Abstract Background The use of stem cells to treat type 1 diabetes mellitus has been proposed for many years, both to downregulate the immune system and to provide β cell regeneration. Conclusion High dose immunosuppression followed by autologous hematopoietic stem cell transplantation is able to induce complete remission (insulin independence) in most patients with early onset type 1 diabetes mellitus.</p

AJ Wagers

AL Notkins

B Keymeulen

Carlos Eduardo Barra Couri

CE Couri

F Bougnères

GD Fischbach

J Silverstein

JC Voltarelli

JD Scandling

JJ Cook

JS Skyler

Júlio C Voltarelli

KC Herold

LC Harrison

P Girman

R Assan

RB Elliott

SI Alexander

T Kawai

W Gepts

English

PubMed

Abstract\ud
            \ud
            \ud
               \ud
                  Background\ud
               \ud
               The use of stem cells to treat type 1 diabetes mellitus has been proposed for many years, both to downregulate the immune system and to provide β cell regeneration.\ud
            \ud
            \ud
               \ud
                  Conclusion\ud
               \ud
               High dose immunosuppression followed by autologous hematopoietic stem cell transplantation is able to induce complete remission (insulin independence) in most patients with early onset type 1 diabetes mellitus

Voltarelli, Júlio C

Couri, Carlos 

Universidade de São Paulo

Stem cell transplantation for type 1 diabetes mellitus

Carlos Couri

Springer - Publisher Connector

BioMed Central
Diabetology & Metabolic Syndrome
ssOpen AcceReview
Stem cell transplantation for type 1 diabetes mellitus
Júlio C Voltarelli* and Carlos Eduardo Barra Couri
Address: Department of Clinical Medicine, Ribeirão Preto School of Medicine, University of São Paulo, Brazil
Email: Júlio C Voltarelli* - jcvoltar@fmrp.usp.br; Carlos Eduardo Barra Couri - ce.couri@yahoo.com.br
* Corresponding author 
Abstract
Background: The use of stem cells to treat type 1 diabetes mellitus has been proposed for many
years, both to downregulate the immune system and to provide β cell regeneration.
Conclusion: High dose immunosuppression followed by autologous hematopoietic stem cell
transplantation is able to induce complete remission (insulin independence) in most patients with
early onset type 1 diabetes mellitus.
Introduction
Type 1 diabetes (T1DM) is an autoimmune disease
through which the patient's immune system loses the
immunologic tolerance against β cells antigens, resulting
in an immune response against the islets which involves
CD8+ and CD4+ cells. Such process results in insulitis, an
inflammatory process which causes the destruction of
pancreatic β cells, thereby eliciting insulin therapy as the
treatment for T1DM [1,2].
Stem cells (SC) have the unique function of asymmetric
division, i.e., they are capable of self-renewing and the
generation of other identical cells. They are undifferenti-
ated cells that perpetuate throughout the body and are
responsible for regenerating all tissues in adults and are
also responsible for tissue morphogenesis in embryos.
Such cells may be obtained from the fetus, the umbilical
cord, the bone marrow and may also be deployed by
peripheral blood and even from different somatic tis-
sues[3,4].
Bone marrow SC originates blood cells, including lym-
phoid cells. In addition to hematopoietic stem cells,
which are the most widely known and studied types of
bone marrow SC, other important SC types have promis-
ing importance in therapeutics. One of them is the
endothelial precursor cells, capable of angiogenesis and
they are widely used nowadays in regenerative therapy.
Another type of SC is the mesenchymal stem cell, which
has a powerful immunosuppressant capacity and is also
capable to differentiate into several tissues. Therefore,
these three types of stem cells, hematopoietic, endothelial
and mesenchymal, have been used in therapy and may be
applied to the treatment of diabetes[5].
The bone marrow transplantion or classic stem cell trans-
plantion has been performed successfully for exactly 40
years since the first successful transplant was performed in
1968. This type of transplantation is typically performed
using SC mobilized from bone marrow cells to the periph-
eral blood or from the umbilical cord of an allogeneic
donor, and transplanted to a patient who most of the
times has hematologic disease. This type of transplant is
preceded by immunosuppression in order to avoid rejec-
tion and the graft reaction against the host. Oppositely
from solid organ transplants, the hematopoietic SC trans-
plant requires limited continuous immunosuppression
which may range from three to six months, depending on
