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Rev Professor Alasdair Coles

Rev Professor Alasdair Coles

Professor of Neuroimmunology

Neuroimmunology

Multiple Sclerosis

Autoimmunity

Vasculitis

Alasdair Coles is accepting applications for PhD students.

Alasdair Coles is available for consultancy.


Departments

Department of Medicine:
Professor of Neuroimmunology

Research Interests

Multiple sclerosis immunotherapy with alemtuzumab

 

My research, since 1994 with Alastair Compston, led to licensing of alemtuzumab as a highly effective treatment for multiple sclerosis in Europe, Canada, Australia, Brazil and Mexico; and also its approval by NICE in 2014. I ran the first investigator-led trial in relapsing-remitting multiple sclerosis and was the UK chief investigator of the commercially-sponsored phase 2 and both phase 3 trials, and first author of the corresponding NEJM (cited 562 times) and two Lancet publications (both sited 149 times). Our work has not only defined the safety and efficacy of this particular drug but has also demonstrated the importance of using immunotherapy early in the course of the multiple sclerosis (Annals of Neurology cited 431 times, J Neurol cited 325 times). We have also shown that alemtuzumab is immunogenic and demonstrated, in a first-in-human study, a novel strategy to reduce immunogenicity of any biological therapy (J Immunol cited 24 times). The principal adverse effect of alemtuzumab is autoimmunity (Lancet cited 431 times). My group has (a) identified serum IL-21 as a predictive biomarker of autoimmunity after alemtuzumab (JCI cited 175 times) and (b) shown that autoimmunity arises when reconstitution of the immune repertoire after alemtuzumab occurs by homeostatic expansion of residual lymphocytes (PNAS cited 13 times). Therefore we are now testing the ability of keratinocyte growth factor to promote thymic lymphopoiesis and so prevent autoimmunity after alemtuzumab, in a MRC-funded clinical trial.  H-index 30. Grant income in last 5 years: £2.2 million.

 

Clinical Neuroimmunology

 

I lead the Addenbrooke’s clinical neuroimmunology service, for people with immunological disorders of the nervous system, which sees 80 patients/month, including joint clinics with renal physicians and psychiatrists. I also do one general neurology clinic / week at Peterborough Hospital, seeing c.400 patients a year. With psychiatry (Belinda Lennox, Peter Jones) and immunology (Angela VIncent) collaborators, my PhD student (Dr Mike Zandi) found serum anti-neuronal (especially anti-NMDAR antibodies) in 5% of acute psychosis patients (Zandi J Neurol 2009). We have demonstrated that these antibodies are pathogenic in 9 cases, with immunotherapy inducing long-lasting remission (Zandi, submitted) and have a preliminary application accepted for a formal trial of immunotherapy in such cases with the MRC

Keywords

monoclonal antibodies ; human studies ; cell culture ; alemtuzumab ; neuroimmunology ; randomised control trials ; campath-1H

