(Stroke. 2001;32:1932.)
© 2001 American Heart Association, Inc.
Letters to the Editor |
Does Antibody to the 
4 Integrin Inhibit the Function of Lymphocytes and Monocytes?
Department of Neurosurgery, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
To the Editor:
We read with great interest the article by Becker and colleagues1 in the January 2001 issue of Stroke, in which the authors sought to assess the contribution of lymphocytes and monocytes to ischemic brain injury. They found that the administration of TA-2, an antibody against 
4 integrin, reduced infarct size and improved neurological outcome when given 2 hours after a stroke. They also observed a peripheral leukocytosis with lymphocyte/monocyte predominance. Because the 4 integrin is thought to be found predominantly on lymphocytes and monocytes rather than neutrophils, they concluded that blockade of the 4 integrin reduced ischemic brain injury by antagonizing the functions of lymphocytes and monocytes. Although TA-2 binding of monocytes has been reported,2 Becker and colleagues neglected to present direct evidence showing that TA-2 administration ultimately blocked lymphocyte/monocyte infiltration and accumulation in the ischemic brain.
We would like to bring to the authors’ attention our study3,4 on the role of 4 integrin in the cell adhesion process. This study revealed that the alternately spliced connecting segment domain (CS-1) of the extracellular matrix protein fibronectin, which interacts with 4 integrin and inhibits monocyte adhesion, inhibits neutrophil accumulation in ischemic brain and reduces infarct size.3 The reduction of neutrophil accumulation by 4 integrin-binding CS-1 peptide seems inconsistent, because neutrophils are devoid of cell surface 4 integrins. Neutrophils can be detected as early as 30 minutes after and peak at 24 hours after ischemia in rat brain.5 In contrast, monocytes are first detected in ischemic tissue 4 to 6 hours after cerebral ischemia in rats.5 Neutrophil migration into inflammatory tissue has been observed following the infiltration of monocytes,6 and neutrophil migration is thought to be initiated, in part, by a factor released by monocytes.6 Although we did not report direct evidence of the participation of lymphocytes and monocytes in those articles, we hypothesized that antagonizing 4 integrin could result in the reduction of neutrophil accumulation by blocking monocyte function. A companion article2 from Becker’s laboratory also found that the administration of TA-2 reduced neutrophil infiltration into the ischemic brain. Becker et al did not examine lymphocyte/monocyte accumulation in the brain and therefore failed to determine a potential therapeutic mechanism of TA-2 administration in stroke. At a minimum, any alteration of lymphocyte/monocyte accumulation into the ischemic brain after administration of TA-2 should have been determined.
Leukocyte adhesion to endothelium and the extracellular matrix occurs via highly specific receptor-ligand-mediated interactions. Much emphasis has been placed on the interaction between ß2 integrin (Mac-1, LFA-1) and intercellular adhesion molecule (ICAM)-1 in mediating neutrophil recruitment to sites of cerebral infarction and on the potential value of blocking this interaction to control neutrophil emigration.7–9 However, the study by Becker et al focused on lymphocyte/monocyte function, and provides an important contribution to the literature. We congratulate the authors on their careful observations.
References
1.
Becker K, Kindrick D, Relton J, Harlan J, Winn R. Antibody to the 4 integrin decreases infarct size in transient focal cerebral ischemia in rats. Stroke. 2001; 32: 206–211.
2.
Relton JK, Sloan KE, Frew EM, Whalley ET, Adams SP, Lobb RR. Inhibition of 4 integrin protects against transient focal cerebral ischemia in normotensive and hypertensive rats. Stroke. 2001; 32: 199–205.
3. Yanaka K, Camarata PJ, Spellman SR, McCarthy JB, Furcht LT, Low WC, Heros RC. Synthetic fibronectin peptides and ischemic brain injury after transient middle cerebral artery occlusion in rats. J Neurosurg. 1996; 85: 125–130.[Medline] [Order article via Infotrieve]
4. Yanaka K, Camarata PJ, Spellman SR, McCarthy JB, Furcht LT, Low WC, Heros RC. Neuronal protection from cerebral ischemia by synthetic fibronectin peptides to leukocyte adhesion molecules. J Cereb Blood Flow Met. 1996; 16: 1120–1125.[Medline] [Order article via Infotrieve]
5. Garcia JH, Liu KF, Yoshida Y, Lian J, Chen S, del Zoppo GJ. Influx of leukocytes and platelets in an evolving brain infarct (Wistar rat). Am J Pathol. 1994; 144: 188–199.[Abstract]
6. Mileski W, Harlan J, Rice C, Winn R. Streptococcus pneumoniae-stimulated macrophage induce neutrophils to emigrate by a CD18-independent mechanism of adherence. Circ Shock. 1990; 31: 259–267.[Medline] [Order article via Infotrieve]
7. Matsuo Y, Kihara T, Ikeda M, Ninomiya M, Onodera H, Kogure K. Role of neutrophils in radical production during ischemia and reperfusion of the rat brain: effect of neutrophil depletion on extracellular ascorbyl radical formation. J Cereb Blood Flow Metab. 1995; 15: 941–947.[Medline] [Order article via Infotrieve]
8. DeGraba TJ. The role of inflammation after acute stroke: utility of pursuing anti-adhesion molecule therapy. Neurology. 1998; 51: 62–68.