the pathology. In this type of transplant, a mutual toler-
ance is established between the donor and the recipient,
Published: 16 September 2009
Diabetology & Metabolic Syndrome 2009, 1:4 doi:10.1186/1758-5996-1-4
Received: 7 April 2009
Accepted: 16 September 2009
This article is available from: http://www.dmsjournal.com/content/1/1/4
© 2009 Voltarelli and Couri; licensee BioMed Central Ltd. 
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), 
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 4
(page number not for citation purposes)
Diabetology & Metabolic Syndrome 2009, 1:4 http://www.dmsjournal.com/content/1/1/4due to chimerism, which characterizes donor cell persist-
ence in the receptor. Chimerism results in a process which
still remains unclear, associated with clonal exhaustion or
clonal depression, which makes the receptor not to react
to the donor or vice versa. Regarding the induction of chi-
merism in allogeneic transplantation, there are two types
of transplant: myeloablative and nonmyeloablative. The
first is the classic transplant, in which a very high dosage
of debulking agents (chemotherapy and/or radiotherapy)
is used to completely eliminate the hematopoietic and
lymphoid tissues of the receptor. After that, these tissues
are replaced by donor tissue, resulting in complete chi-
merism. Due to its intensity, myeloablative immunosup-
pression is highly toxic, resulting in non-eligible mortality
rates. Currently, the nonmyeloablative transplant has
been increasingly used, where the immunosuppression
load is lower resulting in a mixed chimerism which is suf-
ficient to avoid allogeneic reactions graft rejections against
the host.
Such nonmyeloablative transplant strategy with partial
chimerism induction is one hope to induce tolerance in
the long run for solid organ transplants, such as kidney or
pancreas transplants, but it is yet to be obtained. A paper
written almost ten years ago, showed advantage while
using bone marrow SC along with solid organ transplants
in kidney-pancreas transplants in terms of chronic rejec-
tion, acute rejection and even corticoid interruption [6,7].
Recently in 2008, there were some reports of cases of tol-
erance induction including interruption of immunosup-
presion after kidney or liver transplantation [8,9]. These
reports showed the interruption of immunosuppresion in
four out of five patients. In this nonmyeloablative condi-
tioning procedure, a smaller dose of immunosuppressant
drugs was used, which is not enough to completely elimi-
nate recipient hematopoiesis. Such nonmyeloablative
conditioning process is used to allow bone marrow graft-
ing and to induce chimerism deployment. It gives us the
hope that in the near future we may reach the goal of elim-
inating both rejection and graft reaction against hosts,
resulting in the possibility of interrupting immunosup-
pression.
In the near future, according to these papers, allogeneic
stem cell transplant has the perspective of allowing the
grafting of other solid organs and the interruption of
immunosuppression much like it is routinely performed
in hematopoietic stem cell transplants as described in the
literature [10].
Autologous hematopoietic stem cell transplantation for 
type 1 diabetes
Another type of transplant which has been more widely
used clinically, mainly in autoimmune diseases, such as
T1DMs, is the autologous hematopoietic stem cell trans-
plantion (AHSCT). For such transplant, we mobilize the
patient's hematopoietic SC from bone marrow to the
blood with the use of low dose cyclophosphamide and
granulocyte colony-stimulating factor. Then the hemat-
opoietic SC are collected from peripheral blood by leuka-
pheresis and cryopreserved. The cells are re-injected
intravenously only after conditioning with high dose of
chemotherapy - cyclophosphamide (200 mg/kg) and rab-
bit antithymocyte globulin (4.5 mg/kg). This is a lympho-
ablative scheme, as we destroy most of the patient's
lymphocyte clones, which include both autoreactive and
non-autoreactive, and we recover the immunologic sys-
tem with AHSCT. This phenomenon is called immuno-
logic reset.
Such type of transplant has been performed for twelve
years for autoimmune diseases such as multiple sclerosis,
systemic sclerosis, rheumatoid arthritis, systemic lupus
erythematous, Crohn's disease and others. This type of
treatment has significant mortality rates, mainly for more
severe diseases such as systemic sclerosis and lupus. In
most cases, except for rheumatoid arthritis in adults, there
is a prolonged remission in over 50% of the cases, which
may be considered a success, as transplanted patients are
the most severe cases and generally have not responded to
