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author:("cooley, James")
1.  Analysis of FcR non-binding anti-CD3 mAb in humanized mice identifies novel human gut tropic cells with regulatory function that are found in patients 
Science translational medicine  2012;4(118):118ra12.
The development and optimization of immune therapies in patients has been hampered by the lack of preclinical models in which their effects on human immune cells can be studied. As a result, observations that have been made in preclinical studies have suggested mechanisms of drug action in murine models that may not be confirmed in clinical studies. We have utilized a humanized mouse reconstituted with human hematopoetic stem cells to circumvent these limitations. We have studied the effects of teplizumab in this model, a Fc receptor non-binding humanized monoclonal anti-CD3 antibody that has been used to treat patients with Type 1 diabetes mellitus. A novel mechanism of action was identified where human gut tropic CCR6+ T cells leave the circulation and secondary lymph organs and migrate to the small intestine. They become producers of IL-10 which can be detected in the peripheral circulation. Blockade of migration of T cells to the small intestine by natalizumab abolishes the treatment effects of teplizumab. Direct translation of these findings was possible in patients with Type 1 diabetes treated with teplizumab since we found there is increased expression of IL-10 by CD4+CD25highCCR6+FoxP3 cells when they emerge into the peripheral circulation. These findings demonstrate that humanized mice may be used to identify novel immunologic mechanisms that occur in patients treated with immune modulators.
doi:10.1126/scitranslmed.3003401
PMCID: PMC4131554  PMID: 22277969
2.  New and future immunomodulatory therapy in type 1 diabetes 
Trends in molecular medicine  2012;18(3):173-181.
Type 1 diabetes is a common autoimmune disease that affects millions of people worldwide and has an incidence that is increasing at a striking rate, especially in young children. It results from the targeted self-destruction of the insulin-secreting β cells of the pancreas and requires lifelong insulin treatment. The effects of chronic hyperglycemia – the result of insulin deficiency – include secondary endorgan complications. Over the past two decades our increased understanding of the pathogenesis of this disease has led to the development of new immunomodulatory treatments. None have yet received regulatory approval, but this report highlights recent progress in this area.
doi:10.1016/j.molmed.2012.01.001
PMCID: PMC3586241  PMID: 22342807
type 1 diabetes; immunotherapy; metabolic therapy; biologics
3.  The 1.75 Å resolution structure of fission protein Fis1 from Saccharomyces cerevisiae reveals elusive interactions of the autoinhibitory domain 
A 1.75 Å resolution crystal structure of the Fis1 cytoplasmic domain from Saccharomyces cerevisiae is reported which adopts a tetratricopeptide-repeat fold.
Fis1 mediates mitochondrial and peroxisomal fission. It is tail-anchored to these organelles by a transmembrane domain, exposing a soluble cytoplasmic domain. Previous studies suggested that Fis1 is autoinhibited by its N-terminal region. Here, a 1.75 Å resolution crystal structure of the Fis1 cytoplasmic domain from Saccharomyces cerevisiae is reported which adopts a tetratricopeptide-repeat fold. It is observed that this fold creates a concave surface important for fission, but is sterically occluded by its N-terminal region. Thus, this structure provides a physical basis for autoinhibition and allows a detailed examination of the interactions that stabilize the inhibited state of this molecule.
doi:10.1107/S1744309111029368
PMCID: PMC3212442  PMID: 22102223
tetratricopeptide repeats; protein–protein interactions; tail-anchoring; mitochondria; peroxisomes; membrane dynamics
4.  Immediate hypothermia reduces cardiac troponin I following hypoxic-ischemic encephalopathy in newborn pigs 
Pediatric research  2011;70(4):352-356.
Neonatal hypoxic-ischemic encephalopathy (HIE) is a clinically defined neurological condition following lack of oxygen and often associated with cardiac dysfunction in term infants. Therapeutic hypothermia after birth is neuroprotective in infants with HIE. However, it is not known whether hypothermia (HT) is also cardioprotective. Four newborn pigs were used in the pilot study and a further 18 newborn pigs (randomly assigned to 72h-normothermia (NT) or 24h-HT followed by 48h-NT) were subjected to global HIE insults. Serum cTnI was measured prior to and post the HIE insult. Blood pressure, inotropic support, blood gases and heart rate (HR) were recorded throughout. Cardiac pathology was assessed from histological sections. Cooling reduced serum cTnI levels significantly in HT pigs by 6h (NT, 1.36±0.67; HT 0.34±0.23 ng/ml, p=0.0009). After rewarming, from 24 to 30h post insult, HR and cTnI increased in the HT group; from HR[24h]=117±22 to HR[30h]=218±32 beats/minute (p=0.0002) and from cTnI[24h]=0.23±0.12 to cTnI[30h]=0.65±0.53ng/ml, (p=0.05). There were fewer ischemic lesions on cardiac examination (37%) in the HT group compared to the NT group (70%). Hypothermia (24h) pigs did not have the post-insult cTnI increase seen in NT treated pigs. There was a trend that HT improved cardiac pathology in this 3-day survival model.
doi:10.1203/PDR.0b013e31822941ee
PMCID: PMC3173864  PMID: 21691250

Results 1-4 (4)