JCI table of contents July 1, 2005

05/26/05

EDITORS' PICK

Vaccine targets tumors where they live

Vaccine strategies are being designed to battle cancer, but their use for metastatic melanoma is a challenge. Effective vaccines against established tumors require tumor-reactive T cells to traffic to the sites of the tumors and are locally activated there in order to kill cancer cells. A problem is that the T cells lose their tumor-killing power once they reach the environment surrounding the tumor. This happens because T cells decrease stimulatory molecules including one called B7.1.

In a study appearing online on June 2 in advance of the print publication of the July 1 print issue of the Journal of Clinical Investigation, Howard Kaufman and colleagues from Columbia University manipulate the local tumor environment as a method for improving systemic anti-tumor immunity. This concept has been suggested in mouse models but had not established in the clinical setting. The data represent the first clinical trial to directly inject a vaccinia virus expressing the B7.1 costimulatory molecule into humans with melanoma.

The researchers show that this vaccine is safe and feasible to use for local delivery into established melanoma lesions. 2 of the injected lesions showed a partial response and 3 were stable. One patient remained alive without disease recurrence for 59 months after vaccination without any other therapy. This approach may be useful for altering the tumor environment in order to induce anti-tumor immunity and provides a foundation upon which other vaccine strategies can be contemplated for local delivery.

TITLE: Targeting the local tumor microenvironment by vaccinia virus expressing B7.1 for the treatment of melanoma

AUTHOR CONTACT:
Howard Kaufman
Columbia University, New York, NY USA
Phone: 212-342-6042; Fax: 212-342-0234; E-mail: hlk2003@columbia.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=24624

EDITORS' PICK
Protease inhibitors reach beyond HIV

The immunodeficiency that arises in HIV may be due to excessive programmed cell death of immune CD4 T cells. HIV protease inhibitors (PI) can block programmed cell death in virus-infected T cells in vitro, but have also been shown to induce programmed cell death at higher concentrations. The mechanisms for these paradoxical data are unclear, as is whether PI therapy would aid CD4 T cell reconstitution in HIV patients in vivo.

In a study appearing online on June 2 in advance of the print publication of the July 1 print issue of the Journal of Clinical Investigation, Andrew Badley and colleagues from Mayo Clinic examine whether PIs can inhibit programmed cell death in vivo and the mechanisms involved. The authors show that HIV PIs block programmed cell death induced by three relevant, virus-independent mouse models mice with experimental hepatitis, Staphylococcal-induced shock, and experimental stroke.

In each model, HIV PIs block programmed cell death and improve histology, survival, and function. The PIs prevent programmed cell death by maintaining mitochondrial integrity. These data show that PIs block programmed cell death in vivo and that related compounds may be useful for non-HIV disorders also characterized by excessive programmed cell death.

Title: Inhibition of Adenine Nucleotide Translocator Pore Function and Protection Against Apoptosis in vivo by an HIV Protease Inhibitor

AUTHOR CONTACT:
Andrew Badley
Mayo Clinic, Rochester, MN USA
Phone: 507 284 3747; Fax: 507-255-7767; E-mail: badley.andrew@mayo.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=22954

AUTOIMMUNITY

The Type 1 diabetes - T cell link

Autoimmune diabetes is a progressive disease that begins with mild symptoms and becomes more severe with destruction of the pancreatic islets. In a study appearing online on June 2 in advance of the print publication of the July 1 print issue of the Journal of Clinical Investigation, Pere Santamaria and colleagues from the University of Calgary show that, in diabetic mice, this progression is accompanied by an increase in the frequency of immune T cells with a higher affinity for attacking an islet antigen, called Kb/IGRP peptide.

The researchers investigate how the affinity of the Kb/IGRP-specific T cells increases. They show it is due to an increase in the percentage of islet reacting T cells expressing certain rearrangements that affect the antigen-binding site, at the expense of T cells bearing other rearrangements. The latter T cells are silenced in young animals by deletion in the thymus and by peripheral tolerance, but with age they can mature and cause disease. These studies of a spontaneous T-cell avidity maturation response advance our understanding of the progression of autoimmune diabetes.

Title: Developmental control of CD8+ T-cell avidity maturation in autoimmune diabetes

AUTHOR CONTACT:
Pere Santamaria
University of Calgary, Calgary, AB Canada
Phone: 403-220-8735; Fax: 403-270-8520; E-mail: psantama@ucalgary.ca

View the PDF of this article at: https://www.the-jci.org/article.php?id=24219

AUTOIMMUNITY

Nixing arthritis with NIK

In a study appearing online on June 2 in advance of the print publication of the July 1 print issue of the Journal of Clinical Investigation, Deborah Novack and colleagues from Washington University address the role of NF-kappa B, a contributor of autoimmunity and bone destruction, in mouse models of arthritis. The researchers study mice lacking NF kappa B inducing kinase (NIK), a key regulator of NF-kappa B. They find that NIK is required in both the initiator phase of arthritis, and for bone erosion. Thus, NIK represents a novel therapeutic target for inflammatory arthritis.