usual therapies. In Brazil, a cooperative study protocol
was initiated in 2001 and our series comprises is com-
prised of more than 150 patients, including patients with
diabetes, multiple sclerosis, systemic sclerosis and lupus.
In animal models, T1DM may be prevented by allogeneic
bone marrow transplant, and in allogeneic transplants in
human beings, it has been shown that type 1 diabetes may
be transmitted through bone marrow transplants. For
example, a leukemic patient, after receiving a bone mar-
row transplant from a brother who has diabetes, may also
become a diabetic patient, which means that the disease
may be transmitted through stem cells. However, when
type 1 diabetic patients received transplants due to leuke-
mia or other blood-borne diseases, there was no improve-
ment of diabetes after the transplant, which is contrary
evidence to what has been observed in animal models.
These patients have already had diabetes for several years,
and they had small amount of β cell mass, demonstrating
that the hematopoietic stem cell involved in such trans-
plant is not able to differentiate into a significant number
of β cells and to induce remission in the patient with long
term disease.
The beneficial effect of several chronic immunosuppres-
sant schemes was demonstrated in diabetes, however,
after immunosupression interruption, the disease relapses
[11-16]. Several studies tried to induce prolonged immu-
nosuppression after a short term therapy with immu-Page 2 of 4
(page number not for citation purposes)
Diabetology & Metabolic Syndrome 2009, 1:4 http://www.dmsjournal.com/content/1/1/4nomodulatory drugs. One of the most successful results
obtained with acute immunossuppression was with anti-
T cell antibodies, as shown in articles reporting the effects
of OKT3 in increasing C-peptide levels and a decreasing in
daily insulin doses [17,18]. However such effect was tran-
sitory and too short.
As previously discussed, strategies of immunomodulation
are more interesting during a phase in which the patient
still has an important β cell reserve, i.e., in an initial stage
of the disease, blocking the immunological aggression of
T cells against β cells and allowing an endogenous regen-
eration of β cells. In face of this, our research group started
a protocol of nonmyeloablative AHSCT in newly diag-
nosed type 1 diabetic patients in 2003 to transplant indi-
viduals from 12 to 35 years old with recent clinical and
laboratorial diagnosis of type 1 diabetes (<6 weeks). In
the initial protocol, especially in the first patient, we used
corticoids along with rabbit antithymocyte globulin to
avoid anaphylactic reactions. In face of the pro-apoptotic
effects of glucocorticoids on β cells, we stopped use after
that.
All the enrolled patients were checked for HLA hystocom-
patibility system antigens, and most of whom were DR3/
DR4 [19].
Side Effects and Results
Because we apply immunosuppressant leukemia therapy
on an autoimmune disease in young patients, reports of
side effects are extremely important, and the most fre-
quent side effects are infections in general, controlled
using an antibiotic scheme prophylatically or therapeuti-
cally. In three patients, we observed post-transplant
autoimmune diseases due to the transplant or to diabetes.
During a 7- to 58-month follow-up (mean, 29.8 months;
median, 30 months), 20 patients without previous
ketoacidosis and not receiving corticosteroids during the
preparative regimen became insulin free. Twelve patients
maintained this status for a mean 31 months (range, 14-
52 months) and 8 patients relapsed and resumed insulin
use at low dose (0.1-0.3 IU/kg). In the continuous insulin-
independent group, A1c levels were less than 7.0% and
mean (SE) area under the curve (AUC) of C-peptide levels
increased significantly from 225.0 (75.2) ng/mL per 2
hours pretransplantation to 785.4 (90.3) ng/mL per 2
hours at 24 months posttransplantation (P < .001) and to
728.1 (144.4) ng/mL per 2 hours at 36 months (P = .001).
In the transient insulin-independent group, mean (SE)
AUC of C-peptide levels also increased from 148.9 (75.2)
ng/mL per 2 hours pretransplantation to 546.8 (96.9) ng/
mL per 2 hours at 36 months (P = .001), which was sus-
tained at 48 months. In this group, 2 patients regained
insulin independence after treatment with sitagliptin,
which is a DPP-4 inhibitor, an enzyme which metabolizes
GLP-1, and is thus associated with a glucose dependent
increase in C-peptide levels. Two patients developed bilat-
eral nosocomial pneumonia, 3 patients developed late
endocrine dysfunction, and 9 patients developed oli-
gospermia. There was no mortality [19,20].
Conclusion
