Pharmacokinetics and modeling of immune cell trafficking: quantifying differential influences of target tissues versus lymphocytes in SJL and lipopolysaccharide-treated mice

Journal of Neuroinflammation

Steven S Zalcman⁴  Michelle A Erickson²  Nicholas M Ponzio¹  Michael L Niehoff⁵  William A Banks³ 

[1] Department of Pathology and Laboratory Medicine, UMDNJ-New Jersey Medical School, Newark, USA;Department of Pharmacological and Physiological Sciences, Saint Louis University School of Medicine, Saint Louis, USA;VAPSHCS, Rm 810A, 1660 S. Columbian Way, Seattle, WA, 98108, USA;Department of Psychiatry-UMDNJ-New Jersey Medical School, Newark, USA;Division of Geriatric Medicine, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, USA

关键词: Pharmacokinetics;    Neuroimmune;    Neuroinflammation;    Multiple sclerosis;    Lymphocytes;    Immune;    Encephalitis;    Cellular trafficking;    Brain;    Blood–brain barrier;   

Others  :  1160215
DOI  :  10.1186/1742-2094-9-231

 received in 2012-07-03, accepted in 2012-09-17,  发布年份 2012

【 摘 要 】

Background

Immune cell trafficking into the CNS and other tissues plays important roles in health and disease. Rapid quantitative methods are not available that could be used to study many of the dynamic aspects of immune cell-tissue interactions.

Methods

We used pharmacokinetics and modeling to quantify and characterize the trafficking of radioactively labeled lymphocytes into brain and peripheral tissues. We used variance from two-way ANOVAs with 2 × 2 experimental designs to model the relative influences of lymphocytes and target tissues in trafficking.

Results

We found that in male CD-1 mice, about 1 in 5,000 intravenously injected lymphocytes entered each gram of brain. Uptake by brain was 2 to 3 times higher in naïve SJL females, but uptake by spleen and clearance from blood was lower, demonstrating a dichotomy in immune cell distribution. Treatment of CD-1 mice with lipopolysaccharide (LPS) increased immune cell uptake into brain but decreased uptake by spleen and axillary nodes.

Conclusions

Differences in brain uptake and in uptake by spleen between SJL and CD-1 mice were primarily determined by lymphocytes, whereas differences in uptake with LPS were primarily determined by lymphocytes for the brain but by the tissues for the spleen and the axillary lymph node. These results show that immune cells normally enter the CNS and that tissues and immune cells interact in ways that can be quantified by pharmacokinetic models.

