Page 1000 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 71 Type 1 Diabetes 965

reduce the risk of life-threatening ketoacidosis associated with daily) did not alter the rate of progression to diabetes in islet
the classic symptomatic presentation. autoantibody-positive children <3 years of age. However, these
In health, immune responses to autoantigens are regulated children were at very high risk, and many appeared to have had
to prevent development of autoimmune diseases. Autoantigen- borderline β-cell function. As in the oral insulin trial, markers
specific immunotherapy aims to boost or restore autoantigen- of an insulin bioeffect and evidence of immune tolerance were
specific immunoregulatory mechanisms. Its parallel, allergen-specific not reported. In the ongoing Intranasal Insulin Trial II (INIT
immunotherapy, has been shown in randomized trials to be effective II) in Australia, New Zealand, and Germany, higher doses of
in allergic asthma and rhinitis. Such “negative vaccination” can nasal insulin (44 or 440 IU) are being administered weekly for
be achieved in several ways: by administering antigen via a a year to relatives with T1D who have autoantibodies to at least
“tolerogenic” route (mucosal, dermal), cell type (resting dendritic two islet antigens (≈40% risk of diabetes over 5 years). The
cell), mode (with blockade of costimulation molecules), or form primary outcome is clinical diabetes; secondary outcomes are
(as an “altered peptide ligand”). Mechanisms of antigen-induced measures of metabolic and immune function. In INIT II, the
tolerance include deletion and/or anergy of effector T cells and insulin dose is substantially higher than in the Finnish study,
induction of regulatory T cells (iTregs). Of clinical importance is the participants are older and have less advanced subclinical
the ability of iTregs to exert antigen nonspecific “bystander” sup- disease and therefore are at lower risk. The promise of antigen-
pression. Thus by direct cell contact and/or the release of soluble specific therapy, therefore, has yet to be realized in humans. If
immunosuppressive factors, such as IL-10, iTregs impair the a balance between pathogenic and protective T cells is deter-
function of antigen-presenting DCs to elicit effector T-cell responses ministic for disease development, then antigen-specific therapy
to the same or other antigens presented locally in the lesion or is most likely to be effective as a primary preventive strategy.
draining lymph nodes. Bystander suppression does not require Once disease has been initiated, insulin-specific or other antigen-
that the “tolerizing” antigen is necessarily the primary driver of specific approaches may require complementary therapy with
pathology. Its clinical importance is that it obviates specificity other agents to inactivate or delete the burden of pathogenic
restrictions imposed by polymorphisms in the HLA and human effector cells.
T-cell receptors.
In NOD mice, administration of insulin, proinsulin peptides, On tHe HOrIZOn
or proinsulin DNA via oral or nasorespiratory routes, acting
locally on the mucosal immune system, induces Tregs and • Closed-loop insulin delivery—blood glucose monitoring devices will
become more refined, cheaper, and widely available.
decreases the incidence of diabetes. Results of randomized second- • “Linking the -omes” (exposome–microbiome–metabolome–epigenome)
ary prevention trials of insulin or GAD in relatives at risk for across time in early life will provide new insights into how environ-
T1DA (ClinicalTrials.gov) have been summarized elsewhere. 35-37 ment–gene interactions lead to immune dysregulation and type 1A
In the DPT-1 oral insulin trial, relatives with a 5-year diabetes diabetes (T1DA).
risk of 25–50% received 7.5 mg human insulin or placebo daily • Manipulation of the gut microbiome via scientifically formulated probiot-
for a median of 4.3 years. There was no effect overall, but posttrial ics and prebiotics will be used for primary prevention of T1DA.
hypothesis testing revealed a significant delay in diabetes onset • T1DA is primarily an immune disease—autoimmune β-cell disorder
(ABCD)—and only secondarily a metabolic disorder. Recognition of
38
in participants with significant IAA at entry. This outcome has these disease components will expand the therapeutic possibilities
led to an ongoing follow-up international trial by NIH-TrialNet for secondary prevention.
using the same dose of 7.5 mg daily, which is not optimal because
on a body-weight basis this dose is very small compared with
that required to induce protective iTregs in the NOD mouse. Please check your eBook at https://expertconsult.inkling.com/
Apart from the dose, other variables have not been systemati- for self-assessment questions. See inside cover for registration
cally tested in humans, in part because of the expense and duration details.
of prevention trials. These variables include route of administra-
tion, form of the antigen, combinations of antigen with antigen- REFERENCES
nonspecific agents, and the nature of induced immune responses.
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T1D not initially requiring insulin treatment, participants in trials. Diabetes Care 1999;22:1796–801.
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