PolyHeader

Causes

Remedial steps

Cutting Edge

Psychology


IVIG

An article on gene expression shows that IVIG had immunomodulatory effect downregulating 2206 genes more than 1.5 fold in patients with DM. However the same genes were not downregulated in patients with IBM. (Raju, Dalakas 2004)[1].

A more general article by one of the same authors is Intraveneous Immunoglobulin in Autoimmune Neuromuscular Diseases. (Dalakas 2004)[2]. It is a literature review, and provides an exhaustive reference list of studies on the uses of IVIG for autoimmune disease.

A long-term follow-up study on IvIg in polymyositis concluded that 70% of the patients tested improved, and that the improvement remained in 50% of the patients after 3 years. (Cherin, Pelletier, Teixeira, et al 2002)[3].

A 20 person study shows IVIG effective in 75% of the cases against refractory PM and DM. (Cherin, Herson et all 1990)[4]

Article showing GB-0998 (poly ethylene glycol-treated igG) was no more effective than placebo. "... comparison of the GB-0998 group with the pla- cebo group did not show any significant difference between the groups" (Miyasako, Hara. 2011) [5]

A recent article questions the effect of IVIG on a variety of markers in PM and DM. These observations question a role for IVIG as an immune-modulating therapy in patients with inflammatory myopathies.(Helmers, Dastmalchi 2007)[6]

WF10 (Immunokine, Macrokine)

WF10 is available through Health Canada as a Special Access Request, subject to the approval of the manufacturer. [7]

WF10 is a chlorite-based drug that modulates macrophages functional states and can be safely administered to humans. WF10 potentially modulates disease-related up-regulation of immune responses both in vitro and in vivo. Thus immune response is influenced in a way that inappropriate inflammatory reactions are downregulated. (Schempp H, Reim M. 2001)[8]

WF10, which contains chlorite as the active principle, causes profound changes in macrophage function and activation of gene expression, and appears to downregulate inappropriate immunological activation. (McGrath MS, Kahn JO. 2002)[9]

WF10 meets its primary endpoint in phase 2 trial for allergic rhinitis with no adverse effects noted. (NUVO Research company press release)[10]

WF10 is known to have various immunological effects by stimulating innate immune functions, while inhibiting adaptive immune functions. (Kuhne L, Konstandin M, et al. 2011)[11]

First ever shown change of gene expression from inflammatory to non-inflammatory. "The sustained modification of gene expression in macrophages and peripheral blood monocytes apparently associated with WF10 treatment may help to restore the appropriate balance of immune function.". (McGrath, M 2010) [12]

WF10 now in phase 3 trials for augmentation of cellular response in late stage HIV. (PRNewswire)[13]

WF10 has a demonstrated ability to alleviate macrophage dysfunction and immune system self-destruction. (Hanna 1999)[14]

The consistent effect of MACROKINE(R) (WF10) in vitro and in earlier in vivo studies suggests that MACROKINE(R) (WF10) blocks (downregulates) the macrophage-associated T cell activation stimulus, and this should lead to a resolution in part to disease of inappropriate immune activation, such as HCV disease. (The Free Library. 2000). This reference also includes a lenghty result of searches done on WF10[15]

 

Stem Cell transplants and auto-immune disease

Stem cell transplants are at the leading edge of medical science for a host of diseases, including auto-immune diseases. Stem cells are cells that grow into a variety of other cells as needed.

A brief glossary of useful words may help understand the following articles.

Autologous Stem Cells. These are Stem cells that are taken from the patient, purified, multiplied, and then reinduced into the patient.

Allogeneic stem cells are those from a person other than the patient.

Hematopoietic Stem Cells are cells derived from the blood, usually from the bone marrow.

Mesenchymal Stem cells are multi-potent stromal cells that can differentiate into a variety of cell types. Often these have ben obtained from umbilical cord tissue.

Immunoablation is the shutting down or destroying of the patient's own immune system, usually by radiation. Following the immunoablation, the stem cells are transplanted, and the immune system is re-started. This is a very intensive and dangerous operation, with risk of mortality.

