Skip to main content
SpringerLink
Log in

Anti-Adhesion Molecule Monoclonal Antibodies

Therapeutic Potential in Ischaemic Stroke

  • Leading Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Summary

Leucocytes appear to potentiate stroke injury by clogging the microcirculation and infiltrating into the brain where they release free radicals and other substances that are toxic to neurons. Through the use of specific monoclonal antibodies directed against leucocyte adhesion receptors, both the microcirculation obstruction and the leucocyte infiltration can be decreased. Experimental studies have found reduced stroke damage through the use of antibodies that bind to either the CD18 leucocyte adhesion receptor or the corresponding endothelial cell receptor, intercellular adhesion molecule-1 (ICAM-1). These studies have shown the most benefit when anti-adhesion monoclonal antibodies are used in experimental models in which reperfusion follows an initial period of ischaemia. Based on these encouraging experimental results, a clinical trial using an anti—ICAM-1 adhesion agent has just been completed, with final results expected soon.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Engler R, Dahlgren M, Morris D, et al. Role of leukocytes in response to acute myocardial ischemia and reflow in dogs. Am J Physiol 1986; 251: 314–22

    Google Scholar 

  2. Schmid-Schonbein G, Engler R. Granulocytes as active participants in acute myocardial ischemia and infarction. Am J Cardiovasc Path 1986; 1: 15–29

    Google Scholar 

  3. Schmid-Schonbein G. Capillary plugging by granulocytes and the no-reflow phenomenon in the microcirculation. FASEB J 1987; 46: 2397–401

    CAS  Google Scholar 

  4. Mori E, del Zoppo G, Chambers D, et al. Inhibition of polymorphonuclear leukocyte adherence suppresses no-reflow after focal cerebral ischemia in baboon. Stroke 1992; 23: 712–8

    Article  PubMed  CAS  Google Scholar 

  5. Fassbender K, Mössner R, Motsch L, et al. Circulating selectin- and immunoglobulin-type adhesion molecules in acute ischemic stroke. Stroke 1995; 26: 1361–4

    Article  PubMed  CAS  Google Scholar 

  6. Smith C, Rothlein R, Hughes B, et al. Recognition of an endothelial determinant for CD18-dependent human neutrophil adherence and transendothelial migration. J Clin Invest 1988; 82: 1746–56

    Article  PubMed  CAS  Google Scholar 

  7. Argenbright L, Letts L, Rothlein R. Monoclonal antibodies to the leukocyte membrane CD18 glycoprotein complexes and to intercellular adhesion molecule-1 inhibit leukocyte-endothelial adhesion in rabbits. J Leukoc Biol 1991; 49: 253–7

    PubMed  CAS  Google Scholar 

  8. Clark W, Coull B, Corliss L, et al. Role of leukocyte adhesion in clinical stroke. J Stroke Cerebrovasc Dis 1992; 2: 80–4

    Article  Google Scholar 

  9. Clark W, Walsh C, Briley D, et al. Neutrophil adhesion in central nervous system ischemia in rabbits. Brain Behav Immun 1993; 7: 63–9

    Article  PubMed  CAS  Google Scholar 

  10. Barone F, Schmidt D, Hillegass L, et al. Reperfusion increases neutrophils and leukotriene B4 receptor binding in rat focal ischemia. Stroke 1992; 23: 1337–48

    Article  PubMed  CAS  Google Scholar 

  11. Dereski MO, Chopp M, Knight RA, et al. Focal cerebral ischemia in the rat: temporal profile of neutrophil responses. Neurosci Res Commun 1992; 11: 179–85

    Google Scholar 

  12. Hallenbeck J, Dutka A, Tanishima T, et al. Polymorphonuclear leukocyte accumulation in brain regions with low blood flow during the early postischemic period. Stroke 1986; 17: 246–53

    Article  PubMed  CAS  Google Scholar 

  13. Wang P, Kao M, Wand S. Leukocyte infiltration m acute hemispheric stroke. Stroke 1993; 24: 236–40

    Article  PubMed  CAS  Google Scholar 

  14. del Zoppo G, Schmid-Schonbein G, Mori E, et al. Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons. Stroke 1991; 22: 1276–83

    Article  PubMed  Google Scholar 

  15. Ames A, Wright L, Masayoshi K, et al. Cerebral ischemia: the no-reflow phenomenon. Am J Pathol 1968; 52: 437–43

    PubMed  Google Scholar 

  16. Dutka AJ, Kochanek PM, Hallenbeck JM. Influence of granulocytopenia on canine cerebral ischemia induced by air embolism. Stroke 1989; 20: 390–5

    Article  PubMed  CAS  Google Scholar 

  17. Bednar MM, Raymond S, McAuliffe T, et al. The role of neutrophils and platelets in a rabbit model of thromboembolic stroke. Stroke 1991; 20: 44–50

