Monkeying around to improve organ transplantation
Organ transplantation is accompanied by nonspecific immune suppression therapy to prevent T cell-mediated rejection. These immunosuppressants can cause infection, hypertension, cancer, and other undesirable side effects. Therefore, specific suppression of the T cells that attack the transplanted organ is needed.
It was known that anergic T cells (immune T cells that do not respond to antigen stimulation) generated in an artificial environment outside the living organism have immunosuppressive activity in vitro. Now in a study appearing online on June 9 in advance of the print publication of the July 1 print issue of the Journal of Clinical Investigation, Hisashi Bashuda and colleagues from Juntendo University investigate whether this approach can induce indefinite organ allograft survival in vivo, in six rhesus monkeys.
The authors stimulate recipient T cells from the monkeys with donor cells under conditions associated with the development of T cell anergy. Reinfusion of these cells into the recipient after kidney transplantation leads to very prolonged –880 days– and perhaps even indefinite graft survival in three long-surviving animals without administration of additional immunosuppressive agents. This study shows for the first time that anergic T cells generated ex vivo suppress renal allograft rejection in non-human primates. This may be an approach that could be used in human transplant trials.
Title: Renal allograft rejection is prevented by adoptive transfer of anergic T cells in non-human primates
AUTHOR CONTACT:
Hisashi Bashuda
Juntendo University School of Medicine, Tokyo, Japan
Phone: 81-3-5802-1045; Fax: 81-3-3813-0421; E-mail: bashuda@med.juntendo.ac.jp
View the PDF of this article at: https://www.the-jci.org/article.php?id=23743
PHYSIOLOGY
Ihh can hone the bone
Normal growth and development of the bones rely on coordination among cartilage cell (chondrocyte) mass regulation and cartilage structure establishment. Parathyroid hormone-related protein (PTHrP) and Indian hedgehog (Ihh) are important for the precise regulation of cartilage development, but the mechanisms that guide chondrocytes during bone formation were not well understood.
In a study appearing online on June 9 in advance of the print publication of the July 1 print issue of the Journal of Clinical Investigation, Henry Kronenberg and colleagues from Massachusetts General Hospital examine the control of early chondrocyte differentiation by Ihh and the physiological role of this differentiation step in regulating chondrocyte mass and new bone composition.
The researchers analyze mice carrying multiple genetic modifications, in which expression of PTHrP, PTHrP receptor and Ihh, or combinations of these molecules were modified. Their analysis reveals that Ihh stimulates early chondrocyte differentiation, which in turn regulates the mass of proliferating chondrocytes independently of the action of PTHrP. These data provide a new model of bone growth in which Ihh, independent of any changes in PTHrP controls the conversion of early chondrocytes to more rapidly proliferating cells in the growing bones during fetal development.
Title: Indian hedgehog stimulates early chondrocyte differentiation to regulate growth plate length independently of PTHrP
AUTHOR CONTACT:
Henry M. Kronenberg
Massachusetts General Hospital, Boston MA USA
Phone: 617 726-3966; Fax: 617 726-7543; E-mail: hkronenberg@partners.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=24397
IMMUNOLOGY
Learning lessons in lupus
T cells are hyperactive, aberrant, or both in lupus. Sle3 is a lupus susceptibility locus on murine chromosome 7 that is associated with spontaneous immune T cell hyperactivity and autoreactivity when placed into B6 mice with normal genetic backgrounds. In a study appearing online on June 9 in advance of the print publication of the July 1 print issue of the Journal of Clinical Investigation, Chandra Mohan and colleagues from UT Southwestern Medical school analyze the means by which Sle3 affects the phenotype of the B6.Sle3 congenics in which there is T cell hyperactivity, elevated CD4:CD8 ratios, and anti-nuclear antibodies.
The researchers demonstrate that these B6.Sle3 congenic mice exhibit heightened T cell expansion in vitro upon antigen challenge, mediated by hyperstimulated antigen presenting cells. The congenic-derived dendritic cells (DC) and macrophages are more mature/activated, and induce superior co-stimulation to T cells in vitro compared to controls. Finally, adoptive transfer of B6.Sle3-derived DCs into B6 increases the ratio of CD4:CD8 and serum anti-nuclear antibodies. That Sle3 causes aberrant activation of antigen-presenting cells is a novel observation that, and this trigger might account for the hyperactivity of T cells and break in self-tolerance seen in lupus. This new information has important implications towards our understanding of autoimmune disease, and how to manage it clinically.
