STEMCELL THERAPY FOR AUTOIMMUNE DISEASES

D. Chris Peniel RA1811036010013

Introduction
Stem cell therapy, also known as regenerative medicine, promotes the repair response of
diseased, dysfunctional or injured tissue using stem cells or their derivatives. It is the next
chapter in organ transplantation and uses cells instead of donor organs, which are limited
in supply.
Researchers grow stem cells in a lab. These stem cells are manipulated to specialize into
specific types of cells, such as heart muscle cells, blood cells or nerve cells. These
specialized cells can then be implanted into a person. For example, if the person has heart
disease, the cells could be injected into the heart muscle. The healthy transplanted heart
muscle cells could then contribute to repairing defective heart muscle. Researchers have
already shown that adult bone marrow cells guided to become heart-like cells can repair
heart tissue in people, and more research is ongoing.

Treatment of severe autoimmune disease by stem-cell

transplantation
Most patients with autoimmune disease have a near-normal life expectancy. Nevertheless,
some patients suffer severe, therapy-resistant progressive autoimmunity. Haematopoietic-
cell transplantation (HCT) is a potential therapy for people with such severe refractory
diseases. HCT involves the administration of haematopoietic stem cells (HSC), which are
self-renewing and capable of giving rise to all mature haematopoietic cell types and
possibly to some non-haematopoietic cell types. The HSC phenotype is characterized by a
lack of cell-surface lineage markers and the expression of CD34 in humans.

The recipient is prepared for the transplant by potent immunosuppressive treatment,

usually by chemotherapy and/or radiotherapy. This may then be followed by the transfer of
autologous haematopoietic cells (cells harvested from the recipient before patient
conditioning) or allogeneic haematopoietic cells (cells harvested from donors rather than
the recipient) to restore the host immune system.

This procedure can cure autoimmune disease in experimental animal models and is now
being explored in human clinical trials. Auto-HCT has been generally preferred over allo-
HCT because of the increased toxicity and potential for rejection in allo-HCT. The risk of
graft-versus-host-disease in allo-HCT, which arises from the attack of donor allogeneic T
cells on recipient alloantigens, is associated with significant morbidity and mortality.

Allo-HCT has been associated with durable complete remission in a small number of
patients treated for malignant diseases with coincidental autoimmune disorders. Most
recently, several groups have applied non-myeloablative or reduced-intensity conditioning
protocols for allo-HCT to the induction of transplantation tolerance and re-establishment of
self-tolerance in animal models of autoimmune disease. Although these recent advances
have made allo-HCT less toxic, it is an intensive procedure that most probably will not
replace current pharmacological treatment for less severe, conservatively treatable
autoimmune diseases.

Autologous HCT as a therapy for autoimmune disease.

Red cells represent auto-reactive host lymphocytes; green cells represent non-autoreactive
host lymphocytes; blue cells represent HSC.

The steps in autologous HCT include the following. 

 Stem-cell collection: HSCs are either harvested from the bone marrow under
anaesthesia or collected after mobilization to the peripheral blood by treating the
patient with growth factor for example, G-CSF
 HSC harvest, with or without ex vivo selection using antibody specific for CD34 (a
marker of HSCs): efforts may or may not be made to deplete T and B cells from the
marrow or mobilized peripheral blood cells. This is usually achieved by HSC positive
selection on the basis of CD34 expression. The HSC preparation is cryopreserved.
 In vivo lymphocyte depletion: various conditioning regimens with the goal of
minimizing the burden of autoreactive B and T cells are given to patients. These
include combinations of chemotherapeutic agents, total-body irradiation (TBI) and in
vivo lymphocyte depletion by antibodies, such as anti-thymocyte globulin (ATG), and
these treatments often deplete host HSC as well. 
 Stem-cell transplantation: after conditioning, the cryopreserved HSC preparation is
thawed and returned to the recipient to reconstitute haematopoiesis.
Allogeneic HCT as a therapy for autoimmune disease.

Red cells represent autoreactive host lymphocytes;

Green cells represent non-autoreactive host lymphocytes;
Yellow denotes donor lymphocytes;
Blue cells represent HSC.

The steps in allogeneic HCT include the following.

 Mobilization regimen: these are similar to the methods employed for autologous
HCT, except that cyclophosphamide and other chemotherapies are not used to
mobilize stem cells. Mobilization is achieved using the growth factor G-CSF.
 HSC harvest, with or without ex vivo CD34 selection. This step is similar to that used
for auto-HCT. 
 In vivo lymphocyte depletion: this step depletes host T and B cells to prevent
rejection and treat the autoimmune disease; it may also be aimed at depleting donor
T cells (to prevent GVHD).
 Stem-cell transplantation: as for auto-HCT.
  Post-transplantation immunosuppression: as prophylaxis against both rejection
mediated by residual host T cells and GVHD mediated by contaminating donor T cells,
allo-HCT usually requires additional post-transplantation immunosupression with
agents such as cyclosporine A and mycophenolate mofetil.
Mechanisms by which HCT might treat autoimmunity

