Mucosal antigen primes diabetogenic cytotoxic T lymphocytes regardless of dose or delivery route
Hänninen A, Braakhuis A, Heath WR, Harrison LC
Diabetes 50:771-775 (2001)
Administration of antigens via mucosal routes, such as orally or intranasally, can induce specific immunological tolerance and has been used as a rational basis for the treatment of autoimmune diseases, including type 1 diabetes. Recently, however, orally delivered antigens were shown to induce CD8 cytotoxic T-lymphocytes (CTLs) capable of causing autoimmune diabetes. In this report, we have examined several mucosal routes for their ability to induce CTLs and autoimmune diabetes, with the aim of identifying approaches that would maximize tolerance and minimize CTL generation. In normal C57BL/6 mice, ovalbumin (OVA) delivered by either the oral or nasal routes or by aerosol inhalation was able to prime CTL immunity in both high- and low-dose regimens. To address the relevance of these CTLs to autoimmune disease, OVA was given to mice that transgenically expressed this antigen in their pancreatic beta-cells. Irrespective of antigen dose or the route of delivery, mucosal OVA triggered diabetes, particularly after intranasal administration. These findings suggest that CTL immunity is likely to be a consequence of mucosal antigen delivery, regardless of the regimen, and should be considered in the clinical application of mucosal tolerance to autoimmune disease prevention.
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Risk assessment, prediction and prevention of type 1 diabetes
Harrison LC
Pediatric Diabetes 2: 71-82 (2001)
Circulating antibodies to pancreatic beta-cell antigens are markers of islet autoimmunity. In first-degree relatives of persons with type 1 diabetes, the levels and range of antigen specificities of these islet antibodies reflect the risk for clinical diabetes. However, in the general population, in which the disease prevalence is up to 30-fold lower, the predictive value of islet antibodies is correspondingly less. Islet antibody assays are primarily research tools to identify 'prediabetic' individuals for secondary prevention trials, but can also discriminate type 1 diabetes in several clinical situations. Loss of first-phase insulin response (FPIR) to intravenous glucose signifies imminent diabetes, but FPIR is normal in most islet-antibody-positive individuals. The contribution of a single FPIR measurement to risk assessment is therefore limited, but rate of fall of FPIR may be a useful predictor. Although beta cells are destroyed by autoreactive T cells, the assay of islet antigen-reactive T cells is not routine. Genetically, the major histocompatibility complex encoding human leukocyte antigen (HLA) alleles accounts for about 50% of familial clustering of type 1 diabetes. HLA typing is not diagnostic, but can be used to differentiate high- from low-risk individuals, e.g. at birth. While 'preclinical' diagnosis raises important medical and ethical questions, an optimized screening strategy provides a basis for counselling and follow-up. Recent knowledge of disease mechanisms and 'proof-of-principle' in the non-obese diabetic (NOD) mouse model justify expectations that type 1 diabetes is preventable, and even intervention that only delays onset of clinical diabetes is likely to be cost-effective.
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The mucosal interface between 'self' and 'non-self' determines the impact of environment on autoimmune diabetes
Solly NR, Honeyman MC , Harrison LC
Curr Dir Autoimmun 4:68-90 (2001)
The primary role of the immune system is
defence against pathogens, within the context
of maintaining homeostasis between 'self' and 'non-self'. The mucosal surfaces, especially
of the gastrointestinal, naso-respiratory and
genitourinary tracts represent critical physical
and functional interfaces between internal
'self' and external 'non-self'. At these sites,
the mucosal immune system plays a seminal
role in maintaining the delicate balance
between defence against pathogens
(immunity) and accommodation of nonpathogenic
resident bacteria and a host of
potentially immunogenic dietary or inhaled
proteins (mucosal tolerance). Given this
gatekeeper function of the mucosa at the
interface between 'self' and 'non-self', the role
of environmental factors in predisposing to or
triggering autoimmune diabetes must be
considered within the context of mucosal
physiology.
Internal 'self' and external 'non-self' are
separated by a single layer of epithelial cells
covering mucosal surfaces. In addition to
being a physical barrier, mucosal epithelial
cells are actively involved in mucosal
immunity. Intestinal epithelial cells (IEC)
constitutively express major
histocompatability complex (MHC) class II
as well as the non-classical MHC class Ilike
molecules CD1d and thymus
leukaemia antigen (TLA), and interact
directly with intraepithelial lymphocytes
(IEL) via cadherin E - αEβ7 integrin,
respectively. In vitro, IEC can process
and present dietary antigen to primed CD4 T
cells. Although they do not form a
discrete, organised lymphoid tissue, IEL are
distributed between and at the basement of
IEC in number equivalent to that of all T cells
present in the spleen and lymph nodes.
IEL are the first lymphoid cells to contact
external 'non-self', are constitutively
cytotoxic, and have a primary role in mucosal
immune responses. In mice, half the IEL
express Thy-1, αβ T-cell receptor (TCR) and
CD8αβ heterodimer; the others express γδ
(~40%) or αβ TCR (~10%) and CD8αα-
homodimer, and are unique in having an
extrathymic ontogeny . In
humans, γδ T cells constitute a lesser
proportion of small intestinal IEL, although
this increases in the large intestine. In addition to IEL, the mucosal immune system
comprises the loosely organised lamina
propria lymphocytes located directly beneath
the epithelium, lymphoid nodules called
Peyer's patches and mesenteric lymph nodes
that interface with the systemic immune
system.