We have concluded that there are several challenges when
it comes to this type of transplant in recently diagnosed
T1DM, from which the main one is to investigate the
length of the clinical response (insulin independence)
and relapse mechanism. Using embryonic stem cells
could have better results at the long term diseases. Inject-
ing bone marrow mononuclear cells directly into the pan-
creas significantly increased endogenous insulin secretion
in type 2 diabetic patients, but not in persons with T1DM
in studies conducted in Peru and Argentina. The use of
autologous umbilical cord stem cells in children with
T1DM resulted in not significant differences in daily insu-
lin doses and in a decline in C-peptide levels after 1 year
of follow-up. This study is still being conducted at the
University of Florida, in Gainesville.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
All the authors and participated in the manuscript design
and drafting. All authors participated in study coordina-
tion and acquisition and interpretation of the data
showed. All authors read and approved the final manu-
script.
References
1. Notkins AL, Lernmark A: Autoimmune type 1 diabetes:
resolved and unresolved issues. J Clin Invest 2001,
108:1247-1252.
2. Gepts W: Pathologic anatomy of the pancreas in juvenile dia-
betes mellitus. Diabetes 1965, 14:619-633.
3. Fischbach GD, Fischbach RL: Stem cells: science, policy and eth-
ics. Journal of Clinical Investigation 2004, 114:1364-1370.
4. Wagers AJ, Weissman IL: Plasticity of adults stem cells. Cell
2004, 116:639-648.
5. Couri CE, Voltarelli JC: Potential Role of stem cell therapy in
type 1 diabetes mellitus. Arq Bras Endocrinol Metabol 2008,
52:407-415.
6. Alexander SI, Smith N, Hu M, et al.: Chimerism and tolerance in
a recipient of a deceased-donor liver transplant. N Engl J Med
2008, 358:369-374.
7. Girman P, Kriz J, Dovolilova E, Dovolilová E, Cíhalová E, Saudek F:
The effect of bone marrow transplantation on survival of all-
ogeneic pancreatic islets with short term tacrolimus condi-
tioning in rats. Ann Transplant 2001, 6:43-45.
8. Kawai T, Cosimi AB, Spitzer TR, et al.: HLA-mismatched renal
transplantation without maintenance immunosuppression.
N Engl J Med 2008, 358:353-361.
9. Scandling JD, Busque S, Dejbakhsh-Jones S, Benike C, Millan MT, Shi-
zuru JA, Hoppe RT, Lowsky R, Engleman EG, Strober S: Tolerance
and chimerism after renal and hematopoietic-cell transplan-
tation. N Engl J Med 2008, 358:362-368.
10. Skyler JS: Cellular therapy for type 1 diabetes. Has the time
come? JAMA 2007, 297:1599-1560.Page 3 of 4
(page number not for citation purposes)
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11. Elliott RB, Berryman CC, Crossley , James AG: Partial preserva-
tion of pancreatic β-cell function in children with diabetes.
Lancet 1981, 19:631-632.
12. Harrison LC, Colman PG, Dean B, Baxter R, Martin FI: Increased in
remission rate in newly diagnosed type l diabetic subjects
treated with azathioprine. Diabetes 1985, 34:1306-1308.
13. Cook JJ, Hudson I, Harrison LC, Dean B, Colman PG, Werther GA,
Warne GL, Court JM: Double-blind controlled trial of azathio-
prine in children with newly diagnosed type I diabetes. Diabe-
tes 1989, 38:779-783.
14. Silverstein J, Maclaren N, Riley W, Spillar R, Radjenovic D, Johnson S:
Immunosupression with azatioprine and prednisone in
recent-onset insulin-dependent diabetes mellitus. N Engl J
Med 1988, 319:599-604.
15. Assan R, Feutren G, Sirmai J, et al.: Plasma C-peptide levels and
clinical remissions in recent-onset type 1 diabetic patients
treated with cyclosporin A and insulin. Diabetes 1990,
39:768-774.
16. Bougnères F, Landais P, Boisson C, Carel JC, Frament N, Boitard C,
Chaussain JL, Bach JF: Limited duration of remission of insulin
dependency in children with recent overt type I diabetes
treated with low-dose cyclosporin. Diabetes 1990,
39:1264-1272.
17. Herold KC, Hagopian W, Auger JA, et al.: Anti-CD3 monoclonal
antibodiy in new-onset type 1 diabetes mellitus. N Engl J Med
2002, 346:1692-1698.
18. Keymeulen B, Vandemeulebroucke E, Ziegler AG, et al.: Insulin
needs after CD3-antibody therapy in new-onset type 1 diabe-
tes. N Engl J Med 2005, 352:2598-2608.
19. Voltarelli JC, Couri CEB, Stracieri ABPL, et al.: Autologous non-
myeloablative hematopoietic stem cell transplantation in
newly diagnosed type 1 diabetes mellitus. JAMA 2008,
297:1568-1576.
20. Couri CE, Oliveira MC, Stracieri AB, et al.: C-peptide levels and
insulin independence following autologous nonmyeloabla-
tive hematopoietic stem cell transplantation in newly diag-
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(page number not for citation purposes)

