Biomedical Engineering Reference
In-Depth Information
applicable to type 2 diabetics, and only partially applicable to type 1 diabetic
patients because of the existence of autoimmunity that will destroy any upcoming
b cells. In view of type 1 diabetes, a potential therapy should therefore ameliorate
the autoimmunity and at the same time promote b cell regeneration and protect the
remaining b cell mass (as in recent-onset diabetes).
Initial efforts to combat type 1 diabetes, therefore, focused on the use of
immunosuppressive drugs like prednisone, azathioprine, or cyclosporine A, to
preserve the b cell mass in recent-onset diabetes (where a residual b cell mass is
still present) [
91
]. In these studies the treated individuals showed a slower decline
in the plasma C-peptide levels and some patients even achieved an insulin-free
state for a limited period of time. However, the toxicity associated with the long-
term use of immunosuppressive drugs and lack of sustained benefit after discon-
tinuing the treatment makes this approach infeasible.
In 2003, a study by Kodama et al. [
92
] demonstrated the permanent reversal of
autoimmune diabetes in NOD mice following treatment with complete Freund's
adjuvant (CFA) and semi-allogeneic splenocytes. In this study splenocytes were
also shown to contribute toward b cell generation along with their immunomod-
ulatory effect. The same protocol was repeated by Chong et al. [
93
] and confirmed
the reversal of diabetes. However, in this study the regenerated b cells arose from
the host only and splenocytes did not contribute at all. Irrespective of the fact that
splenocytes contribute to b cell mass or not, these studies definitely demonstrate
the ability of b cells to regenerate in cases of type 1 diabetes once the autoim-
munity is ameliorated.
In the above-mentioned treatment regimen CFA was used to induce TNF-a
(tumor necrosis factor-a) production. TNF-a can induce apoptosis in T cells
thereby removing the autoreactive T cell population. At the same time, splenocytes
can induce negative selection of autoreactive T cells [
92
]. Because of its toxicity
CFA cannot be used in humans. In humans the functional equivalent of CFA is
BCG (Bacillus Calmette-Guérin) vaccine that can also induce TNF-a production.
Previous clinical trials with BCG have mostly not shown promising results in the
treatment of type 1 diabetes [
94
-
96
], however, one study reported a beneficial
effect too [
97
]. Considering the possibility that the BCG dosing was not optimal in
previous trials, Dr. Faustman has planned to repeat them. Currently, phase I trials
have been completed and funding for phase II is being raised. Phase I trials showed
no adverse effects in tested individuals and a transient rise in C-peptide levels and
dead autoreactive T cells [
98
].
Other potential approaches to achieve a beneficial immunomodulation for the
treatment of type 1 diabetes include HSCT (hematopoietic stem cell transplanta-
tion), UCB (umbilical cord blood) transfusion, and more recently the use of GABA
(c-aminobutyric acid). It has been shown in many studies that autologous or
allogeneic HSCT can possibly induce tolerance in cases of autoimmune disorders
[
99
]. Hematopoietic stem cells after transplantation did not give rise to pancreatic
b cells [
100
], however, an HSCT prevented diabetes in NOD mice [
101
].
Therefore, HSCT can have an immunomodulatory effect but may not contribute to
regeneration
directly.
Voltarelli
et
al.
[
102
]
carried
out
autologous