Topics

  • multiple sclerosis
  • neuroimmunology
  • ANCA vasculitis

Key Publications

    1. Coles A J, Wing M, Molyneux P, Paolillo A, Davies C, Hale G, Miller D, Waldmann H, Compston A.  Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis.  Annals of Neurology. 1999 Sept; 46 (3): 296-304
    2. Coles A, Wing M, Smith S, Corradu F, Greer S, Taylor C, Weetman A, Hale G, Chatterjee VK, Waldmann H, Compston A.  Pulsed monoclonal antibody treatment and autoimmune thyroid disease. Lancet. 1999 Nov 13; 354: 1691-5
    3. Cox A, Coles AJ [joint first author], Nortje J, Bradley P, Menon D. An investigation of auto-reactivity after head injury. J Neuroimmunol. 2006 May;174(1-2):180-6
    4. Coles AJ, Compston DA, Selmaj KW, Lake SL, Moran S, Margolin DH, Norris K, Tandon PK (CAMMS223 Trial Investigators). Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. New England Journal Medicine. 2008 Oct 23;359(17):1786-801.
    5. Jones JL, Phuah CL, Cox AL, Thompson SA, Ban M, Shawcross J, Walton A, Sawcer SJ, Compston A, Coles AJ. IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). Journal of Clinical Investigation. 2009 Jul;119(7):2052-61.
    6. Somerfield J, Hill-Cawthorne GA, Lin A, Zandi MS, McCarthy C, Jones JL,Willcox M, Shaw D, Thompson SA, Compston AS, Hale G, Waldmann H, Coles AJ. A Novel Strategy To Reduce the Immunogenicity of Biological Therapies. J Immunol. 2010 Jul 1;185(1):763-8.
    7. Zandi MS, Irani SR, Lang B, Waters P, Jones PB, McKenna P, Coles AJ, Vincent A, Lennox BR. Disease-relevant autoantibodies in first episode schizophrenia. J Neurol. 2011 Apr;258(4):686-8.
    8. Cohen JA, Coles AJ [joint first author], Arnold DL, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Fisher E, Brinar VV, Giovannoni G, Stojanovic M, Ertik BI, Lake SL, Margolin DH, Panzara MA, Compston DA; for the CARE-MS I investigators. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012 Nov 24;380(9856):1819-28
    9. Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Miller T, Fisher E, Sandbrink R, Lake SL, Margolin DH, Oyuela P, Panzara MA, Compston DA; for the CARE-MS II investigators. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012 Nov 24;380(9856):1829-39
    10. Jones JL, Thompson SA, Loh P, Davies JL, Tuohy OC, Curry AJ, Azzopardi L, Hill-Cawthorne G, Fahey MT, Compston A, Coles AJ. Human autoimmunity after lymphocyte depletion is caused by homeostatic T-cell proliferation. Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20200-5. doi: 10.1073/pnas.1313654110.

     