Biblioteca Digital da Produção Intelectual da Universidade de São Paulo (BDPI/USP)

Universidade de São Paulo
 
2009
 
Stem cell transplantation for type 1 diabetes
mellitus
 
 
 
http://www.producao.usp.br/handle/BDPI/33189
 
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Diabetology & Metabolic Syndrome
Open AccessReview
Stem cell transplantation for type 1 diabetes mellitus
Júlio C Voltarelli* and Carlos Eduardo Barra Couri
Address: Department of Clinical Medicine, Ribeirão Preto School of Medicine, University of São Paulo, Brazil
Email: Júlio C Voltarelli* - jcvoltar@fmrp.usp.br; Carlos Eduardo Barra Couri - ce.couri@yahoo.com.br
* Corresponding author 
Abstract
Background: The use of stem cells to treat type 1 diabetes mellitus has been proposed for many
years, both to downregulate the immune system and to provide β cell regeneration.
Conclusion: High dose immunosuppression followed by autologous hematopoietic stem cell
transplantation is able to induce complete remission (insulin independence) in most patients with
early onset type 1 diabetes mellitus.
Introduction
Type 1 diabetes (T1DM) is an autoimmune disease
through which the patient's immune system loses the
immunologic tolerance against β cells antigens, resulting
in an immune response against the islets which involves
CD8+ and CD4+ cells. Such process results in insulitis, an
inflammatory process which causes the destruction of
pancreatic β cells, thereby eliciting insulin therapy as the
treatment for T1DM [1,2].
Stem cells (SC) have the unique function of asymmetric
division, i.e., they are capable of self-renewing and the
generation of other identical cells. They are undifferenti-
ated cells that perpetuate throughout the body and are
responsible for regenerating all tissues in adults and are
also responsible for tissue morphogenesis in embryos.
Such cells may be obtained from the fetus, the umbilical
cord, the bone marrow and may also be deployed by
peripheral blood and even from different somatic tis-
sues[3,4].
Bone marrow SC originates blood cells, including lym-
phoid cells. In addition to hematopoietic stem cells,
which are the most widely known and studied types of
bone marrow SC, other important SC types have promis-
ing importance in therapeutics. One of them is the
endothelial precursor cells, capable of angiogenesis and
they are widely used nowadays in regenerative therapy.
Another type of SC is the mesenchymal stem cell, which
has a powerful immunosuppressant capacity and is also
capable to differentiate into several tissues. Therefore,
these three types of stem cells, hematopoietic, endothelial
and mesenchymal, have been used in therapy and may be
applied to the treatment of diabetes[5].
The bone marrow transplantion or classic stem cell trans-
plantion has been performed successfully for exactly 40
years since the first successful transplant was performed in
1968. This type of transplantation is typically performed
using SC mobilized from bone marrow cells to the periph-
eral blood or from the umbilical cord of an allogeneic
donor, and transplanted to a patient who most of the
times has hematologic disease. This type of transplant is
preceded by immunosuppression in order to avoid rejec-
tion and the graft reaction against the host. Oppositely
from solid organ transplants, the hematopoietic SC trans-
plant requires limited continuous immunosuppression
which may range from three to six months, depending on
the pathology. In this type of transplant, a mutual toler-
ance is established between the donor and the recipient,
Published: 16 September 2009
Diabetology & Metabolic Syndrome 2009, 1:4 doi:10.1186/1758-5996-1-4
Received: 7 April 2009
Accepted: 16 September 2009
This article is available from: http://www.dmsjournal.com/content/1/1/4
© 2009 Voltarelli and Couri; licensee BioMed Central Ltd. 
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), 
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Diabetology & Metabolic Syndrome 2009, 1:4 http://www.dmsjournal.com/content/1/1/4
Page 2 of 4
(page number not for citation purposes)
due to chimerism, which characterizes donor cell persist-
ence in the receptor. Chimerism results in a process which
still remains unclear, associated with clonal exhaustion or
clonal depression, which makes the receptor not to react
to the donor or vice versa. Regarding the induction of chi-
merism in allogeneic transplantation, there are two types
of transplant: myeloablative and nonmyeloablative. The
first is the classic transplant, in which a very high dosage
of debulking agents (chemotherapy and/or radiotherapy)
is used to completely eliminate the hematopoietic and
lymphoid tissues of the receptor. After that, these tissues
are replaced by donor tissue, resulting in complete chi-
