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Comment on УInterleukin-2Interleukin-2 antibody therapy induces target organ natural killer cells that inhibit central nervous system inflammationФ.

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ANNALS
of Neurology
2.
Henneke M, Combes P, Diekmann S, et al. GJA12 mutations are
a rare cause of Pelizaeus-Merzbacher-like disease. Neurology
2008;70:748–754.
3.
Schlierf B, Werner T, Glaser G, et al. Expression of connexin47 in
oligodendrocytes is regulated by the Sox10 transcription factor.
J Mol Biol 2006;361:11–21.
4.
Stolt CC, Wegner M. SoxE function in vertebrate nervous system
development. Int J Biochem Cell Biol 2010;42:437–440.
5.
Ruf N, Uhlenberg B. Analysis of human alternative first exons and
copy number variation of the GJA12 gene in patients with
Pelizaeus-Merzbacher-like disease. Am J Med Genet B
Neuropsychiatr Genet 2009;150B:226–232.
DOI: 10.1002/ana.22295
Clinical Pharmacology of Insulin Confounds
Stroke Trials
John F. Bebawy, MD,1,2 Vijay K. Ramaiah, MD,1
Laura B. Hemmer, MD,1 and Dhanesh K. Gupta, MD1,2
The recent results of the clinical trial by McCormick and colleagues, combined with the results of the NICE-SUGAR trial,
raise concerns about the benefits of maintaining normoglycemia
in critically ill patients.1,2 Most trials of intensive insulin therapy
(IIT) in stroke and other critically ill patient populations find an
increased incidence of hypoglycemia that not only may stop the
trial from going to conclusion, but also may confound the true
outcome benefits of maintaining normoglycemia.3 We would
suggest that investigators consider that most insulin protocols to
maintain normoglycemia are inherently flawed because they do
not consider the clinical pharmacology of insulin.
The time to peak effect of an intravenous insulin bolus is
approximately 30 minutes.4,5 Therefore, the time at which the
patient is most likely to become hypoglycemic is within 30
minutes after a bolus is administered. In contrast, a step change
in the insulin infusion rate does not reach 90% of its plateau
concentration for 45 minutes. As a result, a step change in the
insulin infusion rate should produce 90% of its effect within
45 minutes. Therefore, IIT trials that measure glucose every 60
minutes are inherently flawed, because they miss the onset of
insulin action and the opportunity to adjust insulin dosing
prior to reaching critical values. Based on this, we recommend
monitoring glucose at a minimum of every 30 minutes during
the initiation of intravenous insulin.
Frequent glucose monitoring should allow future IIT
clinical trials to reach completion without an increased risk of
hypoglycemia. Of course, more accurate point of care testing,
including continuous subcutaneous tissue glucose and venous
serum glucose monitors, would decrease the workload, which is
currently perceived by many as a hindrance to compliance with
IIT. Interim analysis of our ongoing clinical trial (NCT00993057),
designed to determine the feasibility and performance of a protocol to rapidly achieve normoglycemia (5–6.5mmol/l), has
demonstrated that by measuring serum glucose every 30
minutes, we are able to rapidly achieve and maintain normoglycemia in nondiabetic subjects undergoing craniotomy. Similar to
the performance of other target-controlled drug infusions that
have a stable requirement, after 2 to 6 hours of insulin dose
148
adjustments, most patients are on a stable insulin infusion regimen, allowing surveillance to be done at 60-minute intervals.
We urge clinicians and investigators not to abandon
maintenance of normoglycemia because of concern for hypoglycemia, which can be safely avoided when initial insulin dosing
is titrated to glucose every 30 minutes instead of every 60
minutes. Throwing the baby (maintaining normoglycemia) out
with the bathwater (IIT based on 60–120-minute glucose sampling) may harm our future patients by not taking these trials
to completion because they are stopped for an increased incidence of hypoglycemia or because the excessive incidence of
hypoglycemia confounds the true benefit of normoglycemia.
Until the NICE-SUGAR trial can be replicated in patient populations at risk for primary and secondary neurologic injury,
the preclinical and clinical data supporting the potential benefit
from this easy intervention in patients at risk for secondary
neurologic injury from cerebrovascular accident, aneurysmal
subarachnoid hemorrhage, and traumatic brain injury make this
too important of an intervention to dismiss.3
Potential Conflicts of Interest
Nothing to report.
Department of 1Anesthesiology and 2Neurological Surgery,
Northwestern University Feinberg School of Medicine, Chicago,
IL
References
1.
Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional
glucose control in critically ill patients. N Engl J Med 2009;360:
1283–1297.