Other Publications

  1. Moreau T, Coles A, Wing M, Isaacs J, Hale G, Waldmann H, Compston A. Transient increase in symptoms associated with cytokine release in patients with multiple sclerosis. Brain. 1996;119:225-37
  2. Moreau T, Coles A, Wing M, Thorpe J, Miller D, Moseley I, Issacs J, Hale G, Clayton D, Waldmann H, Compston A. Campath-1H in multiple sclerosis. Multiple Sclerosis. 1996;1:357-65.
  3. Gawne-Cain ML, O'Riordan JI, Coles A, Newell B, Thompson AJ, Miller DH.  MRI lesion volume measurement in multiple sclerosis and its correlation with disability: a comparison of fast fluid attenuated inversion recovery (fFLAIR) and spin echo sequences. J Neurol Neurosurg Psychiatry. 1998 Feb;64(2):197-203.
  4. Tubridy N, Coles AJ, Molyneux P, Compston DA, Barkhof F, Thompson AJ, McDonald WI, Miller DH.  Secondary progressive multiple sclerosis: the relationship between short-term MRI activity and clinical features. Brain. 1998 Feb;121 ( Pt 2):225-31
  5. Coles AJ, Wing MG, Compston DA. Disease activity and the immune set in multiple sclerosis: blood markers for immunotherapy. Multiple Sclerosis. 1998 Jun;4(3):232-8.
  6. O'Riordan JI, Gawne Cain M, Coles A, Wang L, Compston DA, Tofts P, Miller DH T1 hypointense lesion load in secondary progressive multiple sclerosis: a comparison of pre versus post contrast loads and of manual versus semi automated threshold techniques for lesion segmentation. Multiple Sclerosis. 1998 Oct;4(5):408-12.
  7. Paolillo A, Coles A, Molyneux P, Gawne-Cain M, MacManus D, Barker G, Compston A, Miller D. Quantitative MRI in patients with secondary progressive MS treated with monoclonal antibody Campath-1H.  Neurology. 1999 Sep 11; 53(4): 751-7
  8. Coles A J, Wing M, Molyneux P, Paolillo A, Davies C, Hale G, Miller D, Waldmann H, Compston A.  Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis.  Annals of Neurology. 1999 Sept; 46 (3): 296-304
  9. Coles A, Wing M, Smith S, Corradu F, Greer S, Taylor C, Weetman A, Hale G, Chatterjee VK, Waldmann H, Compston A.  Pulsed monoclonal antibody treatment and autoimmune thyroid disease. Lancet. 1999 Nov 13; 354: 1691-5
  10. Coles A, Deans J, Compston.  Multiple sclerosis trial precipitates divorce. J Neurol Neurosurg Psychiatry. 2001; 70: 135
  11. Coles A & Barker R.  A case of stiff-person syndrome responsive to plasma exchange.  J Neurol Neurosurg Psychiatry. 2001 Mar;70(3):407-8
  12. Broadley SA, Sawcer SJ, Chataway SJ, Coraddu F, Coles A, Gray J, Roxburgh R, Clayton D, Compston DA.  No association between multiple sclerosis and the Notch3 gene responsible for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). J Neurol Neurosurg Psychiatry. 2001 Jul;71(1):97-9.
  13. Coles A, Mukherjee M, Compston A. Case reports in The Lancet. Lancet. 2003 Apr 5;361(9364):1230.
  14. Harkness K, Coles A, Pohl U, Xuereb J, Baron J, Lennox G. Rapidly reversible dementia in cerebral amyloid inflammatory vasculopathy. European J Neurology. 2003: 10: 1-4.
  15. Golde S, Coles A, Lindquist JA, Compston A. Decreased iNOS synthesis mediates dexamethasone-induced protection of neurons from inflammatory injury in vitro. European J Neuroscience. 2003 Nov;18(9):2527-37.
  16. Coles A, Deans J, Compston A. Campath-1H treatment of multiple sclerosis: lessons from the bedside for the bench. Clin Neurol Neurosurg.  2004 Jun;106(3):270-4. 
  17. Coles A, Dick D. Unilateral calf hypertrophy J Neurol Neurosurg Psychiatry. 2004 Nov;75(11):1606.
  18. Cox A, Coles A, Antoun N, Malik O, Lucchinnetti C, Compston A. Recurrent myelitis and optic neuritis in a 29-year-old woman. Lancet Neurology. 2005 Aug;4(8):510-6.
  19. Cox A, Thompson S, Jones J, Robertson V, Hale G, Waldmann H, Compston A, Coles A. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis.  European Journal of Immunology. 2005 Nov;35(11):3332-42.
  20. Coles AJ, Thompson S, Cox AL, Curran S, Gurnell EM, Chatterjee VK. Dehydroepiandrosterone (DHEA) replacement in patients with Addison’s disease has a bimodal effect on regulatory (CD4+CD25hi and CD4+FoxP3+) T cells. European Journal of Immunology 2005 Dec;35(12):3694-703
