Antigen-specific Immunotherapy for Type 1 Diabetes: Maximizing the Potential

Mark Peakman; Matthias von Herrath

Diabetes. 2010;59(9):2087-2093.

Abstract and Introduction

Introduction

The identification and study of autoimmune diseases has taught us that recognition of self-antigens can have devastating consequences. Yet there is a paradox to autoreactivity: when correctly balanced, it is at the heart of robust self-tolerance. This concept gives rise to several questions. Can this balance be manipulated? And if so, by what means and through which mechanisms? What are the rules that govern this opportunity to restore homeostasis?

Studies in a variety of animal models, which act as replicas of the major chronic inflammatory diseases that affect humans, have offered many answers to these questions. One of the clearer outcomes is that delivery of autoantigens, administered at different disease stages via a variety of routes, can provide robust, sustained health and protection from inflammatory autoimmune disease. The most appealing element to this approach, termed antigen-specific immunotherapy (ASI), has been that it not only provides an effective means of controlling the autoimmune response via induction or restoration of β-cell–specific tolerance, but that it may achieve these goals without major concerns over safety and certainly without the specter of immune suppression. Yet significant questions remain. Are we doing enough to realize the potential of this sacred cow? How do we move from concept to reality?

In this article, we provide an update on the mechanisms through which ASI is currently thought to operate. We discuss why, despite this body of knowledge, alternative, non-ASI approaches have emerged as the current vogue. We argue that more should be done to counter this trend and realize the potential of ASI, including strategies that combine its strengths with those of other complementary ways forward.

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Table 1. Mechanisms of action of antigen-specific immunotherapy and predicted nature of response
Mechanism	Predicted outcomes	Tolerance induction	Durability
Immune regulation induced against β-cell antigen (typically associated with aTregs, IL-10, TGF-β induction)	Responses should be detectable (e.g., by cytokine production or functional read-out)	Operational tolerance should be achieved	Responses durable in the range of months up to 1 year
	Should offer benefit of linked suppression of response to other β-cell antigens
Immune deviation associated with change of dominant cellular phenotype (e.g., from T_H1 to T_H2)	Responses should be detectable (e.g., by cytokine production or functional read-out)	Operational tolerance should be achieved	Responses durable in the range of months
	May offer benefit of linked suppression
Immune deletion of β-cell antigen-specific T-cells	Difficult to detect deletion	Operational tolerance not guaranteed	Transient (weeks/months)
	No benefit of linked suppression

Table 2. Explanations for the paucity of antigen-specific immunotherapy studies in the intervention setting
	"Biologics" and other nonantigen-specific approaches	Antigen-specific immunotherapy
Biomarkers	Facile (e.g., reduction in B-cells during anti-CD20 therapy)	Emerging but remain typically site and study-specific; lack of consensus
Dosing and route of administration	Clear treatment pathways from Phase I studies and/or other diseases	Often difficult and complex in ASI; issues over use of adjuvants unresolved; optimal routes remain to be determined
Preclinical models	Generally robust and informative	Translation not always straightforward (e.g., is the intranasal route appropriate in humans; antigen or peptide choice; timingof therapy in relation to natural history)
Success in other autoimmune diseases	Yes	Not yet (but whole allergen and allergen peptide immunotherapy are effective)
Target population	All patients with type 1 diabetes	Inclusion criteria may require staging to presence of selected autoantibodies and their titre, and to HLA type for peptides
Efficacy	Often effective as interventions	Intervention is a tough arena for trials with metabolic outcomes (i.e., C-peptide preservation)
Safety	Variable but generally predictable	Good
Biotechnology/Pharmaceutical involvement	High	Variable; e.g., there is still no Good Manufacturing Practice (GMP) grade proinsulin; new Intellectual Property (IP) reliesupon novel modes of delivery

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