    Article  Google Scholar 

  18. Grøgaard B, Schürer L, Gerdin B. Delayed hypoperfusion after incomplete forebrain ischemia in the rat: the role of polymorphonuclear leukocytes. J Cereb Blood Flow Metab 1989; 9: 500–5

    Article  PubMed  Google Scholar 

  19. Price T, Beaty B, Corpuz S. In vivo inhibition of neutrophil function in the rabbit using monoclonal antibody to CD-18. J Immunol 1987; 139: 4174–7

    PubMed  CAS  Google Scholar 

  20. Hernandez L, Grisham M, Twohig B, et al. Role of neutrophils in ischemia reperfusion induced microvascular injury. Am J Physiol 1987; 253: H699–703

    PubMed  CAS  Google Scholar 

  21. Arfors K, Lundberg C, Lindbom L, et al. A monoclonal antibody to the membrane glycoprotein complex CD-18 inhibits PMN accumulation and plasma leakage in vivo. Blood 1987; 69: 338–40

    PubMed  CAS  Google Scholar 

  22. Simpson P, Todd R, Fantoen J, et al. Reduction of experimental canine myocardial reperfusion injury by a monoclonal antibody that inhibits leukocyte adhesion. J Clin Invest 1988; 81: 624–9

    Article  PubMed  CAS  Google Scholar 

  23. Vedder N, Winn C, Rice C, et al. A monoclonal antibody to the adherence promoting leukocyte glycoprotein, CD-18, reduces organ injury and improves survival from hemorrhagic shock and resuscitation in rabbits. J Clin Invest 1988; 81: 939–44

    Article  PubMed  CAS  Google Scholar 

  24. Clark W, Madden K, Rothlein R, et al. Reduction of CNS ischemic injury using leukocyte adhesion antibody treatment. Stroke 1991; 22: 877–83

    Article  PubMed  CAS  Google Scholar 

  25. Chen H, Chopp M, Zhang RL, et al. Anti-CD11b monoclonal antibody reduces ischemic cell damage after transient focal cerebral ischemia in rat. Ann Neurol 1994; 35: 458–63

    Article  PubMed  Google Scholar 

  26. Chopp M, Zhang RL, Chen H, et al. Postischemic administration of an anti-Mac-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in rats. Stroke 1994; 25: 869–76

    Article  PubMed  CAS  Google Scholar 

  27. Matsuo Y, Onodera H, Shiga Y, et al. Role of cell adhesion molecules in brain injury after transient middle cerebral artery occlusion in the rat. Brain Res 1994; 656: 344–52

    Article  PubMed  CAS  Google Scholar 

  28. Lindsberg PJ, Siren AL, Feuerstein GZ, et al. Antagonism of neutrophil adherence in the deteriorating stroke model in rabbits. J Neurosurg 1995; 82: 269–77

    Article  PubMed  CAS  Google Scholar 

  29. Takeshima R, Kirsch JR, Koehler RC, et al. Monoclonal leukocyte antibody does not decrease the injury of transient focal cerebral ischemia in cats. Stroke 1992; 23: 247–52

    Article  PubMed  CAS  Google Scholar 

  30. Cole DJ, Drummond JC, Ghazal EA, et al. A reversible component of cerebral injury as identified by the histochemical stain 2,3,5-triphenyltetrazolium chloride (TTC). Acta Neuropathol 1990; 80: 152–5

    Article  PubMed  CAS  Google Scholar 

  31. Bowes MP, Rothlein R, Fagan SC, et al. Monoclonal antibodies preventing leukocyte activation reduce experimental neurologic injury and enhance efficacy of thrombolytic therapy. Neurology 1995; 45: 815–9

    Article  PubMed  CAS  Google Scholar 

  32. Smith C, Martin S, Rothlein R. Cooperative interactions of LFA1 and MAC1 with intracellular adhesion molecule in facilitating adherence and transendothelial migration of human neutrophils in vitro. J Clin Invest 1989; 83: 2008–17

    Article  PubMed  CAS  Google Scholar 

  33. Kochanek PM, Hallenbeck JM. Polymorphonuclear leukocytes and monocytes/macrophages in the pathogenesis of cerebral ischemia and stroke. Stroke 1992; 23: 1367–79

    Article  PubMed  CAS  Google Scholar 

  34. Wegner C, Gundel R, Reilly P, et al. Intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of asthma. Science 1990; 247: 456–9

    Article  PubMed  CAS  Google Scholar 

  35. Cosimi A, Conti D, Delmonico F, et al. In vivo effects of monoclonal antibody to ICAM in nonhuman primates with renal allografts. J Immunol 1990; 144: 4604–12

    PubMed  CAS  Google Scholar 

  36. Barton R, Rothlein R, Ksiazek J, et al. The effect of anti-intercellular adhesion molecule-1 on phorbol ester induced rabbit lung inflammation. J Immunol 1989; 142: 1278–82

    Google Scholar 

  37. Clark W, Madden K, Rothlein R, et al. Reduction of central nervous system ischemic injury by monoclonal antibody to intercellular adhesion molecule. J Neurosurg 1991; 75: 623–7