 

Hematapoetic stem cells

Interesting article indicates that Hematapoetic stem cell transplant works against rheumatic autoimmune diseases, but is very intensive, as generally the patients own immune system is deliberately shut down first. Suggests a 7% mortality from immunoablation conditioning treatment. [16]

Mesenchymal stem cells

2011 Article in the Journal of Translational Medicine shows stem cell treatment by autologous tissue is safe [17], and somewhat effective for auto-immune disease, including polymyositis. The exciting thing about this type of stem cell treatment is that is does NOT require immunoalblative therapy with the resulting side effects.

Full article on MSCs that delves into the way stem cells migrate to the place of tissue destruction to effect the repair. One thing I notice is the mention of the possible importance of the telomeres in establishing the local environment. I noticed it because of research I have been doing on Alpha linoic acid increasing telomere length and functionality. 13 Also interesting, it suggests adipose MSCs may be easier to harvest, and may be more effective at immune-modulation than marrow MSCs, stating "In humans, systemic administration of autologous human AdMSCs is a promising alternative to treat patients with autoimmune diseases including autoimmune ear disease, MS, polymyositis, atopic dermatitis, and RA [99]" 99. J. C. Ra, S. K. Kang, I. S. Shin, H. G. Park et al., ―Stem cell treatment for patients with autoimmune disease by systemic infusion of culture-expanded autologous adipose tissue derived mesenchymal stem cells‖, Transl Med, vol. 9, pp. 181, 2011.

Small study of 10 patients shows allogeneic mesenchymal stem cell transplantation appears safe and effective. This study applies specifically to patients with polymyositis and dermatomyositis. (Wang, Zheng et al, 2011) [18] This study was also published in the Chinese Journal of Rheumatology [19]Note these patients are all on heavy regimens of immune system busters.

Efficacy of hMSC in other auto-immune diseases

hMSC also appears safe and clinically beneficial following heart attack (myocardial infarction) 10. hMSCT appears safe and beneficial in small study of lupus patients>11

hmsc safe but not very effective in small study of rheumatic arthritis 12

Animal studies

Adipose MSC appear safe and effective in reducing imflammation in Crohns in mice . "ASCs decreased a wide panel of inflammatory cytokines and chemokines and increased interleukin-10 levels (P < .001), directly acting on activated macrophages. hASCs also impaired Th1 cell expansion and induced/activated CD4+CD25+FoxP3+ regulatory T cells with suppressive capacity on Th1 effector responses in vitro and in vivo (P < .001)."

other references

Like BMMSCs, AdMSCs have been demonstrated in clinical trials to be safe and suitable for introduction into the human body following culturing [8991]. Local or systemic administration of AdMSCs was reported to have therapeutic efficacy in treating myocardial infarction [92], liver injury [93], hypoxia-ischemia-induced brain damage [94], allergic rhinitis [73], and muscular dystrophy [95]. Furthermore, the immune regulatory ability of AdMSCs has warranted their therapeutic application to treat immune-related diseases including graft versus host defense (GVHD) [96], rheumatic disease [97], and thyroiditis [98]. Systemic infusion of AdMSCs before transplantation of haploidentical hematopoietic stem cells (HSCs) controls lethal GVHD reaction of allogenic HSCs in mice [96]. Human AdMSCs reduced disease severity in experimental autoimmune thyroiditis via downregulation of Th1 cytokines and improved Th1/Th2 balance [98]. In humans, systemic administration of autologous human AdMSCs is a promising alternative to treat patients with autoimmune diseases including autoimmune ear disease, MS, polymyositis, atopic dermatitis, and RA [99]. In each of these therapeutic applications, the ability of stem cells to home to the site of injury was critical to their in vivo effects on the symptoms or underlying pathologies of these diseases.

