Stem Cell & Autoimmune Disease

By/ Arwa Mohammad Shabana

5th year-Mansoura Medical School

8 Recent Studies Discussing

Relationship between Stem Cell

Transplant & Autoimmune Disease

Scintific Documentation Committee

ن هو قانت آناء الليل ساجدا وق { و رحمة ائما يحذر اآلخرة ويرج أم

ا يتذكر أولوا ون والذين ال يعلمون إنم رب ه قل هل يستوي الذين يعلم

}األلباب

9_ سورة الزمر

Stem Cell is the Hope for treatment of various

Autoimmune Disorders:

•SLE – Systemic Lupus Erythromatosis

• M.S – Multiple Sclerosis

•Pemphigus Vulgaris

• Autoimmune Hepatitis

Autoimmune disease as a stem cell disorder

• Pure Red cell Aplasia

After widespread in-vitro and in-vivo preclinical testing, autologous and

allogeneic MSCs have been applied in a range of immune mediated

conditions, including graft versus host disease, Crohn´s disease, multiple

sclerosis, refractory systemic lupus erythematosus and

systemic sclerosis.

Current data suggests that MSCs may not only replace diseased tissues,

but also exert several trophic, regenerative and antiinfl ammatory effects.

While the clinical outcome in case reports and phase I-II trials seems

occasionally striking, these limited results point to the need to perform

controlled multicenter trials. Future advances from stem cell science can

be expected to pinpoint signifi cant MSC subpopulations and/or stem cell

markers for improved regenerative or immunoregulatory properties.

Mesenchymal Stem Cell treatment for autoimmune

diseases: a critical review

I. Multiple Sclerosis

Autologous mesenchymal stem cells for the treatment of

secondary progressive multiple sclerosis: an open-label

phase 2a proof-of-concept study

Background More than half of patients with multiple sclerosis have progressive

disease characterised by accumulating disability. The absence of treatments for

progressive multiple sclerosis represents a major unmet clinical need. On

the basis of evidence that mesenchymal stem cells have a beneficial effect in

acute and chronic animal models of multiple sclerosis

Methods Patients with secondary progressive multiple sclerosis involving the

visual pathways (expanded disability status score 5・5–6・5) were recruited

from the East Anglia and north London regions of the UK. Participants received

intravenous infusion of autologous bone-marrow-derived mesenchymal stem

cells in this open-label study. Ourprimary objective was to assess feasibility and

safetyanterior visual pathway as a model of wider disease.

Masked endpoint analyses was used for electrophysiological and

selected imaging outcomes.

We used piecewise linear mixed models to assess the change in gradients over

time at the point of intervention. This trial is registered with ClinicalTrials.gov,

number NCT00395200.

.

Findings: We isolated, expanded, characterised, and administered MSCs in 10

patients. The meandose was 1・6×10⁶ cells per kg bodyweight (range 1・1–20).

We did not identify any serious adverse events. We noted improvement after

treatment in visual acuity (diff erence in monthly rates of change–0・02

logMAR units, 95% CI –0・03 to –0・01; p=0・003) and visual evoked response

latency (–1・33 ms, –2・44 to –0・21;p=0・020), with an increase in optic nerve

area (diff erence in monthly rates of change 0・13 mm2, 0・04 to 0・22;p=0・

006).

No significant effects on colour vision, visual fields, macular volume, retinal

nerve fibre layer thickness, or optic nerve magnetisation transfer ratio.

Interpretation: Autologous mesenchymal stem cells were safely given to

patients with secondary progressive multiple sclerosis in our study.

The evidence of structural, functional, and physiological improvement after

treatment in somevisual endpoints is suggestive of neuroprotection

II. Systemic Lupus Erythromatosis

• Systemic lupus erythematosus (SLE) is an autoimmune disease, means

the body's immune system mistakenly attacks healthy tissue.

leads to long -term

(chronic) inflammation.