These mechanisms are not mutually exclusive. Donor-derived cells are shown in green and
host-derived cells are shown in red.
 Immunomodulation by immunosuppressive conditioning: potent
immunosuppressive treatments such as total body irradiation (TBI),
cyclophosphamide (CY), anti-CD2 antibodies (anti-CD2), anti-CD52 antibodies (anti-
CD52), fludarabine and anti-thymocyte globulin (ATG) can eliminate the majority of B
and T cells. In addition to alloreactive and autoreactive memory B cells and T cells,
other T and B cells are depleted.
  Immune-mediated destruction of auto-reactive cells. Donor T cells recognize allo-
antigens and destroy residual memory B and T cells. This mechanism is applicable to
allo-HCT only. 
 Deletion of allo-reactive and auto-reactive T cells in the thymus. If both donor and
host cells contribute to haematopoiesis and to the antigen-presenting cell (APC) pool
in the thymus, the new T-cell repertoire generated in the recipient thymus is deleted
of T cells recognizing both allo- and auto-antigens expressed by haematopoietic cells
of both origins. 
 Induction of anergy and deletion of auto-reactive and allo-reactive T cells in the
periphery. Costimulatory blockade of the CD40–CD154 and CD28–CD80–CD86
pathways in concert with allogeneic BMT can overcome the T-cell barrier to allo-HSC
engraftment, which in turn quickly produces donor-specific tolerance and could
tolerize cross-reactive autoreactive lymphocytes as well. This mechanism plays a role
only in allo-HCT.
 Tolerization of peripheral auto-reactive/allo-reactive T cells by regulatory T cells.
CD4+CD25+ regulatory T cells have been implicated in the maintenance of peripheral
tolerance to organ-specific self-antigens as well as allo-antigens. The secretion of
TGF-β and IL-10 by regulatory T cells has been suggested to mediate this process.
Both allo-HCT and auto-HCT could incorporate this mechanism.
 Tolerization of auto-reactive and allo-reactive B cells. In addition to allo-antigens,
haematopoietic chimaerism could potentially tolerize pre-existing recipient B cells to
autoantigens expressed by donor haematopoietic cells. This mechanism plays a role
only in allo-HCT.

Use of HCT in various autoimmune diseases

Multiple sclerosis
In multiple sclerosis, autoreactive CD4+ T cells are crucial for the development of
inflammatory plaques, demyelination, and consequent axon loss. During autologous HSCT,
significant regeneration of circulating T cell clones results in immunological resetting.
Multiple sclerosis is categorized into four types: rapidly aggravating, relapsing-remitting,
secondary progressive, and primarily progressive. Various autoimmune diseases have
occurred in most autologous HSCT patients with multiple sclerosis. In the early stages of the
disease, autologous HSCT performed in relapsing-remitting types is more effective than in
severe progressive cases.

Juvenile idiopathic arthritis

Autologous HSCT has been used primarily in children with systemic juvenile idiopathic
arthritis. Although the drug-free relapse period was favorable during long-term follow-up,
the method did not spread due to high mortality associated with transplantation (9%-11%)

Crohn's disease
The autologous HSCT in Crohn's
disease is a suitable method for
achieving remission. The rate of 5-
year drug-free remission was 60%.
However, for 45 patients enrolled in
the Autologous Stem Cell
Transplantation for Crohn Disease
study, the results were not
convincing. Only 2/23 patients had
permanent remission, and one patient
died of transplantation-related
complications. According to the
official European Crohn's and Colitis
Organization recommendation, HSCT should only be considered for Crohn's disease
patients with severe illness accompanied by active luminal inflammation and refractory to
any available medication, and surgery alone is not enough

Evans syndrome
Evans syndrome (ES) is a chronic, autoimmune disease associated with multiple
immunocytopenia (hemolytic anemia + thrombocytopenia). The secondary cases of ES
mainly occur in SLE. Based on a limited number of studies, allogeneic HSCT may be the only
curative therapeutic option through reprogramming the immune system. Comparing the
clinical efficacy of autologous and allogeneic HSCTs in ES and immunothrombocytopenia,
overall survival was similar in both methods (84%), while relapse-free survival was more
favorable in allogeneic HSCT (78% vs 45%). In the case of chronically relapsing ES, and if an
HLA-identical blood relative is available, allogeneic HSCT may be preferred. In the absence
of a suitable donor or severe co-morbidity, autologous HSCT is recommended.

Rheumatoid arthritis

Autologous HSCT has been investigated in many studies in

rheumatoid arthritis patients who do not respond to
conventional treatments. According to retrospective
analyses, 2/3 of them had remission, mostly 6 months after
transplantation, but the relapse rate was also significant,
probably due to inadequate T cell repertoire ablation. The 5-
year survival rate was 94%, clearly indicating the safety of
HSCT. Yet, the latest, effective biological treatments in
rheumatoid arthritis have reduced the use of autologous
HSCT

Chronic inflammatory demyelinating polyneuropathy

In the chronic inflammatory demyelinating

polyneuropathy patients who require long-term high-
dose immunosuppressive therapy, initial experience
with autologous HSCT is hopeful. In Europe, nearly 30
patients underwent intervention, with a clear positive
trend in their neurological status. Currently a phase II
study (Haemopoetic Stem Cell Transplantation in
Chronic Inflammatory Demyelinating Polyneuropathy)
is ongoing
Mesenchymal stem cells