merism. Due to its intensity, myeloablative immunosup-
pression is highly toxic, resulting in non-eligible mortality
rates. Currently, the nonmyeloablative transplant has
been increasingly used, where the immunosuppression
load is lower resulting in a mixed chimerism which is suf-
ficient to avoid allogeneic reactions graft rejections against
the host.
Such nonmyeloablative transplant strategy with partial
chimerism induction is one hope to induce tolerance in
the long run for solid organ transplants, such as kidney or
pancreas transplants, but it is yet to be obtained. A paper
written almost ten years ago, showed advantage while
using bone marrow SC along with solid organ transplants
in kidney-pancreas transplants in terms of chronic rejec-
tion, acute rejection and even corticoid interruption [6,7].
Recently in 2008, there were some reports of cases of tol-
erance induction including interruption of immunosup-
presion after kidney or liver transplantation [8,9]. These
reports showed the interruption of immunosuppresion in
four out of five patients. In this nonmyeloablative condi-
tioning procedure, a smaller dose of immunosuppressant
drugs was used, which is not enough to completely elimi-
nate recipient hematopoiesis. Such nonmyeloablative
conditioning process is used to allow bone marrow graft-
ing and to induce chimerism deployment. It gives us the
hope that in the near future we may reach the goal of elim-
inating both rejection and graft reaction against hosts,
resulting in the possibility of interrupting immunosup-
pression.
In the near future, according to these papers, allogeneic
stem cell transplant has the perspective of allowing the
grafting of other solid organs and the interruption of
immunosuppression much like it is routinely performed
in hematopoietic stem cell transplants as described in the
literature [10].
Autologous hematopoietic stem cell transplantation for 
type 1 diabetes
Another type of transplant which has been more widely
used clinically, mainly in autoimmune diseases, such as
T1DMs, is the autologous hematopoietic stem cell trans-
plantion (AHSCT). For such transplant, we mobilize the
patient's hematopoietic SC from bone marrow to the
blood with the use of low dose cyclophosphamide and
granulocyte colony-stimulating factor. Then the hemat-
opoietic SC are collected from peripheral blood by leuka-
pheresis and cryopreserved. The cells are re-injected
intravenously only after conditioning with high dose of
chemotherapy - cyclophosphamide (200 mg/kg) and rab-
bit antithymocyte globulin (4.5 mg/kg). This is a lympho-
ablative scheme, as we destroy most of the patient's
lymphocyte clones, which include both autoreactive and
non-autoreactive, and we recover the immunologic sys-
tem with AHSCT. This phenomenon is called immuno-
logic reset.
Such type of transplant has been performed for twelve
years for autoimmune diseases such as multiple sclerosis,
systemic sclerosis, rheumatoid arthritis, systemic lupus
erythematous, Crohn's disease and others. This type of
treatment has significant mortality rates, mainly for more
severe diseases such as systemic sclerosis and lupus. In
most cases, except for rheumatoid arthritis in adults, there
is a prolonged remission in over 50% of the cases, which
may be considered a success, as transplanted patients are
the most severe cases and generally have not responded to
usual therapies. In Brazil, a cooperative study protocol
was initiated in 2001 and our series comprises is com-
prised of more than 150 patients, including patients with
diabetes, multiple sclerosis, systemic sclerosis and lupus.
In animal models, T1DM may be prevented by allogeneic
bone marrow transplant, and in allogeneic transplants in
human beings, it has been shown that type 1 diabetes may
be transmitted through bone marrow transplants. For
example, a leukemic patient, after receiving a bone mar-
row transplant from a brother who has diabetes, may also
become a diabetic patient, which means that the disease
may be transmitted through stem cells. However, when
type 1 diabetic patients received transplants due to leuke-
mia or other blood-borne diseases, there was no improve-
ment of diabetes after the transplant, which is contrary
evidence to what has been observed in animal models.
These patients have already had diabetes for several years,
and they had small amount of β cell mass, demonstrating
that the hematopoietic stem cell involved in such trans-
plant is not able to differentiate into a significant number
of β cells and to induce remission in the patient with long
term disease.
The beneficial effect of several chronic immunosuppres-
sant schemes was demonstrated in diabetes, however,
after immunosupression interruption, the disease relapses
[11-16]. Several studies tried to induce prolonged immu-
