The Diabetologist #26

the course of autoimmune destruction is needed and
may have efficacy in T1D prevention. In addition, IL-1
blockade in combination with an immunomodulatory
drug such as anti-CD3 may offer synergy and prove
effective in new-onset T1D. This combination has
proven highly effective in NOD mice with new-onset
T1D.29
Another anti-inflammatory approach of interest is
utilizing α-1 anti-trypsin. Once again, this approach
appeared promising in the NOD mouse. An ITNfunded,
initial lead-in, dose-finding study has been
conducted for adults and children with recent-onset
T1D, and plans are underway for a phase II, placebocontrolled,
randomized, new-onset T1D trial to follow
(NCT01183468). Encouraging results have also been
noted in independent smaller phase 1 trials conducted
by P. Gottlieb et al., and by Y. Lebenthal et al. in
Israel.
Immunosuppressants
‏.‏Cyclosporine Immunosuppression is capable of
halting beta-cell destruction, as demonstrated by a
series of early studies with cyclosporine.30,31 This
drug is a general immunosuppressant that has been
used widely in transplantation and suppresses humoral
immunity but is even more effective against
T-cell–dependent mechanisms. In the 1980s and
1990s, a series of clinical trials demonstrated clinical
efficacy in new-onset T1D, but important limitations
were noted. Not all treated subjects responded, and
for those who did, continuous therapy was required.
Furthermore, cyclosporine may be hepato and nephrotoxic,
and continuous immunosuppression may
confer risk for infection and possibly cancer. Thus,
while cyclosporine established proof of principle, it
has not become a viable standard therapy for preserving
beta-cell function. Following these studies,
further trials with immunosuppression were relatively
quiescent as investigators sought novel, more targeted
therapies, especially those not requiring continuous
use.
- a Anti-CD3 monoclonal antibodies. One novel
proach has been to block activation of potentially
autoreactive T-cells (see chapter 2), which occurs
following interaction between T-cells and antigenpresenting
cells (APCs), via the T-cell receptor and
costimulatory receptors at the immunologic synapse
with antigen peptide/major histocompatability
complex (MHC) and costimulatory molecules from
APCs (Figure 3.1). Investigators have utilized a mAb
that targets the CD3-ε subunit of the T-cell receptor,
thereby altering the primary signaling between T-cell
and APC. This approach exhibited remarkable findings
in the NOD mouse, where a short-term course
of antibody induced lasting remission in mice with
new-onset diabetes. Investigators have since modified
the parent OKT3 antibody in two ways to make a
better-tolerated product for humans. These products
are teplizumab (hOKT3γ1 (Ala-Ala)) and otelixizumab
(ChA-glyCD3).
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issue 26 < November. 2013