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Stem Cells and Autoimmune Disease

Stem Cells and Autoimmune Disease. Prof Alan Tyndall Dept of Rheumatology University of Basel On behalf of the EBMT and EULAR. What is a stem cell? On division, one daughter cell replenishes a whole compartment, and the other remains fully “stem“. What types of stem cells are there?.

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Stem Cells and Autoimmune Disease

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  1. Stem Cells and Autoimmune Disease Prof Alan TyndallDept of RheumatologyUniversity of Basel On behalf of the EBMT and EULAR

  2. What is a stem cell? On division, one daughter cell replenishes a whole compartment, and the other remains fully “stem“.

  3. What types of stem cells are there? Mouse ? man

  4. Embryonal „pluripotent“ Stem Cells NB : early differentiation into a tissue type e.g.heart muscle cell is not the same as complete functioning organ. Embryonal stem cells often give rise to tumors.

  5. Adult „multipotent“ stem cells NB: Most adult stem cells only replenish one tissue type successfully e.g. blood stem cells supply all the types of blood cells in the body life long.

  6. Examples of adult stem cells

  7. Speculation multipotent

  8. Speculation

  9. Issues: • Scientific • Ethical • Theological • Cultural • Commercial • Public education

  10. Pluripotent Embryonal stem cell Pluripotent stem cells Totipotent stem cells Somatic stem cell Germ stem cell Somatic Cell Primitive germ cell Endoderm Ectoderm Mesoderm Adult Multipotent stem cell Liver Intestine Pancreas Skin Hair Nerves Blood Muscle Bone Cartilage Gametes Courtesy of Dr F. Prosper Cardoso.

  11. Blood stem cell transplantation • Over 30 years experience. • Saving many lives from e.g. leukemia. • Eradicate good and bad cells then replace the blood system. • Originally bone marrow transplant, now peripheral blood derived stem cells.

  12. Hematopoietic and Mesenchymal Stem Cells

  13. How is it done? (Sykes et al , Nature Med 2005)

  14. Haematopoietic stem cell transplantation (HSCT) for severe autoimmune disease Concept • Intensive immunosuppression with haematopoietic stem cell rescue • „Resetting“ of autoimmunity?

  15. Resetting the Immune system

  16. HSCT for autoimmune disease • Animal models (van Bekkum) • Tolerance induction in an autologous arthritis rat model • Coincidental cases for malignant disease • Allogeneic • Autologous

  17. To establish through prospective randomised clinical trials the role of HSCT in treating autoimmune disease To study immune reconstitution

  18. Autoimmune Disease Working Party (ADWP) EBMT/EULAR

  19. Autoimmune diseases: pts 803Disease classification VASCULITIS 28 Behcet’s 6 Wegener’s 7 Takayasu 2 Microscopic polyarteritis nodosa 2 Classical polyarteritis nodosa 1 Churg-Strauss 1 Other 9 OTHER NEUROLOGICAL 15 Myasthenia gravis 2 Other 13 INFLAMMATORY BOWEL 12 Crohn's disease 6 Ulcerative colitis 2 Other 4 OTHER AD 21 MULTIPLE SCLEROSIS 281 CONNECTIVE TISSUE D. 232 SSc 136 SLE 78 PM/DM 8 Sjoegren 1 Other/Unknown 12 ARTHRITIS 147 Rheumatoid arthritis 93 Juvenile chronic arthritis : • - Systemic JIA 32 • - Other JIA 12 - Polyarticular JIA 5 Psoriatic arthritis 2 Other 3 HAEMATOLOGICAL 54 ITP 18 AIHA 10 Evan’s 8 Pure Red Cell 6 Pure White Cell 2 Other 10 Lyon, March 2007

  20. Systemic sclerosis (SSc)

  21. . Clinical outcome in 57 systemic sclerosis patients followed up to 60 months post transplant. Farge et al , Ann Rheum Dis 2004

  22. Patient selection is critical: Early SSc

  23. Patients with severe systemic sclerosis Immunoablation + SCT 1. Mobilisation (CYC 2x2 g/m2, G-CSF 10 mg/kg) 2. Leukapheresis/CD34 selection 3. Conditioning (CYC 200 mg/kg,rabbit ATG 7.5 mg/kg) 4. Reinfusion CD34+ cells Control treatment 12x monthly iv pulse CYC 750 mg/m2 CYC: Cyclophosphamide Study Administration Office: Jaap van Laar (Leiden)Study coordinators: Jaap van Laar (Leiden), Dominique Farge (Paris), Alan Tyndall (Basel)Project manager: Ingeborg de Jonge (Leiden)Statistician: Jaap Sont (Leiden)