【 授权许可】

   
2012 Banks et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Yednock TA, Cannon C, Fritz LC, Sanchezmadrid F, Steinman L, Karin N: Prevention of experimental autoimmune encephalomyelitis by antibodies against α4β1 integrin. Nature 1992, 356:63-66.
• [2]Persidsky Y, Stins M, Way D, Witte MH, Weinand M, Kim KS, Bock P, Gendelman HE, Fiala M: A model for monocyte migration through the blood–brain barrier during HIV-1 encephalitis. J Immunol 1997, 158:3499-3510.
• [3]Pu H, Tian J, Flora G, Lee YW, Nath A, Hennig B, Toborek M: HIV-1 Tat protein upregulates inflammatory mediators and induces monocyte invasion into the brain. Mol Cell Neurosci 2003, 24:224-237.
• [4]Clausen F, Lorant T, Lewen A, Hillered L: T lymphocyte trafficking: a novel target for neuroprotection in traumatic brain injury. J Neurotrauma 2007, 24:1295-1307.
• [5]Emerich DF, Dean RL, Bartus RT: The role of leukocytes following cerebral ischemia: pathogenic variable or bystander reaction to emerging infarct? Exp Neurol 2002, 173:168-181.
• [6]Janigro D: Are you in or out? Leukocyte, ion, and neurotransmitter permeability across the epileptic blood–brain barrier. Epilepsia 2012, 53(Supp 1):26-34.
• [7]Rezai-Zadeh K, Gate D, Town T: CNS infiltration of peripheral immune cells: D-Day for neurodegenerative disease? J Neuroimmune Pharmacol 2009, 4:462-475.
• [8]Yirmiya R, Goshen I: Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun 2011, 25:181-213.
• [9]Rook GA, Lowry CA, Raison CL: Lymphocytes in neuroprotection, cognition and emotion: is intolerance really the answer. Brain Behav Immun 2011, 25:591-601.
• [10]Greenwood J, Heasman SJ, Alvarez JI, Pratt A, Lyck R, Engelhardt B: Review: leucocyte-endothelial cell crosstalk at the blood–brain barrier: a prerequisite for successful immune cell entry to the brain. Neuropathol Appl Neurobiol 2011, 37:24-39.
• [11]Etienne-Manneville S, Manneville JB, Adamson P, Wilbourn B, Greenwood J, Couraud PO: ICAM-1-coupled cytoskeletal rearrangements and transendothelial lymphocyte migration involve intracellular calcium signaling in brain endothelial cell lines. J Immunol 2000, 165:3375-3383.
• [12]Langer-Gould A, Steinman L: Progressive multifocal leukoencephalopathy and multiple sclerosis: lessons from natalizumab. Curr Neurol Neurosci Rep 2006, 6:253-258.
• [13]Wolburg H, Wolburg-Buchholz K, Engelhardt B: Diapedesis of mononuclear cells across cerebral venules during experimental autoimmune encephalomyelitis leaves tight junctions intact. Acta Neuropathol 2005, 109:181-190.
• [14]Engelhardt B: The blood-central nervous system barriers actively control immune cell entry into the central nervous system. Curr Pharm Des 2008, 14:1555-1565.
• [15]Koyanagi Y, Tanaka Y, Kira J, Ito M, Hioki K, Misawa N, Kawano Y, Yamasaki K, Tanaka R, Suzuki Y, Ueyama Y, Terada E, Tanaka T, Miyasaka M, Kobayashi T, Kumazawa Y, Yamamoto N: Primary human immunodeficiency virus type 1 viremia and central nervous system invasion in a novel hu-PBL-immunodeficient mouse strain. J Virol 1997, 71:2417-2424.
• [16]Ching S, Zhang H, Lai W, Quan N: Peripheral injection of lipopolysaccharide prevents brain recruitment of leukocytes induced by central injection of interleukin-1. Neurosci 2006, 137:717-726.
• [17]Glowinski J, Iversen LL: Regional studies of catecholamines in the rat brain. I. The disposition of [3H]norepinephrine, [3H]dopamine and [3H]dopa in various regions of the brain. J Neurochem 1966, 13:655-669.
• [18]Triguero D, Buciak J, Pardridge WM: Capillary depletion method for quantification of blood–brain barrier transport of circulating peptides and plasma proteins. J Neurochem 1990, 54:1882-1888.
• [19]Gutierrez EG, Banks WA, Kastin AJ: Murine tumor necrosis factor alpha is transported from blood to brain in the mouse. J Neuroimmunol 1993, 47:169-176.
• [20]Samii A, Bickel U, Stroth U, Pardridge WM: Blood–brain barrier transport of neuropeptides: analysis with a metabolically stable dermorphin analogue. Am J Physiol 1994, 267:E124-E131.
• [21]Feldman SH, Gografe SI, Kohn DF, Swindle MM: Laboratory Mouse Handbook. Memphis: American Association for Laboratory Animal Science; 2006.
• [22]Kety SS: Cerebral circulation and its measurement by inert diffusible tracers. In Encyclopedia of Neuroscience. I edition. Edited by Adelman G. Boston: Birkhäuser; 1987:206-208.
• [23]Ohno K, Pettigrew KD, Rapoport SI: Local cerebral blood flow in the conscious rat as measured with 14C-antipyrine, 14C-iodoantipyrine and 3H-nicotine. Stroke 1979, 10:62-67.
• [24]Patlak CS, Blasberg RG, Fenstermacher JD: Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab 1983, 3:1-7.
• [25]D’Agostino PM, Kwak C, Vecchiarelli HA, Toth JG, Miller JM, Masheeb Z, McEwen BS, Bulloch K: Viral-induced encephalitis initiates distinct and functional CD103+ CD11b+ brain dendritic cell populations within the olfactory bulb. Proc Natl Acad Sci USA 2012, 109:6175-6180.
• [26]Lochhead JJ, Thorne RG: Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev 2012, 64:614-628.
• [27]Chou S, Dix RD: Implications of the blood–brain barrier and its manipulation. In Implications of the Blood–brain Barrier and Its Manipulation. Volume 2: Clinical Aspects. 2nd edition. Edited by Neuwelt EA. New York: Plenum Publishing Corporation; 1989:449-468.
• [28]Baxter AG: The origin and application of experimental autoimmune encephalomyelitis. Nature Rev Immunol 2007, 7:904-912.
• [29]Desideri G, Ferri C: Endothelial activation: sliding door to atherosclerosis. Curr Pharm Des 2005, 11:2163-2175.
• [30]Hudson LC, Bragg DC, Tompkins MB, Meeker RB: Astrocytes and microglia differentially regulate trafficking of lymphocyte subsets across brain endothelial cells. Brain Res 2005, 1058:148-160.