Allogeneic mesenchymal stem cell transplantation in severe and refractory

systemic lupus erythematosus: 4 years experience.

• bone marrow derived MSCs from both SLE patients and

lupus prone MRL/lpr mice are defective structurally and

functionally

• 87 patients with persistently active SLE who were refractory

to standard treatment or had life-threatening visceral

involvement were enrolled.

• Allogeneic bone marrow or umbilical cord derived MSCs

were harvested and infused intravenously (1×10⁶ cells/kg of

body weight)

• . Primary outcomes were rates of survival, disease remission

and relapse, as well as transplantation related adverse

events

• Secondary outcomes included SLE disease activity index

(SLEDAI) and serologic features

During the 4 years follow up,, of Prospictive

study

• the overall rate of survival was 94% (82/87).

• Complete clinical remission rate was 28% at 1 year (23/83),

31% at 2 years (12/39), 42% at 3 years (5/12) and 50% at 4

years (3/6).

• Rates of relapse were 12% (10/83) at 1 year, 18% (7/39) at

2 years, 17% (2/12) at 3 years and 17% (1/6) at 4 years.

• The overall rate of relapse was 23% (20/87).

•Disease activity declined as revealed by significant changes

in SLEDAI score, levels of serum autoantibodies, albuminand

complements.

• A total of 5 patients (6%) died after MSCT from non-

treatment-related events in 4 years follow up,

• no transplantation-related adverse event was observed.

•Allogeneic MSCT resulted in the induction of clinical

remission and improvement in organ dysfunction in drug-

resistant SLE patients.

• No transplantation-related adverse event was observed.

Autoimmune Hepatitis

Autoimmune hepatitis frequently has an abrupt onset of symptoms, and it can

present with acute liver failure.

The abrupt presentation can indicate spontaneous exacerbation of a pre-existent

chronic disease, newly created disease, a superimposed infectious or toxic injury,

or new disease after viral infection, drug therapy, or liver transplantation.

Deficiencies in the classical phenotype may include a low serum immunoglobulin

G level and low or absent titers of the conventional autoantibodies.

The original revised diagnostic scoring system of the International Autoimmune

Hepatitis Group can guide the diagnostic evaluation, but low scores do not

preclude the diagnosis

What does that Mean ??

Digestive Diseases and Sciences

October 2012

Although there are many medical treatments to recover

liver function, liver transplantation is the only definitive way

to improve the situation. However, there are many unsolved

problems relating to liver transplantation such as lack of

donors, operative damages, risk of rejection, and side

effects of immunosuppressants.3 Alternative effective

treatments for fulminant hepatitis without relying on liver

transplantation are expected.

Lopez MM, Valenzuela JE, Alvarez FC, Lopez-Alvarez MR, Cecilia GS, Paricio PP.

Long-term problems related to immunosuppression. Transpl. Immunol. 2006; 17: 31–5.

CrossRef,

PubMed,

CAS,

Web of Science® Times Cited: 27

Abstract

Background and Aim: Fulminant hepatitis is mainly caused by excessive immune

response-mediated liver injury and its definitive therapy is liver transplantation.

Mesenchymal stem cells, one of the adult stem cells, have an immunomodulatory

effect on immune cells and reside in various tissues. The aim of this study was to

investigate a therapeutic effect of adipose tissue-derived mesenchymal stem cells

(ASCs) on fulminant hepatitis induced by concanavalin A (ConA).

Efficacy of adipose tissue-derived mesenchymal stem

cells for fulminant hepatitis in mice induced by

concanavalin A

Methods: The ASCs were isolated from adipose tissues of BALB/c mice and

confirmed by detection of cell surface markers and induction of multi-lineage

differentiation. BALB/c mice were injected with ConA and treated with ASCs,

phosphate buffered saline (PBS) or splenocytes (SPLCs).

Survival rates, levels of serum liver enzymes, titers of serum cytokines,

histopathology and localization of ASCs were investigated.