nosuppression after a short term therapy with immu-
Diabetology & Metabolic Syndrome 2009, 1:4 http://www.dmsjournal.com/content/1/1/4
Page 3 of 4
(page number not for citation purposes)
nomodulatory drugs. One of the most successful results
obtained with acute immunossuppression was with anti-
T cell antibodies, as shown in articles reporting the effects
of OKT3 in increasing C-peptide levels and a decreasing in
daily insulin doses [17,18]. However such effect was tran-
sitory and too short.
As previously discussed, strategies of immunomodulation
are more interesting during a phase in which the patient
still has an important β cell reserve, i.e., in an initial stage
of the disease, blocking the immunological aggression of
T cells against β cells and allowing an endogenous regen-
eration of β cells. In face of this, our research group started
a protocol of nonmyeloablative AHSCT in newly diag-
nosed type 1 diabetic patients in 2003 to transplant indi-
viduals from 12 to 35 years old with recent clinical and
laboratorial diagnosis of type 1 diabetes (<6 weeks). In
the initial protocol, especially in the first patient, we used
corticoids along with rabbit antithymocyte globulin to
avoid anaphylactic reactions. In face of the pro-apoptotic
effects of glucocorticoids on β cells, we stopped use after
that.
All the enrolled patients were checked for HLA hystocom-
patibility system antigens, and most of whom were DR3/
DR4 [19].
Side Effects and Results
Because we apply immunosuppressant leukemia therapy
on an autoimmune disease in young patients, reports of
side effects are extremely important, and the most fre-
quent side effects are infections in general, controlled
using an antibiotic scheme prophylatically or therapeuti-
cally. In three patients, we observed post-transplant
autoimmune diseases due to the transplant or to diabetes.
During a 7- to 58-month follow-up (mean, 29.8 months;
median, 30 months), 20 patients without previous
ketoacidosis and not receiving corticosteroids during the
preparative regimen became insulin free. Twelve patients
maintained this status for a mean 31 months (range, 14-
52 months) and 8 patients relapsed and resumed insulin
use at low dose (0.1-0.3 IU/kg). In the continuous insulin-
independent group, A1c levels were less than 7.0% and
mean (SE) area under the curve (AUC) of C-peptide levels
increased significantly from 225.0 (75.2) ng/mL per 2
hours pretransplantation to 785.4 (90.3) ng/mL per 2
hours at 24 months posttransplantation (P < .001) and to
728.1 (144.4) ng/mL per 2 hours at 36 months (P = .001).
In the transient insulin-independent group, mean (SE)
AUC of C-peptide levels also increased from 148.9 (75.2)
ng/mL per 2 hours pretransplantation to 546.8 (96.9) ng/
mL per 2 hours at 36 months (P = .001), which was sus-
tained at 48 months. In this group, 2 patients regained
insulin independence after treatment with sitagliptin,
which is a DPP-4 inhibitor, an enzyme which metabolizes
GLP-1, and is thus associated with a glucose dependent
increase in C-peptide levels. Two patients developed bilat-
eral nosocomial pneumonia, 3 patients developed late
endocrine dysfunction, and 9 patients developed oli-
gospermia. There was no mortality [19,20].
Conclusion
We have concluded that there are several challenges when
it comes to this type of transplant in recently diagnosed
T1DM, from which the main one is to investigate the
length of the clinical response (insulin independence)
and relapse mechanism. Using embryonic stem cells
could have better results at the long term diseases. Inject-
ing bone marrow mononuclear cells directly into the pan-
creas significantly increased endogenous insulin secretion
in type 2 diabetic patients, but not in persons with T1DM
in studies conducted in Peru and Argentina. The use of
autologous umbilical cord stem cells in children with
T1DM resulted in not significant differences in daily insu-
lin doses and in a decline in C-peptide levels after 1 year
of follow-up. This study is still being conducted at the
University of Florida, in Gainesville.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
All the authors and participated in the manuscript design
and drafting. All authors participated in study coordina-
tion and acquisition and interpretation of the data
showed. All authors read and approved the final manu-
script.
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Abstract Background The use of stem cells to treat type 1 diabetes mellitus has been proposed for many years, both to downregulate the immune system and to provide β cell regeneration. Conclusion High dose immunosuppression followed by autologous hematopoietic stem cell transplantation is able to induce complete remission (insulin independence) in most patients with early onset type 1 diabetes mellitus.</p