9. Yanaka K, Kujiraoka Y, Okazaki M, Asakawa H, Kato N, Matsumaru Y, Nose T. Current and future therapies for ischemic cerebrovascular disease. Drugs Today. 2001; 36: 807–815.
Response
Department of Neurology
Division of Hematology, Department of Medicine
Department of Surgery, University of Washington School of Medicine, Harborview Medical Center, Seattle, Washington
We recently showed that inhibition of the 4 integrin decreases infarct size in an experimental model of transient focal cerebral ischemia.1 Very late activation antigen-4 (VLA-4 or 4ß1) mediates lymphocyte/monocyte adherence to the endothelium through interaction with VCAM-1,2 an interaction that also results in lymphocyte/monocyte activation.3,4 Because VLA-4 is primarily expressed on lymphocytes/monocytes, we hypothesized the apparent benefit of anti-4 therapy was related to inhibition of lymphocyte/monocyte trafficking into brain or to inhibition of lymphocyte/monocyte activation. This hypothesis, as Yanaka and colleagues point out, was not directly tested.
Based on their own experiments with synthetic fibronectin peptides, Yanaka and colleagues argue that inhibition of lymphocytes/monocytes may indirectly prevent neutrophil accumulation in brain.5 This argument is based on the fact that administration of synthetic fibronectin peptides results in a decrease in infarct size and in myeloperoxidase (MPO) activity in ischemic brain. Because the fibronectin peptides bind to and inhibit ß1 integrins, which are expressed on lymphocytes/monocytes but not ß2 integrins, which are found on neutrophils, the authors hypothesize that the decrease in MPO activity, and hence neutrophil influx, results from an effect of the fibronectin peptides on lymphocytes/monocytes. In the article by Relton et al6 that also appeared in the January 2001 issue of Stroke, the authors reported that animals treated with an antibody to the 4 integrin expressed less MPO activity in infarcted brain than animals treated with an isotype control antibody. Both of these studies suggest a role for lymphocytes/monocytes in modulating the initial inflammatory response after stroke. A similar role for lymphocytes/monocytes in modulating inflammation in other organs has also been shown.7 An alternative explanation for the observed effects of anti-4 therapy is that neutrophils, at least in certain situations, may express VLA-4 and bind to endothelium through VCAM-1.8,9
The comments of Yanaka and colleagues are appreciated. We agree that interpretation of results in experiments using anti-adhesion therapy is complicated, especially without direct visualization of leukocytes in the organ of interest. Quantitative immunocytochemistry on the brains from our experiments is currently being done and will hopefully allow us to determine whether an inhibition of neutrophil or lymphocyte influx was responsible for the observed benefit of anti-4 therapy.
References
1. Becker K, Kindrick D, Relton J, Harlan J, Winn R. Antibody to the alpha 4 integrin decreases infarct size in transient focal cerebral ischemia in rats. Stroke. 2001; 32: 206–211.
2.
Alon R, Kassner PD, Carr MW, Finger EB, Hemler ME, Springer TA. The integrin VLA-4 supports tethering and rolling in flow on VCAM-1. J Cell Biol. 1995; 128: 1243–1253.
3. Silvy A, Altevogt P, Mondiere P, Bella C, Defrance T. A role for the VLA-4 integrin in the activation of human memory B cells. Eur J Immunol. 1997; 27: 2757–2764.[Medline] [Order article via Infotrieve]
4. Rabinowich H, Manciulea M, Herberman RB, Whiteside TL. Beta1 integrin-mediated activation of focal adhesion kinase and its association with Fyn and Zap-70 in human NK cells. J Immunol. 1996; 157: 3860–3868.[Abstract]
5. Yanaka K, Camarata PJ, Spellman SR, McCarthy JB, Furcht LT, Low WC, Heros RC. Synthetic fibronectin peptides and ischemic brain injury after transient middle cerebral artery occlusion in rats. J Neurosurg. 1996; 85: 125–130.
6. Relton JK, Sloan KE, [ Frew EM, Whalley ET, Adams SP, Lobb RR. Inhibition of alpha-4 integrin protects against transient focal cerebral ischemia in normotensive and hypertensive rats. Stroke. 2001; 32: 199–205.
7. Altavilla D, Squadrito F, Ammendolia L, Squadrito G, Campo GM, Canale P, Ioculano M, Musolino C, Alonci A, Sardella A, Urna G, Saitta A, Caputi AP. Monocytes and lymphocytes as active participants in the pathogenesis of experimental shock. Inflamm Res. 1996; 45: 398–404.[Medline] [Order article via Infotrieve]
8. Johnston B, Kubes P. The alpha4-integrin: an alternative pathway for neutrophil recruitment? Immunol Today. 1999; 20: 545–550.[Medline] [Order article via Infotrieve]
9. Gao JX, Issekutz AC. The beta 1 integrin, very late activation antigen-4 on human neutrophils can contribute to neutrophil migration through connective tissue fibroblast barriers. Immunology. 1997; 90: 448–454.[Medline] [Order article via Infotrieve]
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