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“The Development of Hematopoietic and Mesenchymal stem cell Transplantation

as an effective treatment of Multiple Sclerosis”

Faryal Kabir08-arid-942

Ph.D Biochemistry1st Semester

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Autoimmune disease

The body’s immune system mistakenly attacks and damages the myelin sheath protecting nerve cells, leading to demyelination and neuronal loss

Disrupts ability of the nerves to conduct nerve impulses

Progressive inflammatory disorder of CNS(Calabresi, 2004)

Multiple Sclerosis (MS)

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This affects the ability of neurons to communicate with each other

Inflammation can cause demyelination by cytokine overproduction via the upregulation of tumor necrosis factor or interferon

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Cognitive and language problems Fatigue Difficulty in walking Vision problems Depression Emotional changes Impaired balance and movement Bowel/bladder dysfunction Changes in sensation Weakness

(McDonald and Sears, 1970)

Symptoms of MS

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1) Relapsing-remitting MS (RRMS)Most common type of MS

Affected 85% of the MS population

Periods of acute attacks followed by partial or complete recovery

2) Secondary-progressive MS (SPMS)After 10-25 years period of RRMS, many people develop SPMS

This is characterized by reduced remission period and increased neurological deterioration

Types of Multiple Sclerosis

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3) Primary-progressive MS (PPMS)Affects approximately 10% of MS population

This is characterized by neurological decline with no distinct period of relapse and remission

4) Progressive-relapsing MS (PRMS)Less common

Around 5% of people diagnosed have this form of MS

Patients show a progressive functional decline

(Compston and coles, 2002)

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MS first described by Jean-Martin Charcot in 1868 Affects young adults b/w 20-40 years age Over 2 million people affected worldwide

(Compston and Coles, 2008; Ebers 2008; Duquette et al., 1992)

Epidemiology of MS

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Exact etiology of MS remains unclear

Key hypothesis that explain MS are: Immune response against CNS Pathogen trigger Oligodendrocyte degeneration

Other factors may influence MS Vitamin D deficiency Genetic and environmental factor

MHC genes in chromosome six, particularly DR15 and DQ6 alleles

(Ebers, 2008)

Etiology of MS

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The Current hypothesis for the etiology of multiple sclerosis is “fertile field hypothesis”

Multiple risk factors combined with specific viral or bacterial infections activate the patient’s immune system for autoreactivity

Then infection with a fertile field of diverse micro-organisms triggers autoimmunity within a patient

The patient then suffers from acute or chronic CNS inflammation leading to demyelination and axonal loss

(Von Herrath, 2003)

Fertile Field Hypothesis

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The current therapies for MS consist of immune-modulating agents, interferon beta or Glatiramer acetate (GA)

(Arnold et al., 2013)

Oral agents like fingolimod, teriflunomide

(chun and Hartung, 2010)

Non-oral agents such as Natalizumab, mitoxantrone

(Zivadinov et al., 2012; Chanvillard et al., 2012)

Current therapies

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Depression Flu like symptoms Local injection site irritation Chest pain Decreased white cell count and platelets

Side effects of MS medication

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In December 2010 the Multiple Sclerosis Society announced a way to reverse damage to myelin in laboratory models using the stem cells (Cambridge centre for myelin repair).

Stem cell therapy is any treatment that uses or targets stem cells. This is usually to help replace or repair damaged cells or tissues

Stem cell therapy might either involve:

transplanting stem cells

giving drugs that target stem cells already in the body.

Stem Cell Therapy

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Immunomodulation – preventing immune damage to the nervous system

Remyelination – repairing the myelin sheath that has already been damaged

Both these treatments for MS are considered ‘neuroprotective’ therapies because they protect the nerve fibres inside the myelin sheath

How could stem cells help in MS?

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When stem cells are tested as potential treatments for MS, there are three ways they can be injected:

• Intravenous – injected into the vein

• Intrathecal – injected into the space around the spinal cord

• Intraparenchymal – injected directly into the brain

How are stem cells injected?

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There are several different types of stem cell that have shown potential benefit. They have all been extensively studied in animals. Some of these are already in the early stages of clinical trials.

Two Stem cell therapies currently being used to treat MS are:

Hematopoietic Stem Cell Transplantation (HSCT) Mesenchymal Stem Cell Transplantation (MSCT)

What types of stem cells might be used for MS?

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HSCT was proposed as a treatment for multiple sclerosis (MS) in 1995 based on favorable results in animal models

(Burt and Burns, 1995)

HSCs are adult stem cells, found in bone marrow and blood

They are capable of producing all of the cells that make the blood and immune system.

Have the potential to differentiate into the main hematopoietic and lymphopoietic precursors which then differentiate into mature cells.