Voltarelli Júlio C

Couri Carlos

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Diabetology & Metabolic Syndrome

Crossref

al.: HLA-mismatched renal transplantation without maintenance immunosuppression.

Anti-CD3 monoclonal antibodiy in new-onset type 1 diabetes mellitus.

Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA

C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA

Chimerism and tolerance in a recipient of a deceased-donor liver transplant.

Cíhalová E, Saudek F: The effect of bone marrow transplantation on survival of allogeneic pancreatic islets with short term tacrolimus conditioning in rats. Ann Transplant

FI: Increased in remission rate in newly diagnosed type l diabetic subjects treated with azathioprine. Diabetes

Fischbach RL: Stem cells: science, policy and ethics.

Immunosupression with azatioprine and prednisone in recent-onset insulin-dependent diabetes mellitus.

Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes.

JF: Limited duration of remission of insulin dependency in children with recent overt type I diabetes treated with low-dose cyclosporin. Diabetes

JM: Double-blind controlled trial of azathioprine in children with newly diagnosed type I diabetes. Diabetes

Lernmark A: Autoimmune type 1 diabetes: resolved and unresolved issues.

Partial preservation of pancreatic β-cell function in children with diabetes. Lancet

Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes

Plasma C-peptide levels and clinical remissions in recent-onset type 1 diabetic patients treated with cyclosporin A and insulin. Diabetes

Tolerance and chimerism after renal and hematopoietic-cell transplantation.

Voltarelli JC: Potential Role of stem cell therapy in type 1 diabetes mellitus. Arq Bras Endocrinol Metabol

Weissman IL: Plasticity of adults stem cells. Cell

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Stem cell transplantation for type 1 diabetes mellitus

Abstract

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