  1. Raju R, Dalakas M. Gene expression profile in the muscles of patients with inflammatory myopathies: effect of therapy with IVIG and biological validation of clinically relevant genes. Brain August 2005 128(8)1887-1896. Found at http://brain.oxfordjournals.org/content/128/8/1887.short
  2. Dalakas M. Intravenous Immunoglobulin in Autoimmune Neuromuscular Diseases. JAMA. 2004;291(19):2367-2375. Found at http://jama.jamanetwork.com/article.aspx?articleid=198740
  3. Cherin P, Pelletier S, Teixeira A. Results and long-term followup of intravenous immunoglobulin infusions in chronic, refractory polymyositis: an open study with 35 adult patients. Arthritis Rheum.2002 Feb;46(2):467-74. Found at http://www.ncbi.nlm.nih.gov/pubmed/11840450?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum#
  4. Cherin P, Herson S, Wechsler B, et al. Effect of intravenous gammaglobulin therapy in chronic refractory polymyositis and dermatomyositis: an open study with 20 adult patients. American Journal of Medicine Volume 91, issue 2, pp162-168, August 1991
  5. Nobuyuki M, Hara M. Effects of intravenous immunoglobulin therapy in Japanese patients with polymyositis and dermatomyositis resistant to corticosteroids: a randomized double-blind placebo-controlled trial. Mod Rheumatol (2012) 22:382–393, as found at http://rd.springer.com/article/10.1007/s10165-011-0534-4
  6. Helmers S, Dastmalchi M, Alexanderson H et al. Ann Rheum Dis. 2007 October; 66(10): 1276–1283. Found at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1994317/,.
  7. Drugs R D. 2004;5(4):242-4. Found at http://www.ncbi.nlm.nih.gov/pubmed/15230635
  8. Schempp H, Reim M, Elstner EF. Chlorite-Hemoprotein Interaction as Key Role for the Pharmacological Activity of the Chlorite-based Drug WF10. Arzneimittelforschung 2001;51(7):554-62.
  9. McGrath MS, Kahn JO, Herndier BG. Development of WF10, a novel macrophage regulating agent. Curr Opin Investig Drugs 2002 Mar;3(3):365-73
  10. Nuvo Research Press Release November 8, 2010, found at http://www.news-medical.net/news/20101108/NUVO-announces-positive-results-from-WF10-Phase-2-clinical-trial-for-severe-allergic-rhinitis.aspx
  11. Kuhne L, Konstandin M, Samstag Y, et al. WF10 Stimulates NK Cell Cytotoxicity by Increasing LFA-1-Mediated Adhesion to Tumor Cells Journal of Biomedicine and Biotechnology, vol. 2011, Article ID 436587, 6 pages, 2011. doi:10.1155/2011/436587 found at http://www.hindawi.com/journals/biomed/2011/436587/cta/
  12. McGrath, Dr. M Interview via PRNewswire, Found at http://www.prnewswire.com/news-releases/oxo-chemie-presents-exciting-data-of-quantitatively-detectable-changes-of-gene-expression-pattern-in-macrophage-and-pbmcs-of-patients-treated-with-wf10-at-the-4th-international-workshop-on-hiv-cells-of-macrophage-lineage-and-ot-77481377.html
  13. Press release via PRNewswire, found at http://www.prnewswire.com/news-releases/canadian-sites-approved-for-phase-3-clinical-trial-of-wf10-an-innovative-immune-approach-for-advanced-hiv-disease-73923957.html
  14. Hanna L. WF10: A new, Immunomodulating Approach to HIV Treatment. Bulletin of experimental Treatment for AIDS, Summer 1999. Found at http://ww1.aegis.org/pubs/beta/1999/be990709.html
  15. Extract found at http://www.als.net/forum/?g=posts&t=49246
  16. Hugle T, van Laaar J. Stemcell transplantation for rheumatic autoimmune diseases. Arthritis Research and Therapy 2008 10:217 (doi:10.1186/ar2486) as found at http://arthritis-research.com/content/10/5/217
  17. Ra JC, Kang, S, Shin l. Stem cell treatment for patients with autoimmune disease by systemic infusion of culture-expanded autologous adipose tissue derived stem cells. Journal of Translational Medicine 2011, 9:181 found at http://www.biomedsearch.com/attachments/00/22/01/78/22017805/1479-5876-9-181.pdf.
