This document summarizes recent studies on the relationship between stem cell transplants and autoimmune diseases. It discusses how stem cell transplants, particularly mesenchymal stem cell transplants, have shown promise in treating several autoimmune disorders like multiple sclerosis, systemic lupus erythematosus, pemphigus vulgaris, autoimmune hepatitis, and pure red cell aplasia. The document reviews specific studies that have found stem cell transplants can reduce disease activity, induce remission, and improve organ function for these conditions. It also notes that mesenchymal stem cell transplants appear to exert anti-inflammatory and regenerative effects with few adverse side effects reported.

1. 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

2. }َ‫ق‬ َ‫و‬ ‫ًا‬‫د‬ ِ‫اج‬َ‫س‬ ِ‫ل‬ْ‫ي‬َّ‫الل‬ َ‫ء‬‫َا‬‫ن‬‫آ‬ ٌ‫ت‬ِ‫ن‬‫ا‬َ‫ق‬ َ‫و‬ُ‫ه‬ ْ‫ن‬َّ‫م‬َ‫أ‬ُ‫ج‬ ْ‫ر‬َ‫ي‬ َ‫و‬ َ‫ة‬َ‫ر‬ ِ‫اآلخ‬ ُ‫ر‬َ‫ذ‬ْ‫ح‬َ‫ي‬ ‫ا‬ً‫م‬ِ‫ئ‬‫ا‬َ‫ة‬َ‫م‬ْ‫ح‬َ‫ر‬ ‫و‬
ُ‫م‬َ‫ل‬ْ‫ع‬َ‫ي‬ َ‫ين‬ِ‫ذ‬َّ‫ال‬ ‫ي‬ِ‫و‬َ‫ت‬ْ‫س‬َ‫ي‬ ْ‫ل‬َ‫ه‬ ْ‫ل‬ُ‫ق‬ ِ‫ه‬ِ‫ب‬َ‫ر‬َ‫م‬َّ‫ن‬ِ‫إ‬ َ‫ون‬ُ‫م‬َ‫ل‬ْ‫ع‬َ‫ي‬ ‫ال‬ َ‫ين‬ِ‫ذ‬َّ‫ال‬ َ‫و‬ َ‫ون‬‫وا‬ُ‫ل‬ ْ‫و‬ُ‫أ‬ ُ‫ر‬َّ‫ك‬َ‫ذ‬َ‫ت‬َ‫ي‬ ‫ا‬
ِ‫ب‬‫ا‬َ‫ب‬ْ‫ل‬َ‫أل‬‫ا‬{
‫الزمر‬ ‫سورة‬_9

3. 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

4. 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

5. I. Multiple Sclerosis

6. 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.
.

7. 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

8. 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.

9. 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

10. 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).

11. •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.

13. 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

14. 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

15. 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

16. 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

17. Pemphigus Vulgaris

18. • 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

19. 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.

22. 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

23. (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)

24. (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

25. Can any of Stem cell Transplant be
Complicated by Auoimmune Disease ??

26. Pure Red Cell Aplasia

27. 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.

28. Thank You !