Local immune responses in the rat cerebral cortex after middle cerebral artery occlusion

doi:10.1016/0165-5728(94)90010-8

Journal of Neuroimmunology

Volume 55, Issue 2, December 1994, Pages 195-203

https://doi.org/10.1016/0165-5728(94)90010-8 Get rights and content

Abstract

This study describes local immune responses in cerebral ischemia induced by permanent occlusion of the middle cerebral artery (MCAO) in the rat. The temporal and spatial pattern of leukocyte infiltration was characterized immunocytochemically using monoclonal antibodies against CD5, a pan T cell marker, against CD4 and CD8 for subtyping of T lymphocytes, and ED1, a marker for macrophages. CD5⁺ T cells were present in some animals on the pial surface at day 1 and with increasing numbers mainly at the edges of the infarcts all days 3 and 7. By day 14 their number had significantly decreased. Subtyping of T lymphocytes revealed that CD4⁺ helper/inducer T cells were rare, while CD8⁺ lymphocytes were abundant. Moreover, CD8⁺ lymphocytes outnumbered CD5⁺ T cells indicating the presence of CD5⁻/CD8⁺ natural killer (NK) cells. ED1⁺ macrophages primarily infiltrated the core of the infarct starting on day 1. Infiltrating leukocytes expressed leukocyte function associated antigen-1 and MHC class I and II antigens. Early after infarction, increased expression of the intercellular adhesion molecule-1 was found on vessel and leukocytes. In conclusion, this study shows that lymphocytes enter the nervous system not only in autoimmune diseases, but also in response to primarily ‘non-immune’ neuronal damage such as stroke.

References (35)

E.C. Butcher
Leukocyte-endothelial cell recognition: three (or more) steps to specifity and diversity
Cell
(1991)
G.J. Lees
The possible contribution of microglia and macrophages to delayed neuronal death after ischemia
J. Neurol. Sci.
(1993)
V.H. Perry et al.
Macrophages and inflammation in the central nervous system
Trends Neurosci.
(1993)
D. Piani et al.
Murine brain macrophages induce NMDA receptor-mediated neurotoxicity in vitro by secreting glutamate
Neurosci. Lett.
(1991)
M.P. Sethna et al.
Immune modulation within the brain: recruitement of inflammatory cells and increased major histocompatability antigen expression following intracerebral injection of interferon-γ
J. Neuroimmunol.
(1991)
G. Stoll et al.
The role of macrophages in degeneration and immune-mediated demyelination of the peripheral nervous system
Adv. Neuroimmunol.
(1992)
J.B. Bederson et al.
Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination
Stroke
(1986)
W.H. Chambers et al.
Monoclonal antibody to a triggering structure expressed on natural killer cells and adherent lymphokine-activated killer cells
J. Exp. Med.
(1989)
W.H. Chambers et al.
Functional heterogeneity between NKR-P1 bright/lycopersicon esculentum lectin (L.E.) bright and NHR-P1 bright/L.E. dim subpuopulations of rat natural killer cells
J. Immunol.
(1992)
W.M. Clark et al.
Reduction of central nervous system ischemic injury in rabbits using leukocyte adhesion antibody treatment
Stroke
(1991)

I. Dusart et al.

Secondary cell death and the inflammatory reaction after dorsal hemisection of the rat spinal cord

Eur. J. Neurosci.

(1994)

M.L. Dustin et al.

Induction by IL1 and interferon-γ: tissue distribution, biochemistry, and function of a natural adherence molecule (ICAM-1)

J. Immunol.

(1986)

D. Duverger et al.

The quantification of cerebral infarction following focal ischemia in the rat: influence of strain, arterial pressure, blood glucose concentration, and age

J. Cerebr. Blood Flow Metab.

(1988)

J.H. Garcia et al.

Progression from ischemic injury to infarct following middle cerebral artery occlusion in the rat

Am. J. Pathol.

(1993)

J.H. Garcia et al.

Influx of leukocytes and platelets in an evolving brain infarct (Wistar rat)

Am. J. Pathol.

(1994)

D. Guilian et al.

Inhibition of mononuclear phagocytes reduces ischemic injury in the spinal cord

Ann. Neurol.

(1990)

J.M. Hallenbeck et al.

Polymorphonuclear leucocyte accumulation in brain regions with low blood flow during the early postischemic period

Stroke

(1986)

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Research paperLocal immune responses in the rat cerebral cortex after middle cerebral artery occlusion

Abstract

Cell

J. Neurol. Sci.

Trends Neurosci.

Neurosci. Lett.

J. Neuroimmunol.

Adv. Neuroimmunol.

Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination

Stroke

Monoclonal antibody to a triggering structure expressed on natural killer cells and adherent lymphokine-activated killer cells

J. Exp. Med.

Functional heterogeneity between NKR-P1 bright/lycopersicon esculentum lectin (L.E.) bright and NHR-P1 bright/L.E. dim subpuopulations of rat natural killer cells

J. Immunol.

Reduction of central nervous system ischemic injury in rabbits using leukocyte adhesion antibody treatment

Stroke

Secondary cell death and the inflammatory reaction after dorsal hemisection of the rat spinal cord

Eur. J. Neurosci.

Induction by IL1 and interferon-γ: tissue distribution, biochemistry, and function of a natural adherence molecule (ICAM-1)

J. Immunol.

The quantification of cerebral infarction following focal ischemia in the rat: influence of strain, arterial pressure, blood glucose concentration, and age

J. Cerebr. Blood Flow Metab.

Progression from ischemic injury to infarct following middle cerebral artery occlusion in the rat

Am. J. Pathol.

Influx of leukocytes and platelets in an evolving brain infarct (Wistar rat)

Am. J. Pathol.

Inhibition of mononuclear phagocytes reduces ischemic injury in the spinal cord

Ann. Neurol.

Polymorphonuclear leucocyte accumulation in brain regions with low blood flow during the early postischemic period

Stroke

Research paper
Local immune responses in the rat cerebral cortex after middle cerebral artery occlusion