  18. Wang D, Zhang H, Cao M, et al. Efficacy of allogeneic mesenchymal stem cell transplantation in patients with drug-resistant polymyositis and dermatomyositis. Ann Rheum Dis 2011;70:1285-1288 doi:10.1136/ard.2010.141804. Found at http://www.medscape.com/viewarticle/745053
  19. CHINESE JOURNAL OF RHEUMATOLOGY Volume 15, Issue 03, 2011DOI:10.3760/cma.j.issn.1007-7480.2011.03.009. Found at http://eng.med.wanfangdata.com.cn/PaperDetail.aspx?qkid=zhfsbx98&qcode=zhfsbx98201103009
  20. K. S. Cho, H. K. Park, H. Y. Park et al., “IFATS collection: immunomodulatory effects of adipose tissue-derived stem cells in an allergic rhinitis mouse model,” Stem Cells, vol. 27, no. 1, pp. 259–265, 2009. View at Publisher · View at Google Scholar · View at Scopus
  21. C. Ries, V. Egea, M. Karow, H. Kolb, M. Jochum, and P. Neth, “MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: differential regulation by inflammatory cytokines,” Blood, vol. 109, no. 9, pp. 4055–4063, 2007. View at Publisher · View at Google Scholar · View at Scopus
  22. V. Sordi, M. L. Malosio, F. Marchesi et al., “Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets,” Blood, vol. 106, no. 2, pp. 419–427, 2005. View at Publisher · View at Google Scholar · View at Scopus
  23. S. J. Baek, S. K. Kang, and J. C. Ra, “In vitro migration capacity of human adipose-derived mesenchymal stem cells and their expression of a distinct set of chemokine and growth factor receptors,” Experimental and Molecular Medicine, vol. 43, no. 10, pp. 596–603, 2011.
  24. H. K. Salem and C. Thiemermann, “Mesenchymal stromal cells: current understanding and clinical status,” Stem Cells, vol. 28, no. 3, pp. 585–596, 2010. View at Publisher · View at Google Scholar · View at Scopus
  25. J. Tolar, K. Le Blanc, A. Keating, and B. R. Blazar, “Concise review: hitting the right spot with mesenchymal stromal cells,” Stem Cells, vol. 28, no. 8, pp. 1446–1455, 2010. View at Publisher · View at Google Scholar · View at Scopus
  26. E. M. Horwitz, D. J. Prockop, L. A. Fitzpatrick et al., “Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta,” Nature Medicine, vol. 5, no. 3, pp. 309–313, 1999. View at Publisher · View at Google Scholar · View at Scopus
  27. R. Quarto, M. Mastrogiacomo, R. Cancedda et al., “Repair of large bone defects with the use of autologous bone marrow stromal cells,” The New England Journal of Medicine, vol. 344, no. 5, pp. 385–386, 2001. View at Publisher · View at Google Scholar · View at Scopus
  28. R. H. Lee, M. J. Seo, R. L. Reger et al., “Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 46, pp. 17438–17443, 2006. View at Publisher · View at Google Scholar · View at Scopus
  29. H. Kawada, J. Fujita, K. Kinjo et al., “Nonhematopoietic mesenchymal stem cells can be mobilized and differentiate into cardiomyocytes after myocardial infarction,” Blood, vol. 104, no. 12, pp. 3581–3587, 2004. View at Publisher · View at Google Scholar · View at Scopus
  30. S. L. Chen, W. W. Fang, F. Ye et al., “Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction,” American Journal of Cardiology, vol. 94, no. 1, pp. 92–95, 2004. View at Publisher · View at Google Scholar · View at Scopus
  31. R. S. Ripa, M. Haack-Sorensen, Y. Wang et al., “Bone marrow-derived mesenchymal cell mobilization by granulocyte-colony stimulating factor after acute myocardial infarction: results from the Stem Cells in Myocardial Infarction (STEMMI) trial,” Circulation, vol. 116, no. 11, pp. I24–I30, 2007. View at Publisher · View at Google Scholar · View at Scopus
  32. M. Duijvestein, A. C. Vos, H. Roelofs et al., “Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn's disease: results of a phase I study,” Gut, vol. 59, no. 12, pp. 1662–1669, 2010. View at Publisher · View at Google Scholar · View at Scopus