Title: NF kappa B inducing kinase controls lymphocyte and osteoclast activities in inflammatory arthritis

AUTHOR CONTACT:
Deborah Novack
Washington University School of Medicine, St. Louis, MO USA
Phone: 314-454-8472; Fax: 314-454-5505; E-mail: novack@path.wustl.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=23763

IMMUNOLOGY

Regulating regulatory T cells without thymic help

It was not clear whether the generation of regulatory T cells after oral administration of antigen can occur in the periphery, without de novo production of regulatory T cells (Treg) in the thymus. In a study appearing online on June 2 in advance of the print publication of the July 1 print issue of the Journal of Clinical Investigation, Juan Lafaille and colleagues from New York University mice devoid of Treg and susceptible to asthma to address this issue. Using these mice, the authors show that oral administration of antigen leads to T and B cell tolerance. Thus, Tregs are generated in these mice and this does not require production of T cells in the thymus with other antigen specificities or that express other antigen receptors. These data are of interest in the field of immune tolerance.

Title: Oral tolerance in the absence of naturally-occurring regulatory Tregs

AUTHOR CONTACT:
Juan J. Lafaille
NYU Medical Center, New York, NY USA
Phone: 212-263-1489; E-mail: lafaille@saturn.med.nyu.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=24487

IMMUNOLOGY

Treating HIV with IL-2 produces a new subset of T cells

The use of IL-2 to treat HIV infection is controversial despite the first trial having been completed ten years ago. While it is established that IL-2 therapy increases the CD4+ T cell count a good thing in HIV-infected patients the immunological and clinical significance of this CD4+ T cell increase is unclear. A thorough characterization of these IL-2-induced CD4+ T cells is important to determine whether or not IL-2 will ever become standard practice in treating HIV infection.

In a study appearing online on June 2 in advance of the print publication of the July 1 print issue of the Journal of Clinical Investigation, Irini Sereti and colleagues from the NIAID examine T cells that are induced in vivo by IL-2 administration to HIV infected patients. The scientists describe a new and interesting subset of CD4+ T cells with many features of classical nave CD4+ T cells and some features of regulatory CD4+ T cells (Tregs). These cells are long-lived and express high levels of a factor called foxP3, which is involved in Treg development and function. These T cells retain their nave phenotype and remain distinct from Treg cells. This is the first demonstration of this new subset of T cells with a potentially important role in T cell activation and proliferation.

Title: In Vivo Expansion Of CD4+/CD45RO-/CD25+ T Cells Expressing FoxP3 In IL-2 Treated HIV Infected Patients

AUTHOR CONTACT:
Irini Sereti
National Institute of Allergy and Infectious Disease, Bethesda, MD USA
Phone: 301-496-5533; Fax: 301-402-0070; E-mail: isereti@niaid.nih.gov

View the PDF of this article at: https://www.the-jci.org/article.php?id=24307

ONCOLOGY

TGF beta system sees cancer coming

TGF beta1 is a protein that has both tumor suppression and promotion effects. Although it is clear that the TGF beta type II receptor (TGFbetaRII) is required for TGF beta1-mediated tumor suppression, studies regarding to the role of in TGFbeta1-mediated tumor promotion remain controversial.

In a study appearing online on June 2 in advance of the print publication of the July 1 print issue of the Journal of Clinical Investigation, Xiao-Jing Wang and colleagues from Oregon Health and Science University use a transgenic mouse model system to address the effect of increased TGF beta 1 and decreased TGFbetaRII in skin cells on skin tumorigenesis, The question is important as this combination of perturbations in the TGF-beta system is seen frequently in clinical tumor samples. The results show that this combination enhances the rate of malignant conversion and the incidence of metastasis. Interestingly, TGF-beta's role in promoting metastasis can be uncoupled from its role in promoting the phenotypic changes that foretell cancer. The authors hypothesize that skin cancers exhibiting TGFbeta1 overexpression together with loss of functional TGFbetaRII in tumor epithelia are likely to have a poor prognosis.

Title: Distinct mechanisms of TGFbeta1-mediated epithelial-mesenchymal transition and metastasis during skin carcinogenesis

AUTHOR CONTACT:
Xiao-Jing Wang
Oregon Health & Science University, Portland, OR USA
Phone: (503) 220-8262 x54273; Fax: (503) 402-2817; E-mail: wangxiao@ohsu.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=24399

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
    Published on PsychCentral.com. All rights reserved.

 

 

Nothing in life is to be feared. It is only to be understood.
-- Marie Curie