Drawing a crowd: recruiting cells from the bone marrow to blood vessels in tumor growth
Cells within the bone marrow (progenitor cells) that express a protein called CD34 have been shown to leave the marrow and travel to sites of tissue injury to mediate repair. Once the cells arrive at the site of injury it has been demonstrated that they can turn into a variety of different cell types, including blood vessel cells, muscle cells, nerve cells, and blood cells, which enhances wound healing. However, the mechanisms responsible for recruiting these CD34-positive progenitor cells from the bone marrow and to the site of tissue damage are unclear. Now, in a study appearing online on February 23 in advance of print publication in the March issue of the Journal of Clinical Investigation, Judy Varner and colleagues from the University of California, San Diego show that a protein called alpha4-beta1 integrin (or VLA-4) promotes the homing of these progenitor cells to VLA-4–binding molecules called VCAM and fibronectin found on both actively healing and tumor-associated blood vessels. The researchers found that progenitor cells were drawn to sites of active blood vessel formation in tumors, but not to normal tissues, due to the presence of VLA-4 in the tumor vessels. In addition, the authors found that blocking VLA-4 with an antibody prevented the progenitor cells from sticking to blood vessels, from migrating to newly formed vessels, and from changing into different cell types. Together these studies support a potent role of VLA-4 in the regulation of bone marrow–derived progenitor cells in wound repair and migration. The authors suggest that inhibiting this homing process could be useful in suppressing new blood vessel formation in tumors.
TITLE: A homing mechanism for bone marrow–derived progenitor cell recruitment to the neovasculature
AUTHOR CONTACT:
Judy Varner
University of California, San Diego, La Jolla, California, USA
Phone: (858) 822-0086; Fax (858) 822-1325; E-mail: jvarner@ucsd.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=24751
IMMUNOLOGY
B cells behaving badly: understanding the causes of B cell tumors in AIDS patients
Approximately one-fourth to one-third of all human cancers are related to viral infection. The immune systems of AIDS patients, in particular, are compromised and suppressed, which makes these individuals susceptible to infection and subsequent cancer development, such as the onset of Kaposi sarcoma. In a study appearing online on February 23 in advance of print publication in the March issue of the Journal of Clinical Investigation, Dirk P. Dittmer and colleagues from University of North Carolina in Chapel Hill, provide evidence that a protein called LANA from the Kaposi sarcoma–associated herpesvirus (KSHV) is responsible for the excessive B cell proliferation and lymphoma development in AIDS patients and in patients with two other B cell diseases known as PEL and MCD. The researchers created genetically modified mice, known as transgenic mice, that overexpress the LANA protein in mature B cells. The authors found that LANA was able to activate B cells in the absence of any antigen stimulation, which resulted in the development of extremely enlarged spleens (an indication of increased B cell numbers), B cell tumors, and lymphoma in 100% of these transgenic animals, in contrast to their healthy siblings. As no previous animal model exists to recapitulate KSHV-dependent B cell lymphoma development, these animals provide a valuable model for understanding how viral infection contributes to B cell activation, growth, and lymphoma.
TITLE: The latency-associated nuclear antigen of Kaposi sarcoma–associated herpesvirus induces B cell hyperplasia and lymphoma
AUTHOR CONTACT:
Dirk P. Dittmer
University of North Carolina, Chapel Hill, North Carolina USA
Phone: (919) 966-7960; Fax: (919) 962-8103; E-mail:ddittmer@med.unc.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=26190
IMMUNOLOGY
Rejecting a donation: activated platelets in organ transplantation
Organ transplantation, by necessity, involves surgically induced physical trauma at the time the tissue graft or donor tissue is encountered by the immune system. A molecule called CD154 is a surface protein found on activated immune system T cells, and its blockade has been shown to prevent graft rejection. However, CD154 is also released in soluble form by activated platelets. To date, there has been no direct evidence that this form of the molecule independently mediates any pathological immune response. Now, in a study appearing online on February 23 in advance of print publication in the March issue of the Journal of Clinical Investigation, Allan Kirk and colleagues at the National Institutes of Health in Bethesda, Maryland, show that CD154 released from surgically activated platelets is sufficient to induce rejection of cardiac allografts (the mouse version of a heart transplant) independently of cell-bound CD154. The authors studied CD154-deficient mice with cardiac allografts and found that, although normally these mice are resistant to graft rejection, the animals demonstrated acute cellular rejection following treatment with CD154-expressing human platelets or soluble CD154. To identify the specific role of CD154 in this process, the authors treated the mice with a human CD154–specific antibody (5c8), which prevented the induced rejection. The data in this study demonstrate that, in addition to the previously established role of T cell–expressed CD154 in immune responses, the soluble form of this protein released by activated platelets mediates rejection, providing a link between trauma and acquired immune system activation.