Title: Genetic dissection of lupus: T-cell hyperactivity as a consequence of hyperstimulatory antigen presenting cells
AUTHOR CONTACT:
Chandra Mohan
UT Southwestern Medical Center, Dallas, TX USA
Phone: 214 648 9675; Fax: 214 648 7995; E-mail: chandra.mohan@utsouthwestern.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=23049
NEUROBIOLOGY
The brain is at the heart of a chromosomal deletion disorder
Williams Syndrome (WS) is a disease caused by a chromosomal deletion and is characterized by several neural and behavioral abnormalities. There have been indications that the hippocampus in the brain is involved in WS but no human data were available. This was largely because most individuals with WS have severe mental retardation, precluding use of demanding tasks and comparison to matched normal controls.
In a study appearing online on June 9 in advance of the print publication of the July 1 print issue of the Journal of Clinical Investigation, Andreas Meyer-Lindenberg and colleagues from the NIMH addressed this problem by studying a unique group of internationally recruited, high-functioning participants with WS. The scientists show clear metabolic, functional and structural impairment of the hippocampal formation and other subtle structural changes in WS patients using a combination of four neuroimaging techniques. These results clarify a biological mechanism for WS and advance our understanding of the genetic and physiological basis of this disease.
Title: Functional, structural and metabolic abnormalities of the hippocampal formation in Williams syndrome
AUTHOR CONTACT:
Andreas Meyer-Lindenberg
National Institute for Mental Health, Bethesda, MD USA
Phone: 301-517-5760; Fax: 301-496-7437; E-mail: am-l@nih.gov
View the PDF of this article at: https://www.the-jci.org/article.php?id=24892
PHYSIOLOGY
A new role for NO in blood vessel maturation
Angiogenesis, the formation of new blood vessels from existing ones, is involved in many physiological and pathological processes. However, despite a growing list of molecules that regulate vessel growth, basic mechanistic insight into vessel maturation remained unclear. In a study appearing online on June 9 in advance of the print publication of the July 1 print issue of the Journal of Clinical Investigation, Dai Fukumura and colleagues from Harvard Medical School provide evidence that nitric oxide (NO) mediates vessel maturation. The authors show that NO recruits cells to the vessels, facilitates branching, and stabilizes the new vasculature. These data have broad implications for the areas of vascular biology, cancer biology, and regenerative medicine.
TITLE: NO mediates mural cell recruitment and vessel morphogenesis in murine melanomas and tissue-engineered blood vessels
AUTHOR CONTACT:
Dai Fukumura
Massachusetts General Hopital and Harvard Medical School, Boston, MA USA
Phone: 617-724-1354; Fax: 617-724-5841; E-mail: dai@steele.mgh.harvard.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=24015
PHYSIOLOGY
Prompting pregnancy without gonadal LHR
Two gonadotropic hormones called leutinizing hormone (LH) and follicle-stimulating hormone (FSH) control normal fertility. LH can bind to receptors located in the gonads, these receptors (LHR) are also found in other tissues including the brain, uterus, cervix, and more. In a study appearing online on June 9 in advance of the print publication of the July 1 print issue of the Journal of Clinical Investigation, Tomi Pakarainen and colleagues from University of Turku address the long-standing question of the role of non-gonadal LHR in reproductive function. The authors transplant normal ovarian tissue into mice lacking LHR and examine reproductive functioning: fertility, pregnancy, litter size, parturition, and lactation. The authors show that non-gonadal LHR, at least in mice, are not required for pregnancy.
TITLE: Fertility in leutinizing hormone receptor knockout mice after wild-type ovary transplantation demonstrates redundancy of extragonadal leutinizing hormone action
AUTHOR CONTACT:
Tomi Pakarainen
University of Turku, Turku, Finland
Phone: 35-82333-7295; Fax: 35-82250-2610; E-mail: tojupa@utu.fi
View the PDF of this article at: https://www.the-jci.org/article.php?id=24562
Journal
Journal of Clinical Investigation