After 4 years of follow-up of patients with severe who underwent allogeneic bone marrow
transplantation, it was found that nearly 50% of patients experienced clinical remission and
the overall survival rate was 94%. Despite encouraging clinical efficacy and apparent safety,
the biological mechanisms explaining the therapeutic effect of mesenchymal stem cells in
SLE have not yet been elucidated.For SSc, there are only a small number of case reports
suggesting that the use of mesenchymal stem cells is safe and effective, but comprehensive
clinical trials have not yet been conducted. In severe refractory rheumatoid arthritis, two
studies have been investigated for the therapeutic use of intravenously administered bone
marrow-derived mesenchymal stem cells. Based on the results, the method was safe, no
serious adverse effects occurred, and clinically significant remission was observed. Three to
six months after the intervention, the level of inflammatory cytokines in the peripheral
blood decreased and the number of Treg cells increased. Mesenchymal stem cells derived
from adipose tissue have been shown to have similarly good results, but in order to
maintain the therapeutic effect, the introduction of stem cells was repeated every 3
months. Fifty percent of patients with Crohn's disease were in remission after half a year
with parenteral administration of mesenchymal stem cells isolated from placenta. At the
same time, by increasing the number of stem cells administered, only one-third of the
patients had an appreciable therapeutic effect, and after 6 months none of them were in
remission.

Adipose tissue-derived Mesenchymal stem cells

Adipose tissue-derived MSC (AT-MSC) are becoming an alternative source of MSC for
therapeutic applications because adipose tissues are abundant, easily accessible, easily
obtainable with little patient discomfort and large amounts of AT-MSC can be easily
obtained. Currently, AT-MSC were clinically applied for the regenerative treatment and
wound healing; In the first clinical trial, autologous adipose tissue derived mesenchymal
stem cells were used for the treatment of widespread traumatic calvarial bone defects . In
this clinical trial, new bone formation and almost complete calvarial continuity was
obtained.
In 2006, Yañez et al. reported AT-MSC have immunosuppressive properties that can be
used to control graft-versus host disease (GVDH) in murin model . From this concept, AT-
MSC were administered intravenously to patients with steroid-refractory acute GVDH.
Acute GVDH resolved completely in five of six patients, four of whom were alive after a
median follow-up period of 40 months without side effects .
Intravenous administration of AT-MSC before disease onset significantly reduces the
severity of EAE by immune modulation and decreases spinal cord inflammation and
demyelination. Administration of AT-MSC in chronic established EAE significantly
ameliorates the disease course and reduces both demyelination and axonal loss, and
induces a Th2-type cytokine shift in T cells .Inflammatory bowel diseases are associated
with uncontrolled innate and adaptive immunity. Gonzalez-Rey et al. induced acute and
chronic colitis in mice with dextran sulfate sodium .Colitic and septic mice were treated
with hAT-MSC or murine AT-MSC intraperitoneally. Treatment of AT-MSC significantly
ameliorated the clinical and histopathological severity of colitis by decrease of
inflammatory cytokines and increase of IL-10 . In same group, González et al. reported
systemic infusion of human AT-MSC significantly reduced the incidence and severity of
experimental arthritis by inducing the generation and activation of regulatory T cells.
Gene transfected stem cell therapy in autoimmune disease
Some studies on gene therapy using
stem cells as a vehicle in autoimmune
disease were reported. For examples,
there were Brain-derived
neurotrophic factor (BDNF) gene
delivery in an animal model of
multiple sclerosis using bone marrow
stem cells and human insulin gene
transfected BM-MSC therapy in
murine type 1 insulin-dependent
diabetes .Xu et al. evaluated the
effect of transplantation of bone
marrow-derived stem cells expressing
human insulin gene on murine type I
insulin-dependent diabetes which
induced by streptozoticin injection. After transplantation, the body weight increased and
the average blood glucose level 7 day and 42 day were significantly lower compaired with
control group. Immunohistochemistry showed secretion of human insulin in serum and
liver. Makar et al. conducted BDNF gene transfected bone marrow stem cells therapy in
experimental murine EAE, an animal model of multiple sclerosis. After therapy, EAE onset
was significantly delayed and overall clinical severity was significantly reduced in mice
which had received BDNF-transfected BM-MSC compared with control receiving BM-MSC
transfected with an empty vector lacking the BDNF gene. Another study of human ciliary
neurotrophic factor-overexpressed MSC therapy reduced demyelination and induced
clinical recovery in murine EAE .Okada et al. reported that hepatocyte growth factor-
overexpressed MSCT attenuated autoimmune myocarditis in rats .
Conclusion
the progress in clinical trials using stem cells for disease modification, immunomodulation,
or regenerative purposes are undoubtedly encouraging, but most are still in the early
stages, and the clinical results reported are not clear about therapeutic efficacy and
potential side effects. Uniform regulation of the clinical application of stem cells is also
indispensable for this highly customizable, minimally invasive, and individualized
therapeutic method to become a successful and safe treatment alternative in many
different disorders.