  24. ASTIS trial March 2001 – July 2007: 98 patients randomised: 46 SCT + 52 controls in 20 centres no graft failures or unexpected toxicities; 1x probable TRM Leeds (3) Amsterdam (6) Herne-Bochum (3) Leiden (20) Frankfurt (1) Nijmegen (7) Tübingen (2) Paris* (18) Würzburg (1) Freiburg (1) Strassbourg (1) Basel-Bern (5) Bordeaux (1) Vienna (3) Clerm Ferr (1) Grenoble (1) Florence (10) Toulouse (2) Thessaloniki (1) Marseille (1) *includes Martignique, Poitiers

  25. SCOT ( Scleroderma Cyclophophamide Or Transplant) Patients with severe systemic sclerosis Immunoablation + SCT 1. Mobilisation (CYC 2x2 g/m2, G-CSF 10 mg/kg) 2. Leukapheresis/CD34 selection 3. Conditioning (CYC 200 mg/kg,equine ATG 90 mg/kg), Radiation 4. Reinfusion CD34+ cells Control treatment 12x monthly iv pulse CYC 750 mg/m2 CYC: Cyclophosphamide Principle investigator : KeithSullivanStudy coordinators: Dan Furst, Peter McSweeneySponsor: NIH/NIAMS ( Linda Griffith)

  26. Mesenchymal stem cell transplantation for severe autoimmune disease Concept • Homing to inflammed tissue then antiinflammatory effect • Repair of damaged tissue??

  27. Hematopoietic and Mesenchymal Stem Cells

  28. Multilineage differentiation Support for haemopoiesis Self-renewal capacity Immunoregulation MSCs Courtesy of F. Dazzi

  29. Immunomodulation: in-vivo models • Baboon skin graft - yes ( Bartholemew et al , Exp Hematol, 2002) • Mouse MS model (EAE) – yes (Uccelli A et al, Blood 2005;106:1755-61) • Mouse MS model (EAE) – yes (Zhang J et al, Exp Neurol 2005;195:16-26)) • Mouse RA model CIA – worse. TNF effect? (Jorgensen J, Arthritis Rheum 2005, 52:1595-603)- yes ( Pennesi et al , Arthritis Rheum in press ) • Mouse acute GvHD model – yes (Dazzi F et al) • Other e.g. SLE, colitis , CIA etc

  30. Tissue injury : in-vivo models • Rat kidney ischaemia/reperfusion renal failure model – protects pre and 12 hours (Togel F et al, Kidney Int 2005;67(5):1772-1784) • Mouse bleomycin lung fibrosis model • Home to affected lung • Reduce inflammation and fibrosis • Most effective immediately after injury (Ortiz L et al, Proc Natl Acad Sci U S A 2003;100(14):8407-8411) • Carbon tetrachloride hepatic fibrosis mouse • Protect immediately, not one week later • Some transdifferentiation to epthelium (Fang B et al, Transplantation 2004;78(1):83-88)

  31. Immunomodulation: clinical • Acute GvHD stage IV (9-year-old boy, leukaemia) • MSCs (expanded ex vivo from mother) • Arrested gut, skin and liver acute GvHD(Le Blanc K et al, Lancet 2004;363(9419):1439-1441) • 52 GvHD patients stage III/IV from 4 centres- sibs, haploidentical, HLA mismatched 3rd party - median 1 X 106 / Kg body weight - CR 73% , PR 9%, NR 17%, relapse 9%, alive 45%, chronic GvHD 18% (Ball et al personal communication) • Standardisation of definition and expansion of MSCs - EBMT Stem Cell Subcommittee - International Society of Cellular Therapies (ISCT)

  32. Mechanisms of Immunomodulation ? • Soluble factors:TGFb, IL-10, HGF (Di Nicola M et al, Blood 2002;99(10):3838-3843) • Indoleamine 2,3 –deoxygenase (Meisel et al, Blood 2004;103(12):4619-4621) • Classical anergy – IL- 2 reversible (Zappia E et al, Blood 2005;106:1755-61) • Cell cycle arrest – irreversible(Glennie S et al, Blood 2005;105(7):2821-2827) • Apoptosis – activated T cells(Plumas J et al, Leukemia 2005;19:1597-1604) • Nitric oxide reduces Stat5 phosphorylation ( murine) ( Sato et al, Blood 2006) • Interleukin 1 receptor antagonist ( Ortiz et al, PNAS 2007)

  33. Residual proliferation(%)of allogeneic and autologous blood lymphocytes in presence of 5 AD BM-MSC (Bocelli-Tyndall C et al Rheumatology 2006)

  34. MSC and Autoimmune Diseases Genoa, Italy. October 26th/ 27th/28th, 2007EULAR, ISNI, and EBMT Development Committee

  35. The Future – make haste slowly. A perfection of means, and confusion of aims, seems to be our main problem.Albert Einstein Any man who can drive safely while kissing a pretty girl is simply not giving the kiss the attention it deserves.Albert Einstein ( in a lighter mood)

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