Result: The survival rate of ASC-injected mice significantly increased compared to

PBS or SPLC-injected mice. This effect was dependent on doses and timing of ASCs

injected. Improvement of liver enzyme levels, histopathological changes and

suppression of inflammatory cytokine production were observed in ASC-injected

mice. Fluorescent stained ASCs were detected in inflammatory liver, but not in normal

liver.

Conclusion: These results suggest that ASC treatment has a high potential to be

an innovative therapy for fulminant hepatitis

Pemphigus Vulgaris

• Vulgaris Pemphigus is a chronic bullous disease of

autoimmune nature.

• is mediated by desmoglein-3 autoantibodies

• It is rare disease, especially in pediatric patients.

• It is manifested clinically by blistering flaccid, easily ruptured,

crusts and erosions in areas of skin and mucous membranes,

especially the oral region.

• The diagnosis is based on clinical and histopathological

lesions.

• The treatment is to suppress the production of auto

antibodies and is mainly based on glucocorticoid therapy

Allogenic Hematopoietic Stem Cell

Transplantation in Pemphigus Vulgaris: A Single-

Center Experience

. We carried out a prospective clinical trial of hematopoietic stem cell transplantation

(HSCT) in thymus, bone marrow (BM) and periphery to reconstitute central and

peripheral arms of self-tolerance.

Materials and Methods:

Eleven (M:F=5:6) patients with mean age 33.5 years and mean duration of disease

22.8 months, having painful pruritic blisters and ulcers resistant to corticosteroids,

were treated with cytokine-stimulated allogeneic HSCT (mean dose: 21.8 × 108

cells/kg BW) from blood group-matched related donors. BM with mean CD34+ count

1.1% was inoculated into thymus, marrow and periphery, followed by two peripheral

blood stem cell (PBSC) infusions.

Results:

Recovery began within 24 hours of HSCT and new lesions stopped after 6 months. No

graft versus host disease (GvHD)/adverse effect was observed in any patient/donor.

Over a mean follow-up of 8.02 years, all patients were well without recurrence/new

lesions.

Conclusion:

Drug-resistant PV can be successfully and safely treated by allogeneic HSCT.

A 26-year-old lady suffering from pemphigus vulgaris with pruritic blisters seen on face

and neck: (a) status before HSCT; (b) 3 years after HSCT

(a) Suprabasal bullous cavity of pemphigus vulgaris with few acantholytic cells

(Hematoxylin and Eosin stain, ×40) before HSCT;

(b) indirect immunofluorescence stain showing linear IgG deposits on basal

layer of bullous cavity (×250)

(a) Completely recovered skin after HSCT, showing unremarkable epidermis,

dermis and underlying connective tissue (Hematoxylin and Eosin stain, ×40);

(b) negative immunofluorescence with anti-human IgG

Can any of Stem cell Transplant be

Complicated by Auoimmune Disease ??

Pure Red Cell Aplasia

Successful Treatment of Pure Red Cell Aplasia with Rituximab in

Patients after ABO-Compatible Allogeneic Hematopoietic Stem Cell

Transplantation Abstract

Pure red cell aplasia (PRCA) following allogeneic hematopoietic stem cell

transplantation (HSCT) has been mostly reported Involving major ABO

incompatibility between donor and recipient. Conventional treatments such as

plasma exchange, erythropoietin, and steroid are often unsatisfactory. Rituximab

has been reported to be highly effective for PRCA following major ABO-

incompatible allogeneic HSCT. A 49-year-old woman with PRCA following ABO-matched

allogeneic HSCT for acute lymphoblastic leukemia, refractory to erythropoietin treatment, received 4

doses of rituximab 375 mg/m2 weekly. After the 3rd dose of rituximab, she exhibited a striking rise in her

reticulocyte count with an increase in her hemoglobin level. To our knowledge, this is the first

case of PRCA following major ABO-compatible allogeneic HSCT resolving

completely after rituximab treatment.

Thank You !