  21. Coles AJ, Cox A, Le Page E, Jones J, Trip S, Deans J, Seaman S, Miller D, Hale G, Waldmann H, Compston DAS. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy in relapsing-remitting and secondary progressive disease. J Neurology 2006 January; 253 (1): 98-108
  22. Cox A, Coles AJ [joint first author], Nortje J, Bradley P, Menon D. An investigation of auto-reactivity after head injury. J Neuroimmunol. 2006 May;174(1-2):180-6
  23. Coles AJ, Compston DA, Selmaj KW, Lake SL, Moran S, Margolin DH, Norris K, Tandon PK (CAMMS223 Trial Investigators). Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. New England Journal Medicine. 2008 Oct 23;359(17):1786-801.
  24. Jones JL, Phuah CL, Cox AL, Thompson SA, Ban M, Shawcross J, Walton A, Sawcer SJ, Compston A, Coles AJ. IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). Journal of Clinical Investigation. 2009 Jul;119(7):2052-61.
  25. Thompson SA, Jones JL, Cox AL, Compston DA, Coles AJ. B-cell reconstitution and BAFF after alemtuzumab (Campath-1H) treatment of multiple sclerosis. J Clin Immunol. 2010 Jan;30(1):99-105.
  26. Marsh EA, Hirst CL, Llewelyn JG, Cossburn MD, Reilly MM, Krishnan A, Doran M, Ryan AM, Coles AJ, Jones JL, Robertson NP. Alemtuzumab in the treatment of IVIG-dependent chronic inflammatory demyelinating polyneuropathy. J Neurol. 2010 Jun;257(6):913-9.
  27. Somerfield J, Hill-Cawthorne GA, Lin A, Zandi MS, McCarthy C, Jones JL,Willcox M, Shaw D, Thompson SA, Compston AS, Hale G, Waldmann H, Coles AJ. A Novel Strategy To Reduce the Immunogenicity of Biological Therapies. J Immunol. 2010 Jul 1;185(1):763-8.
  28. Jones JL, Anderson JM, Phuah CL, Fox EJ, Selmaj K, Margolin D, Lake SL, Palmer J, Thompson SJ, Wilkins A, Webber DJ, Compston DA, Coles AJ. Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity. Brain. 2010 Aug;133(Pt 8):2232-47
  29. Goya RL, Busch R, Mathur R, Coles AJ, Barker RA. Human fetal neural precursor cells can up-regulate MHC class I and class II expression and elicit CD4 and CD8 T cell proliferation. Neurobiol Dis. 2010 Oct 16.  
  30. Schoenmakers E, Agostini M, Mitchell C, Schoenmakers N, Papp L, Rajanayagam O, Padidela R, Ceron-Gutierrez L, Doffinger R, Prevosto C, Luan J, Montano S, Lu J, Castanet M, Clemons N, Groeneveld M, Castets P, Karbaschi M, Aitken S, Dixon A, Williams J, Campi I, Blount M, Burton H, Muntoni F, O'Donovan D, Dean A, Warren A, Brierley C, Baguley D, Guicheney P, Fitzgerald R, Coles A, Gaston H, Todd P, Holmgren A, Khanna KK, Cooke M, Semple R, Halsall D, Wareham N, Schwabe J, Grasso L, Beck-Peccoz P, Ogunko A, Dattani M, Gurnell M, Chatterjee K. Mutations in the  selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans. J Clin Invest. 2010 Dec 1;120(12):4220-35
  31. Zandi MS, Irani SR, Lang B, Waters P, Jones PB, McKenna P, Coles AJ, Vincent A, Lennox BR. Disease-relevant autoantibodies in first episode schizophrenia. J Neurol. 2011 Apr;258(4):686-8.
  32. Shah AJ, Breen DP, Thomas D, Cross J, Coles A, Molyneux P. An evolving case of headaches and strokes. Pract Neurol. 2011 Apr;11(2):113-7
  33. Coles AJ, Fox E, Vladic A, Gazda SK, Brinar V, Selmaj KW, Bass AD, Wynn DR, Margolin DH, Lake SL, Moran S, Palmer J, Smith MS, Compston DA. Alemtuzumab  versus interferon beta-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. Lancet Neurol. 2011 Apr;10(4):338-48.
  34. Oomatia A, Young A, Hall FC, Jayne DR, Coles AJ, Shenker N, Zandi MS, Mulford M Multiple Cranial Neuropathies, A Rare Complication Of Systemic Sclerosis. Clin Exp Rheumatol 29(1):191-191 Jan 2011
  35. Jones JL, Dean AF, Antoun N, Scoffings DJ, Burnet NG, Coles AJ.'Radiologically compatible CLIPPERS' may conceal a number of pathologies. Brain. 2011 Aug;134(Pt 8):e187.
  36. Cossburn M, Pace AA, Jones J, Ali R, Ingram G, Baker K, Hirst C, Zajicek J, Scolding N, Boggild M, Pickersgill T, Ben-Shlomo Y, Coles A, Robertson NP. Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort. Neurology. 2011 Aug 9;77(6):573-9.
  37. Cuker A, Coles AJ, Sullivan H, Fox E, Goldberg M, Oyuela P, Purvis A, Beardsley DS, Margolin DH. A distinctive form of immune thrombocytopenia in a phase 2 study of alemtuzumab for the treatment of relapsing-remitting multiple sclerosis. Blood 2011 Dec 8;118(24):6299-305.
