To test the hypothesis that chronic stimulation of T cells with a weak agonistic antigen will generate regulatory T cells and immune tolerance, a study reported in this issue employed the redesign of a minor histocompatibility antigen. Using knowledge of residues at which the antigen contacts the T cell receptor, a weak agonist was produced. Pretreatment with this altered antigen produced transplant tolerance, generation of regulatory T cells, and a loss of many antigen-reactive T cells.
Terry B. Strom
Numerous signaling pathways have been shown to mediate cardioprotection, but the end effectors that mediate protection are only beginning to be elucidated. Numerous cardioprotective drugs are shown to converge on glycogen synthase kinase-3β (GSK-3β) . The phosphorylation and inhibition of GSK-3β lead to inhibition or delayed activation of the mitochondrial permeability transition, a key regulator of apoptosis.
Elizabeth Murphy
The collecting ducts of the kidney are composed of intercalated cells (responsible for acid/base transport), principal cells (mediating salt and water absorption), and inner medullary cells, which mediate all three types of transport. Forkhead box (Fox) genes are a large family of transcription factors that are important in cell-type specification during organogenesis. In this issue, Blomqvist et al. find that mice lacking Foxi1 have no intercalated cells in the kidney . The collecting ducts of the null mice contained primitive cells that expressed both intercalated cell and principal cell proteins, yet the acid/base transport function of the kidney was disrupted and the mice exhibited distal renal tubular acidosis. These findings suggest that Foxi1 plays a critical role in determining cell identity during collecting duct development.
Qais Al-Awqati, George J. Schwartz
Increased plasma fatty acid concentrations may be responsible for many of the metabolic abnormalities associated with abdominal obesity. Excessive visceral fat is associated with insulin resistance and other metabolic risk factors for coronary heart disease. A study reported in this issue of the JCI evaluates the relative contribution of fatty acids released during lipolysis of visceral adipose tissue triglycerides to portal and systemic fatty acid flux in human subjects.
Samuel Klein
Implantation of expandable stents into stenotic arteries after percutaneous coronary intervention to relieve arterial narrowing has become a standard therapeutic tool. The improvement in vascular interventional technology, and especially stent technology, has, arguably, outstripped understanding of the biologic consequences of opening an obstructed artery. In the case of bifurcation stenoses, new evidence suggests that opening a stenotic subsidiary branch may create unfavorable hemodynamics in the stented main branch that can lead to in-stent restenosis.
R. Wayne Alexander
Antibodies specific for the β1-adrenergic receptor are found in patients with chronic heart failure of various etiologies. From work presented in this issue of the JCI, we can now infer that these antibodies actually contribute to the pathogenesis of chronic heart failure. This commentary discusses mechanisms by which these antibodies may engender cardiomyopathy.
Neil J. Freedman, Robert J. Lefkowitz
There currently exist a great number of different mouse lines in which the activity of a particular gene of interest has been inactivated or enhanced. However, it is also possible to insert specific mutations in a gene so that the pharmacological sensitivity of the gene product is altered. An example of such an approach shows how the abolition of the sensitivity of an L-type Ca2+ channel isoform to dihydropyridines allows the investigation of the physiological role of these channels in different tissues .
Emmanuel Bourinet, Matteo E. Mangoni, Joël Nargeot
The amyloid β-peptide (Aβ peptide) is assumed to play a crucial and early role in the pathogenesis of Alzheimer disease. Thus, strategies for a pharmacotherapy aim at reducing Aβ peptide generation, which proteolytically derives from the amyloid precursor protein (APP). The main targets so far have been β- and γ-secretase, the two proteases that cleave APP at the N- and C-terminus of the Aβ peptide and are thus directly responsible for Aβ peptide generation. A different strategy, namely the activation of α-secretase, has barely been investigated for its therapeutic potential. α-Secretase cleaves within the Aβ peptide domain and thus precludes Aβ peptide generation. Now, new results demonstrate that activation of α-secretase indeed reduces Aβ peptide generation and toxicity in vivo.
Stefan F. Lichtenthaler, Christian Haass
Systemic bacterial infection may culminate in a frequently fatal septic shock syndrome. The underlying pathology is the result of an uncontrolled inflammatory response, stimulated by the pathogen and its products. Toll-like receptors (TLRs) are critically involved in sensing bacteria and, in the case of sepsis, stimulate a pathogenic response by the innate immune system. A new study reports a successful attempt to inhibit systemic inflammation in mice by disrupting the formation of complexes between Gram-positive bacteria and their cognate receptor, TLR2.
Thomas Decker
What are the true origins of the smooth muscle cells (SMCs) present in the intimal lesions of transplant arteriosclerosis? A new study in the JCI shows that Sca-1+ cells purified from the mouse aortic root can migrate through an irradiated vein graft to the neointima of the vessel and transdifferentiate to express the early SMC differentiation marker gene SM22. Do Sca-1+ cells transdifferentiate into SMC-like cells, or is activation of SMC marker genes a consequence of fusion of these cells with preexisting SMCs, a possibility raised by results of studies of adult stem cells in animal models of liver regeneration ? Or could this be bona fide transdifferentiation that recapitulates the pathologic processes in humans?
Mark H. Hoofnagle, Brian R. Wamhoff, Gary K. Owens
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