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Antigen-specific immunotherapy for type 1 diabetes: maximizing the potential.

Peakman M, von Herrath M - Diabetes (2010)

View Article: PubMed Central - PubMed

Affiliation: Department of Immunobiology, National Institute for Health Research, Comprehensive Biomedical Research Centre at Guy's and St Thomas' National Health Service Foundation Trust, King's College London, London, UK. mark.peakman@kcl.ac.uk

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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... Predicting the outcome of immunization with islet antigens is complex... The resulting immune response depends not only on the dose, frequency, and route of administration but also on the precise context, in which the use of suitable adjuvants and inflammation can profoundly influence the resulting immune response or lack thereof... Thus, successful ASIs that prevent type 1 diabetes in animal models are associated with the induction of cytokines, which can be considered as protective from type 1 diabetes (immune deviation) and are produced by CD4+ T-cells that can function as aTregs... In this context, the difference between immune deviation and Treg induction is mainly a semantic argument... The control of effector responses of various specificities (bystander suppression) likely occurs through modulation of antigen-presenting cells (APCs) resulting in a lack of anti-islet effector T-cell expansion, but not their deletion... There are three major areas of concern for the use of ASI in type 1 diabetes: acceleration of disease, leading to more rapid β-cell loss; induction of life-threatening hypersensitivity; and induction of “off-target” autoimmunity... For example, an extensive analysis of the literature in relation to the nonobese diabetic (NOD) model of spontaneous autoimmune diabetes (in which, for example, approximately 100 published studies since 1996 have involved injection or ingestion of whole or peptide autoantigens, either as simple solutions or in conjunction with powerful adjuvants) has revealed that it is extremely unusual to accelerate disease; in most cases the maneuvers are protective or have no effect... Based on preclinical models, several factors are emerging as critical in determining the outcome of antigen-specific immunizations, most notably dose, route, adjuvant, and frequency of administration... Studies have shown that too frequent antigen administrations, as well as very high dosages, do not result in optimal induction of immune regulation and tolerance... IL-4 is exquisitely protective in various animal models for type 1 diabetes and has a large therapeutic range, especially when delivered locally to the pancreatic islets or lymph nodes via β-cell antigen–specific Tregs... These options include strategies for the delivery of multiple epitopes from multiple antigens to mirror the approach that is proving successful in clinical allergy; the use of steroid hormone adjuvants (glucocorticoids and vitamin D) to modulate APCs presenting autoantigens both in vitro for adoptive transfer and in vivo to enhance tolerance induction in the skin; new methods for the delivery of antigens to the gut using Lactococcus lactis gene modified to deliver islet autoantigens and cytokines; using soluble T-cell receptors specific for islet peptides (for details, see http://naimit.eu/); and antigens coupled to inert cells... We would advocate a return to these questions, addressed in the context of small clinical studies with the emphasis on mechanistic outcomes... A second line approach will be the development of suitable combinations of antigens with immune modulators that have been specifically selected to foster Treg function and expansion while reducing the effector cell load.

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Approaches currently under evaluation for delivery of antigen-specific immunotherapy. DCs, dendritic cells.
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Figure 3: Approaches currently under evaluation for delivery of antigen-specific immunotherapy. DCs, dendritic cells.

Mentions: The future is not all bleak: several new strategies are emerging that may well achieve success in enhancing the delivery and potency of ASI and when assembled together, the ASI portfolio offers a number of appealing options (Fig. 3). These options include strategies for the delivery of multiple epitopes from multiple antigens to mirror the approach that is proving successful in clinical allergy; the use of steroid hormone adjuvants (glucocorticoids and vitamin D) to modulate APCs presenting autoantigens both in vitro for adoptive transfer (32,33) and in vivo to enhance tolerance induction in the skin; new methods for the delivery of antigens to the gut using Lactococcus lactis gene modified to deliver islet autoantigens and cytokines; using soluble T-cell receptors specific for islet peptides (for details, see http://naimit.eu/); and antigens coupled to inert cells. As discussed above, these approaches tend to center on novel modes of antigen delivery, perhaps partially as a means to generate funding interest or intellectual property and thus to sustain the effort. Additional strategies will also be useful if conducted in parallel; notable among these strategies is the emerging interest in analyzing immune responses, tolerance, and ASI through investigation of disease models generated in silico (34).


