary immune response were able to generate memory cells, meaning that the aLN recipients made long-lived responses to the immunizing protein. The authors therefore suggest that aLNs might of therapeutic use in immunodeficient patients.

TITLE: Artificial lymph nodes induce potent secondary immune responses in naive and immunodeficient mice

AUTHOR CONTACT:
Takeshi Watanabe
Research Center for Allergy and Immunology, RIKEN Institute, Yokohama, Japan.
Phone: +81-45-503-7025; Fax: +81-45-503-7004; E-mail: wtakeshi@rcai.riken.jp.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30379