  33. P. Taupin, “OTI-010 Osiris therapeutics/JCR pharmaceuticals,” Current Opinion in Investigational Drugs, vol. 7, no. 5, pp. 473–481, 2006. View at Scopus
  34. E. Zappia, S. Casazza, E. Pedemonte et al., “Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy,” Blood, vol. 106, no. 5, pp. 1755–1761, 2005. View at Publisher · View at Google Scholar · View at Scopus
  35. A. Augello, R. Tasso, S. M. Negrini, R. Cancedda, and G. Pennesi, “Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis,” Arthritis and Rheumatism, vol. 56, no. 4, pp. 1175–1186, 2007. View at Publisher · View at Google Scholar · View at Scopus
  36. S. Ciavarella, M. Dominici, F. Dammacco, and F. Silvestris, “Mesenchymal stem cells: a new promise in anticancer therapy,” Stem Cells and Development, vol. 20, no. 1, pp. 1–10, 2011. View at Publisher · View at Google Scholar · View at Scopus
  37. B. Fang, Y. Song, L. Liao, Y. Zhang, and R. C. Zhao, “Favorable response to human adipose tissue-derived mesenchymal stem cells in steroid-refractory acute graft-versus-host disease,” Transplantation Proceedings, vol. 39, no. 10, pp. 3358–3362, 2007. View at Publisher · View at Google Scholar · View at Scopus
  38. J. C. Ra, I. S. Shin, S. H. Kim et al., “Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem cells in animals and humans,” Stem Cells and Development, vol. 20, no. 8, pp. 1297–1308, 2011. View at Publisher · View at Google Scholar
  39. L. Cai, B. H. Johnstone, T. G. Cook et al., “IFATS collection: human adipose tissue-derived stem cells induce angiogenesis and nerve sprouting following myocardial infarction, in conjunction with potent preservation of cardiac function,” Stem Cells, vol. 27, no. 1, pp. 230–237, 2009. View at Publisher · View at Google Scholar · View at Scopus
  40. A. Banas, T. Teratani, Y. Yamamoto et al., “IFATS collection: in vivo therapeutic potential of human adipose tissue mesenchymal stem cells after transplantation into mice with liver injury,” Stem Cells, vol. 26, no. 10, pp. 2705–2712, 2008. View at Publisher · View at Google Scholar · View at Scopus
  41. X. Wei, Z. Du, L. Zhao, et al., “IFATS collection: the conditioned media of adipose stromal cells protect against hypoxia-ischemia-induced brain damage in neonatal rats,” Stem Cells, vol. 27, no. 2, pp. 478–488, 2009. View at Publisher · View at Google Scholar · View at Scopus
  42. F. Bacou, R. B. el Andalousi, P. A. Daussin et al., “Transplantation of adipose tissue-derived stromal cells increases mass and functional capacity of damaged skeletal muscle,” Cell Transplantation, vol. 13, no. 2, pp. 103–111, 2004. View at Scopus
  43. R. Yañez, M. L. Lamana, J. García-Castro, I. Colmenero, M. Ramírez, and J. A. Bueren, “Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease,” Stem Cells, vol. 24, no. 11, pp. 2582–2591, 2006. View at Publisher · View at Google Scholar · View at Scopus
  44. B. Zhou, J. Yuan, Y. Zhou et al., “Administering human adipose-derived mesenchymal stem cells to prevent and treat experimental arthritis,” Clinical Immunology, vol. 141, no. 3, pp. 328–337, 2011. View at Publisher · View at Google Scholar
  45. E. W. Choi, I. S. Shin, H. W. Lee et al., “Transplantation of CTLA4Ig gene-transduced adipose tissue-derived mesenchymal stem cells reduces inflammatory immune response and improves Th1/Th2 balance in experimental autoimmune thyroiditis,” Journal of Gene Medicine, vol. 13, no. 1, pp. 3–16, 2011. View at Publisher · View at Google Scholar · View at Scopus
  46. J. C. Ra, S. K. Kang, I. S. Shin et al., “Stem cell treatment for patients with autoimmune disease by systemic infusion of culture-expanded autologous adipose tissue derived mesenchymal stem cells,” Journal of Translational Medicine, vol. 9, no. 1, article 181, 2011. View at Publisher · View at Google Scholar