TITLE: Platelet-derived or soluble CD154 induces vascularized allograft rejection independent of cell-bound CD154
AUTHOR CONTACT:
Allan D. Kirk
National Institutes of Health, Bethesda, Maryland, USA
Phone: (301) 496-3047; Fax: (301) 451-6989; E-mail:allanK@intra.niddk.nih.gov
View the PDF of this article at: https://www.the-jci.org/article.php?id=27155
IMMUNOLOGY
Understanding how the body mediates allergic reactions
Allergy (or anaphylaxis), mediated by the production of a protein called IgE on immune cells known as mast cells, is a common immune response to foreign substances called allergens. It is hypothesized that allergen immunization can prevent allergies by stimulating the body to produce IgG blocking antibodies (BA) which neutralize the allergen at a subsequent exposure. Alternatively, studies of cells in laboratory dishes suggest that a BA-allergen complex forms and inhibits signaling by mast cells via cross-linking the mast cell protein Fc(epsilon)RI to another receptor called Fc(gamma)RIIb, found on immune cells called macrophages. Unfortunately, no evidence exists for either of these mechanisms in live animals or humans. Now, in a study appearing online on February 23 in advance of print publication in the March issue of the Journal of Clinical Investigation, Fred D. Finkelman and colleagues from the University of Cincinnati report that while a low dose of allergen is sufficient to activate the IgG/ Fc(gamma)III/ macrophage pathway, high doses of allergen are required to induce IgE/mast cell responses. The authors performed several mouse immunization experiments to demonstrate that the reason for these different responses is that the IgG BA was intercepting the allergen before it reached the IgE to stimulate mast cells. Mice immunized with a goat antibody against mouse allergen (GantiMD) demonstrate strong mast cell and IgE responses, and severe anaphylaxis (as demonstrated by rapid drops in body temperature). In addition, the authors determined that IgG BA not only intercepts allergen, but also cross-links the Fc(epsilon)RI to the Fc(gamma)RIIIb molecule, amplifying the inhibitory effect of IgG BA. These studies provide direct evidence in a live animal model that allergen-specific IgG BA can protect against mast cell (IgE)-mediated severe allergic immune responses.
TITLE: IgG-blocking antibodies inhibit IgE-mediated anaphylaxis in vivo through both antigen interception and Fc(gamma)RIIb cross-linking
AUTHOR CONTACT:
Fred D. Finkelman
University of Cincinnati, Cincinnati, Ohio, USA
Phone: (513) 558-4701; Fax: (513) 558-3799; E-mail: ffinkelman@pol.net
View the PDF of this article at: https://www.the-jci.org/article.php?id=25575
NEUROBIOLOGY
Don't forget about me: an antibody fights memory loss in Alzheimer disease
The destruction of special "cholinergic" neurons in a part of the brain called the hippocampus in Alzheimer disease (AD) has led researchers to investigate cholinergic dysfunction as a primary cause of AD. Evidence suggests that deposits of the small protein called amyloid beta (Abeta) contribute to AD-associated memory deficits. In a new study appearing online on February 23 in advance of print publication in the March issue of the Journal of Clinical Investigation, Kelly Bales and colleagues at Eli Lilly in Indianapolis, Indiana, integrate these two mechanisms by showing reduced hippocampal release of a neuron signaling molecule called acetylcholine (ACh) in transgenic mice overexpressing human Abeta (PDAPP mice). Although levels of the ACh precursor choline were elevated in PDAPP mice compared with healthy mice, levels of a key neuronal choline regulator called the high-affinity choline transporter ChT-1 were similar, suggesting that Abeta did not affect ACh biosynthesis. To identify the cause of the choline elevations, the authors performed experiments called "coimmunoprecipitation" studies of hippocampal homogenates and identified a direct interaction between Abeta peptide and ChT-1 in PDAPP animals. Disruption of this interaction using an anti-Abeta antibody not only restored hippocampal ACh release, but also improved a measure of learning called habituation in the PDAPP mice. Taken together, these data demonstrate that disruption of the direct interaction between Abeta and ChT-1 using an anti-Abeta antibody may be an effective approach to improving memory and cholinergic dysfunction in AD through the restoration of ACh release.
TITLE: Cholinergic dysfunction in a mouse model of Alzheimer disease is reversed by an anti-Abeta antibody
AUTHOR CONTACT:
K.R. Bales
Eli Lilly & Company, Indianapolis, Indiana, USA
Phone: (317) 277-3061; Fax: (317) 277-6146; E-mail: KRBales@Lilly.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=27120
Journal
Journal of Clinical Investigation