Antigen-specific immunotherapy for type 1 diabetes: maximizing the potential.

Peakman M, von Herrath M - Diabetes (2010)

Approaches currently under evaluation for delivery of antigen-specific immunotherapy. DCs, dendritic cells.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2927927&req=5

Figure 3: Approaches currently under evaluation for delivery of antigen-specific immunotherapy. DCs, dendritic cells.
Mentions: The future is not all bleak: several new strategies are emerging that may well achieve success in enhancing the delivery and potency of ASI and when assembled together, the ASI portfolio offers a number of appealing options (Fig. 3). These options include strategies for the delivery of multiple epitopes from multiple antigens to mirror the approach that is proving successful in clinical allergy; the use of steroid hormone adjuvants (glucocorticoids and vitamin D) to modulate APCs presenting autoantigens both in vitro for adoptive transfer (32,33) and in vivo to enhance tolerance induction in the skin; new methods for the delivery of antigens to the gut using Lactococcus lactis gene modified to deliver islet autoantigens and cytokines; using soluble T-cell receptors specific for islet peptides (for details, see http://naimit.eu/); and antigens coupled to inert cells. As discussed above, these approaches tend to center on novel modes of antigen delivery, perhaps partially as a means to generate funding interest or intellectual property and thus to sustain the effort. Additional strategies will also be useful if conducted in parallel; notable among these strategies is the emerging interest in analyzing immune responses, tolerance, and ASI through investigation of disease models generated in silico (34).

View Article: PubMed Central - PubMed

Affiliation: Department of Immunobiology, National Institute for Health Research, Comprehensive Biomedical Research Centre at Guy's and St Thomas' National Health Service Foundation Trust, King's College London, London, UK. mark.peakman@kcl.ac.uk

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

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... Predicting the outcome of immunization with islet antigens is complex... The resulting immune response depends not only on the dose, frequency, and route of administration but also on the precise context, in which the use of suitable adjuvants and inflammation can profoundly influence the resulting immune response or lack thereof... Thus, successful ASIs that prevent type 1 diabetes in animal models are associated with the induction of cytokines, which can be considered as protective from type 1 diabetes (immune deviation) and are produced by CD4+ T-cells that can function as aTregs... In this context, the difference between immune deviation and Treg induction is mainly a semantic argument... The control of effector responses of various specificities (bystander suppression) likely occurs through modulation of antigen-presenting cells (APCs) resulting in a lack of anti-islet effector T-cell expansion, but not their deletion... There are three major areas of concern for the use of ASI in type 1 diabetes: acceleration of disease, leading to more rapid β-cell loss; induction of life-threatening hypersensitivity; and induction of “off-target” autoimmunity... For example, an extensive analysis of the literature in relation to the nonobese diabetic (NOD) model of spontaneous autoimmune diabetes (in which, for example, approximately 100 published studies since 1996 have involved injection or ingestion of whole or peptide autoantigens, either as simple solutions or in conjunction with powerful adjuvants) has revealed that it is extremely unusual to accelerate disease; in most cases the maneuvers are protective or have no effect... Based on preclinical models, several factors are emerging as critical in determining the outcome of antigen-specific immunizations, most notably dose, route, adjuvant, and frequency of administration... Studies have shown that too frequent antigen administrations, as well as very high dosages, do not result in optimal induction of immune regulation and tolerance... IL-4 is exquisitely protective in various animal models for type 1 diabetes and has a large therapeutic range, especially when delivered locally to the pancreatic islets or lymph nodes via β-cell antigen–specific Tregs... These options include strategies for the delivery of multiple epitopes from multiple antigens to mirror the approach that is proving successful in clinical allergy; the use of steroid hormone adjuvants (glucocorticoids and vitamin D) to modulate APCs presenting autoantigens both in vitro for adoptive transfer and in vivo to enhance tolerance induction in the skin; new methods for the delivery of antigens to the gut using Lactococcus lactis gene modified to deliver islet autoantigens and cytokines; using soluble T-cell receptors specific for islet peptides (for details, see http://naimit.eu/); and antigens coupled to inert cells... We would advocate a return to these questions, addressed in the context of small clinical studies with the emphasis on mechanistic outcomes... A second line approach will be the development of suitable combinations of antigens with immune modulators that have been specifically selected to foster Treg function and expansion while reducing the effector cell load.

Show MeSH