  38. Hill-Cawthorne GA, Button T, Tuohy O, Jones JL, May K, Somerfield J, Green A, Giovannoni G, Compston DA, Fahey MT, Coles AJ. Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):298-304.
  39. Coles AJ, Fox E, Vladic A, Gazda SK, Brinar V, Selmaj KW, Skoromets A, Stolyarov I, Bass A, Sullivan H, Margolin DH, Lake SL, Moran S, Palmer J, Smith MS, Compston DA. Alemtuzumab more effective than interferon β-1a at 5-year follow-up of CAMMS223 Clinical Trial. Neurology. 2012 Apr 3;78(14):1069-78.
  40. Button T, Altmann D, Tozer D, Dalton C, Hunter K, Compston A, Coles A, Miller D. Magnetization transfer imaging in multiple sclerosis treated with alemtuzumab. Mult Scler. 2013 19(2), 241-244
  41. Cohen JA, Coles AJ [joint first author], Arnold DL, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Fisher E, Brinar VV, Giovannoni G, Stojanovic M, Ertik BI, Lake SL, Margolin DH, Panzara MA, Compston DA; for the CARE-MS I investigators. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012 Nov 24;380(9856):1819-28
  42. Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Miller T, Fisher E, Sandbrink R, Lake SL, Margolin DH, Oyuela P, Panzara MA, Compston DA; for the CARE-MS II investigators. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012 Nov 24;380(9856):1829-39
  43. Meyer D., Coles, A., Oyuela, P., Purvis, A., & Margolin, D. H. (2013). Case report of anti-glomerular basement membrane disease following alemtuzumab treatment of relapsing-remitting multiple sclerosis. Multiple Sclerosis and Related Disorders. 2013; 2(1), 60-63.
  44. Abrahamsson SV, Angelini DF, Dubinsky AN, Morel E, Oh U, Jones JL, Carassiti D, Reynolds R, Salvetti M, Calabresi PA, Coles AJ, Battistini L, Martin R, Burt RK, Muraro PA. Non-myeloablative autologous haematopoietic stem cell transplantation expands regulatory cells and depletes IL-17 producing mucosal-associated invariant T cells in multiple sclerosis. Brain. 2013 Sep;136(Pt 9):2888-903
  45. McCarthy CL, Tuohy O, Compston DA, Kumararatne DS, Coles AJ, Jones JL. Immune competence after alemtuzumab treatment of multiple sclerosis. Neurology. 2013 2013 Sep 3;81(10):872-6
  46. Brown J, Coles A, Jones J. First use of alemtuzumab in Balo's concentric sclerosis: a case report. Mult Scler. 2013 Oct;19(12):1673-5
  47. Jones JL, Thompson SA, Loh P, Davies JL, Tuohy OC, Curry AJ, Azzopardi L, Hill-Cawthorne G, Fahey MT, Compston A, Coles AJ. Human autoimmunity after lymphocyte depletion is caused by homeostatic T-cell proliferation. Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20200-5. doi: 10.1073/pnas.1313654110.
  48. Tuohy O, Costelloe L, Hill-Cawthorne G, Bjornson I, Harding K, Robertson N, May K, Button T, Azzopardi L, Kousin-Ezewu O, Jones J, Compston DA, Coles A. Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy. J Neurol Neurosurg Psychiatry. 2014 May 21. pii: jnnp-2014-307721.
  49. Brown JW, Martin PJ, Thorpe JW, Michell AW, Coles AJ, Cox AL, Vincent A, Zandi MS. Long-term remission with rituximab in refractory leucine-rich glioma inactivated 1 antibody encephalitis. J Neuroimmunol. 2014 Jun 15;271(1-2):66-8.
  50. Kousin-Ezewu O, Azzopardi L, Parker RA, Tuohy O, Compston A, Coles A, Jones J. Accelerated lymphocyte recovery after alemtuzumab does not predict multiple sclerosis activity. Neurology. 2014 Jun 17;82(24):2158-64
  51. Azzopardi L, Thompson SA, Harding KE, Cossburn M, Robertson N, Compston A, Coles AJ, Jones JL. Predicting autoimmunity after alemtuzumab treatment of multiple sclerosis.  J Neurol Neurosurg Psychiatry 2014 Jul;85(7):795-8
  52. Zandi MS, Paterson RW, Ellul MA, Jacobson L, Al-Diwani A, Jones JL, Cox AL,Lennox B, Stamelou M, Bhatia KP, Schott JM, Coles AJ, Kullmann DM, Vincent A.Clinical relevance of serum antibodies to extracellular N-methyl-d-aspartate receptor epitopes. J Neurol Neurosurg Psychiatry. 2014 Sep 22. pii:jnnp-2014-308736. doi: 10.1136/jnnp-2014-308736. [Epub ahead of print]
  53. Deakin J, Zandi M, Morris K, Buckley C, Joabcon L, Scoriels L, Cox, A, Coles A, Jones, P, Vincent A, Lennox B.  Immunotherapy for patients with acute psychosis and serum N-Methyl D-Aspartate receptor (NMDAR) antibodies: a description of a treated case series. Schizophrenia Research. 2014 (in press)