Hematopoietic stem cell transplantation (HSCT)

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HSCT or autologous stem cell transplantation (ASCT) is a potential approach that destroy the T cells of an MS patients and then reconstituting the patient’s immune system with non- autoreactive T-cells

The basic process of HSCT consists of following steps:

Extraction of patients stem cell Intense Chemotherapy is performed to destroy the patients immune system Insertion of patient’s stem cells to rebuild or “reboot” the immune system Recovery

Mechanism of HSCT

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This process begins by administering drugs such as: granulocyte colony stimulating factor (G-CSF) and cyclophosphamide (CY), to induce WBCs proliferation into the blood

After proliferation the patients HSCs are harvested by utilizing antibodies specific for the stem cell antigen CD34 that is present on hematopoietic progenitor cells (Rowley et al., 1998)

Chemotherapy destroys the patients bone marrow

This is followed by the infusion of the previously harvested HSCs to reconstitute a healthy immune system

(Carreras et al., 2003)

Mechanism of HSCT

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Bone Marrow (Hematopoietic Stem Cell) Transplant Example of a tissue-specific stem cell therapy

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HSCT or autologous stem cell transplantation

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Thus reconstituting the patient’s immune system through HSCT prevents further damage but does not stop neurological deterioration in late-stage MS patients.

Researchers conclude that HSCT is an effective treatment only for those young patients which have:

recent disease onset active inflammatory lesions of short duration rapidly progressive disease unresponsive to conventional therapy

(Rogojan and Frederiksen, 2009)

HSCT is not considered as an effective treatment for late stage MS patients (Shevchenko et al., 2012)

Consequences of HSCT

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Mesenchymal stem cells (MSCs) are bone marrow- or placenta-derived stem cells, although they can also be found in low numbers in almost all adult tissues (Kuznetsov et al., 2001; Da Silva et al., 2006)

MSCs have shown immunomodulatory and immunosuppressive capabilities which decrease the inflammatory environment that degrades myelin.

(Uccelli and Prockop, 2010)

A 2012 study proposed that the implantation of MSCs would affect the proliferation and pathogenesis of CD4+ T lymphocytes

(Zhu et al., 2012)

Mesenchymal Stem cell Transplantation (MSCT)

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In one of the study of mice, MSCs were isolated and cultured from bone marrow.

When mice received that transplant, the cell samples were taken after 40 days of post transplantation revealed following significant findings:

First, the clinical disease scores of the MSCT recipients improved for a week following the transplant and then declined.

Second, this improved neurological function following MSCT was associated with an upregulation of IL-10, TGF-beta, Foxp3 and the CD4+CD25+Foxp3+T cell in immune system tissues. The CD4+CD25+ regulatory lymphocytes suppress pathogenic, self-reactive T cells.

(Zhu et al., 2012).

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Alternatively to bone marrow-derived MSCs, a 2012 animal study proposed the use of placental tissue

as a more accessible more useful less invasive source for MSCs

(Fisher-Shoval et al., 2012)

Bone marrow/Placenta derived MSCs

Improvements in MS Patients Who Replace Bone Marrow With Stem Cells

Researchers in Greece observed that by replacing bone marrow with the body’s own stem cells may help patients with aggressive forms of multiple sclerosis go for years without seeing their disease progress

By purposefully wiping out the immune cells in a patient’s bone marrow with chemotherapy and then repopulating it with healthy stem cells, researchers hope the body’s immune system will stop attacking its own nerves.

The US Food and Drug Administration (FDA) has approved a new clinical

trial of a groundbreaking strategy using stem cells for the treatment of MS (multiple sclerosis). Researchers from the Tisch MS Research Center of New York say that FDA has granted approval to begin early clinical investigation (phase 1 trial) of autologous neural stem cells in the treatment of MS.

Immunomodulatory effects of MSCs on immune cells

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MSCs can induce neuron recovery in multiple sclerosis (Mohammed et al., 2012)

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Several advantages of MSCT as compared to HSCT

Like HSCT, the MSCT readily uses the patient as the donor and eliminates the risk of rejection

Animal studies with human MSCs (xenogeneic) have shown that MSCs can exert their benefits before being phagocytized by immune cells.

MSCs readily multiply in-vitro and maintain their multipotent properties until integrated into various tissues.

(Uccelli and Prockop, 2010)

Advantages of MSCT

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Stem cells offer hope for a new effective treatment for MS. It was observed that low intensity of HSCT can significantly reduce the adverse side effects.Similarly recent clinical trials show that MSCT is feasible and safe treatment method.Aditionally HSCT and MSCT could work synergistically to furthur decrease adverse side effects and increase potential outcomes.