2.
McCormick M, Hadley D, McLean JR, et al. Randomized, controlled trial of insulin for acute poststroke hyperglycemia. Ann
Neurol 2010;67:570–578.
3.
Kruyt ND, Biessels GJ, Devries JH, Roos YB. Hyperglycemia in
acute ischemic stroke: pathophysiology and clinical management.
Nat Rev Neurol 2010;6:145–155.
4.
Lin S, Chien YW. Pharmacokinetic-pharmacodynamic modelling of
insulin: comparison of indirect pharmacodynamic response with
effect-compartment link models. J Pharm Pharmacol 2002;54:
791–800.
5.
Insel PA, Liljenquist JE, Tobin JD, et al. Insulin control of glucose
metabolism in man: a new kinetic analysis. J Clin Invest 1975;55:
1057–1066.
DOI: 10.1002/ana.22377
Comment on ‘‘Interleukin-2/Interleukin-2
Antibody Therapy Induces Target Organ Natural
Killer Cells That Inhibit Central Nervous System
Inflammation’’
Bibiana Bielekova, MD, and Henry McFarland, MD
Animal studies, especially humanized animal models, can elucidate mechanisms behind the observations defined in humans.
Volume 71, No. 1
The question of regulatory potential of human CD56bright vs
CD56dim natural killer (NK) cells subsets in controlling central
nervous system (CNS) inflammation is indeed very important
and cannot be easily answered in humans with current methodologies. Thus, the recent work of Hao and colleagues1 is welcomed addition in this regard.
By adoptive transfer of CD56bright or CD56dim human
NK cells together with microglia and T cells into recipient
RAG / cc / mice, the authors determined that both NK cell
subsets inhibit CNS inflammation, through cytotoxicity (toward
microglia and encephalitogenic T cells) and cytokine production.
Unfortunately, the article does not specify the source of the transferred microglia and T cells. It is unlikely that the microglia and
encephalitogenic T cells were derived from the same subject who
was the donor of transferred human NK cell subsets, because the
method section specifies only microglia isolation from mouse
brain; human encephalitogenic T cells would not be able to
become activated upon adoptive transfer to RAG / cc / mice,
as these mice do not express human major histocompatibility
complex (MHC). If the microglia and encephalitogenic T cells
were of murine origin, then they lacked MHC-I alleles that
define ‘‘self ’’ for NK cells, making them natural targets for cytotoxicity of CD56dim NK cells. Introducing such a nonphysiological situation may falsely identify CD56dim NK cells as immunoregulatory. In contrast, under a physiological situation in humans,
only CD56bright NK cells can kill autologous cells expressing selfMHC-I,2,3 because they lack killer inhibitory receptors (KIRs),
which would deliver inhibitory signal after engagement of self-
MHC-I. CD56bright NK cells are also main physiological producers of large amounts of cytokines.4
Having said that, we do not refute a possibility that both
NK cell subsets may play an immunoregulatory role; however,
so far there is no evidence that this is the case for CD56dim
NK cells in humans, and if the study by Hao and colleagues1
indeed utilized the nonautologous system, then the required
proof is still lacking.
Neuroimmunology Branch, National Institute of Neurological
Disorders and Stroke National Institutes of Health, Bethesda, MD
References
1.
Hao J, Campagnolo D, Liu R, et al. Interleukin-2/interleukin-2 antibody therapy induces target organ natural killer cells that inhibit
central nervous system inflammation. Ann Neurol 2011;69:
721–734.
2.
Bielekova B, Catalfamo M, Reichert-Scrivner S, et al. Regulatory
CD56bright natural killer cells mediate immunomodulatory effects
of IL-2R-alpha-targeted therapy (daclizumab) in multiple sclerosis.
Proc Natl Acad Sci U S A 2006;103:5941–5946.
3.
Della Chiesa M, Vitale M, Carlomagno S, et al. The natural killer
cell-mediated killing of autologous dendritic cells is confined to a
cell subset expressing CD94/NKG2A, but lacking inhibitory killer
Ig-like receptors. Eur J Immunol 2003;33:1657–1666.
4.
Cooper MA, Fehniger TA, Turner SC, et al. Human natural killer
cells: a unique innate immunoregulatory role for the CD56(bright)
subset. Blood 2001;97:3146–3151.
DOI: 10.1002/ana.22547
ERRATUM
In Annals of Neurology, volume 70, issue 1, pp. 181-182,
the author name should read as: Giampiero Avruscio, not
Avruscio Giampiero. The publisher apologizes for this
oversight.
DOI: 10.1002/ana.23532
January 2012
149
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