    Article  PubMed  CAS  Google Scholar 

  38. Bowes MP, Zivin JA, Rothlein R. Monoclonal antibody to the ICAM-1 adhesion site reduces neurological damage in a rabbit cerebral embolism stroke model. Exp Neurol 1993; 119: 215–9

    Article  PubMed  CAS  Google Scholar 

  39. Zhang RL, Chopp M, Jiang N, et al. Anti-intercellular adhesion molecule-1 antibody reduces ischemic cell damage after transient but not permanent middle cerebral artery occlusion in the Wistar rat. Stroke 1995; 26: 1438–43

    Article  PubMed  CAS  Google Scholar 

  40. Zhang R, Chopp M, Li Y, et al. Anti-ICAM-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in the rat [abstract]. Neurology 1994; 44: 1747

    Article  PubMed  CAS  Google Scholar 

  41. Clark WM, Lauten JD, Lessov N, et al. The influence of anti-adhesion therapies on leukocyte subset accumulation in central nervous system ischemia in rats. J Molec Neurosci 1995; 6: 43–50

    Article  PubMed  CAS  Google Scholar 

  42. Clark WM, Lauten JD, Lessov N, et al. Time course of ICAM-1 expression and leukocyte subset infiltration in rat forebrain ischemia. Molec Chem Neuropathol 1995; 26: 213–30

    Article  CAS  Google Scholar 

  43. Anderson DC, Springer TA. Leukocyte adhesion deficiency: an inherited defect in the Mac-1, LFA-1, and p150.95 glycoproteins [abstract]. Annu Rev Med 1987; 38: 175

    Article  PubMed  CAS  Google Scholar 

  44. Todd RF, Freyer DR. The CD11/CD18 leukocyte glycoprotein deficiency [abstract]. Hematol Oncol Clin North Am 1988; 2: 13

    PubMed  Google Scholar 

  45. Sharar SR, Winn RK, Murray CE, et al. A CD18 monoclonal antibody increases the incidence and severity of subcutaneous abscess formation after high-dose Staphylococcus aureus injection in rabbits. Surgery 1991; 110: 213–20

    PubMed  CAS  Google Scholar 

  46. Mileski WJ, Sikes P, Atiles L. Inhibition of leukocyte adherence and susceptibility to infection. J Surg Res 1993; 54: 349–54

    Article  PubMed  CAS  Google Scholar 

  47. Gabler W, Tsukuda N. The influence of divalent cations and doxycyclinc on iodoacetamide-inhibitable leukocyte adherence. Res Commun Chem Pathol Pharmacol 1991; 74: 131–40

    PubMed  CAS  Google Scholar 

  48. Gabler W, Creamer H. Suppression of human neutrophil function by tetracyclines. J Periodont Res 1991; 26: 52–8

    Article  PubMed  CAS  Google Scholar 

  49. Clark WM, Calcagno FA, Gabler WL. Reduction of central nervous system reperfusion injury in rabbits using doxycycline treatment. Stroke 1994; 25: 1411–6

    Article  PubMed  CAS  Google Scholar 

  50. Williams TJ, Hellewell PG. Endothelial cell biology: adhesion molecules involved in the microvascular inflammatory response. Am Rev Respir Dis 1992; 146: 45–50

    Google Scholar 

  51. Vasthare US, Heinel LA, Rosenwasser RH, et al. Leukocyte involvement in cerebral ischemia and reperfusion injury. Surg Neurol 1990; 33: 261–5

    Article  PubMed  CAS  Google Scholar 

  52. Aspey BS, Jessimer C, Pereira S, et al. Do leukocytes have a role in the cerebral no-reflow phenomenon? J Neurol Neurosurg Psychiatry 1989; 52: 526–8

    Article  PubMed  CAS  Google Scholar 

  53. Schott RJ, Natale JE, Ressler SW, et al. Neutrophil depletion fails to improve neurologic outcome after cardiac arrest in dogs. Ann Emerg Med 1989; 18: 517–22

    Article  PubMed  CAS  Google Scholar 

  54. Dimagl U, Niwa K, Sixt G, et al. Cortical hypoperfusion after global forebrain ischemia in rats is not caused by microvascular leukocyte plugging. Stroke 1994; 25: 1028–38

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Oregon Stroke Center, Department of Neurology, Oregon Health Sciences University, Portland, Oregon, USA

    Wayne M. Clark

  2. Department of Neurosciences, University of California, San Diego, La Jolla, California, USA

    Justin A. Zivin

Authors
  1. Wayne M. Clark
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Justin A. Zivin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wayne M. Clark.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Clark, W.M., Zivin, J.A. Anti-Adhesion Molecule Monoclonal Antibodies. CNS Drugs 6, 90–99 (1996). https://doi.org/10.2165/00023210-199606020-00002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00023210-199606020-00002

Keywords

Search

Navigation