Summary

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Kuznetsov, S. A., M. H. Mankani, S. Gronthos, K. Satomura, P. Bianco and P. G. Robey. 2001. Circulating skeletal stemcells. J. Cell

Biol. 153: 1133–1140. Compston, A. and A. Coles. 2008. Multiple sclerosis. Lancet 372: 1502–

1517 Ebers, G. C. 2008. Environmental factors and multiple sclerosis. Lancet

Neurol. 7: 268–277. Duquette, P., J. Pleines, M. Girard, L. Charest, M. Senecal-Quevillon

and C. Masse. 1992. The increased susceptibility of women to multiple sclerosis. Can. J. Neurol. Sci. 1992, 19: 466–471.

Rogojan, C. and J. L. Frederiksen. 2009. Hematopoietic stem cell transplantation in multiple sclerosis. Acta Neurol Scand. 120: 371- 382.

References

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Compston, A. and A. Coles. 2002. Multiple sclerosis. Lancet. 359: 1221–1231. Compston, A. and A. Coles. 2008. Multiple sclerosis. Lancet. 372: 1502–1517. Von Herrath, M. G., R. S. Fujinami and J. L. Whitton. 2003. Microorganisms and

autoimmunity: making the barren field fertile? Nat. Rev. Microbiol., 1: 151- 157.

Da Silva, M. L., P. C. Chagastelles and N. B. Nardi. 2006. Mesenchymal stem cells reside in virtually all post- natal organs and tissues. J. Cell. Sci. 119:

2204– 2213. McDonald, W. I. and T. A. Sears. 1970. The effects of experimental demyelination

on conduction in the central nervous system. Brain. 93: 583–598. Calabresi, P. A. 2004. “Diagnosis and management of multiple sclerosis,” The

American Family Physician, 70(10): 1935-1944.

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Fisher-Shoval, Y., Y. Barhum, O. Sadan, S. Yust-Katz, T. Ben-Zur, N. Lev, C. Benkler, M. Hod, E. Melamed and D. Offen. 2012. Transplantation of Placenta-Derived Mesenchymal Stem Cells in the EAE Mouse Model of MS. J. Mol. Neurosci., 48: 176-184.

Zhu, J., J. Zhang, Q. Li, Y. Du, B. Qiao and X. Hu. 2012. Transplanting of mesenchymal stem cells may affect proliferation and function of CD4(+)T cells in experimental autoimmune encephalomyelitis. Exp. Clin. Transplant. 10: 492-500.

Uccelli, A. and D. J. Prockop. 2010. Why should mesenchymal stem cells (MSCs) cure autoimmune diseases? Curr. Opin. Immunol., 22: 768-774.

Burt, R. K. and W. Burns. 1995.A Bone marrow transplantation for multiple sclerosis. Bone Marrow Transplant. 161- 6.

Chun, J., H. P. Hartung. 2010. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin. Neuropharmacol. 33: 91-101.

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Rowley, S. D., M. Loken, J. Radich, L. A. Kunkle, B. J. Mills, T. Gooley, L. Holmberg, P. McSweeney, K. Beach, B. MacLeod, F. Appelbaum and W. I. Bensinger. 1998. Isolation of CD34+ cells from blood stem cell components using the Baxter Isolex system. Bone Marrow Transplant. 21: 1253-1262.

Zivadinov, R., M. G. Dwyer, S. Hussein, E. Carl, C. Kennedy, M. Andrews, D. Hojnacki, M. Heininen-Brown, L. Willis, M. Cherneva, N. Bergsland and B. Weinstock-Guttman. 2012. Voxel-wise magnetization transfer imaging study of effects of natalizumab and IFNbeta-1a in multiple sclerosis. Mult. Scler., 18:1125-1134.

Chanvillard, C., J. M. Millward, M. Lozano, I. Hamann, F. Paul, F. Zipp, J. Dorr and C. I. Duarte. 2012. Mitoxantrone induces natural killer cell maturation in patients with secondary progressive multiple sclerosis. PLoS. One. 7:

325-96.

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Shevchenko, J. L., A. N. Kuznetsov, T. I. Lonova, V. Y. Melnichenko, D. A. Fedorenko, A. V. Kartashov, K. A. Kurbatova, G. I. Gorodokin and A. A. Novik. 2012. Stem Cell Transplantation with Reduced Intensity Conditioning in Multiple Sclerosis. Exp. Hematol., 40: 892-8.

Carreras, E., A. Saiz, P. Marin, C. Martinez, M. Rovira, N. Villamor, M. Aymerich, M. Lozano, F. Fernandez-Aviles, A. Urbano-Izpizua, E. Montserrat and F. Graus. 2003. CD34+ selected autologous peripheral blood stem cell

transplantation for multiple sclerosis: report of toxicity and treatment results at one year of follow-up in 15 patients. Haematologica. 88: 306-314.

Arnold, D. L., S. Narayanan and S. Antel. 2013. Neuroprotection with glatiramer acetate: evidence from the PreCISe trial. J. Neurol.

Brenda Goodman, Health news reviewed by Laura J. Martin march 21.2011