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CD28/CD154 blockade prevents autoimmune diabetes by inducing nondeletional tolerance after effector t-cell inhibition and regulatory T-cell expansion.

Rigby MR, Trexler AM, Pearson TC, Larsen CP - Diabetes (2008)

Bottom Line: Blocking T-cell signaling is an effective means to prevent autoimmunity and allograft rejection in many animal models, yet the clinical translation of many of these approaches has not resulted in the success witnessed in experimental systems.Improved understanding of these approaches may assist in developing safe and effective means to treat disorders such as autoimmune diabetes.Immunotherapies that selectively suppress effector T-cells while permitting the development of natural regulatory mechanisms may have a unique role in establishing targeted long-standing immune protection and peripheral tolerance.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA. mrigby@emory.edu

ABSTRACT

Objective: Blocking T-cell signaling is an effective means to prevent autoimmunity and allograft rejection in many animal models, yet the clinical translation of many of these approaches has not resulted in the success witnessed in experimental systems. Improved understanding of these approaches may assist in developing safe and effective means to treat disorders such as autoimmune diabetes.

Research design and methods: We studied the effect of anti-CD154 and CTLA4-Ig on diabetes development, and the requirements to induce tolerance in nod.scid mice after transfer of transgenic beta-cell reactive BDC2.5.NOD T-cells.

Results: Nod.scid recipients of diabetogenic BDC2.5.NOD cells were protected indefinitely from diabetes by a short course of combined costimulation blockade, despite the continued diabetogenic potential of their T-cells. The presence of pathogenic T-cells in the absence of disease indicates peripheral immune tolerance. T-cell maturation occurred in protected recipients, yet costimulation blockade temporarily blunted early T-cell proliferation in draining pancreatic nodes. Tolerance required preexisting regulatory T-cells (Tregs), and protected recipients had greater numbers of Tregs than diabetic recipients. Diabetes protection was successful in the presence of homeostatic expansion and high T-cell precursor frequency, both obstacles to tolerance induction in other models of antigen-specific immunity.

Conclusions: Immunotherapies that selectively suppress effector T-cells while permitting the development of natural regulatory mechanisms may have a unique role in establishing targeted long-standing immune protection and peripheral tolerance. Understanding the mechanism of these approaches may assist in the design and use of therapies for human conditions, such as type 1 diabetes.

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Related in: MedlinePlus

More FoxP3+ T-cells are found in tolerant than diabetic or donor BDC.NOD mice. Lymphocytes were isolated from pancreatic (Panc LN) and mesenteric and cervical nondraining LNs (ND LN) from nod.scid mice rendered diabetic, protected from diabetes with costimulation blockade (both 6 weeks after adoptive transfer), from BDC.NOD mice, and from NOD mice. Cells were stained for surface molecules, fixed, permeabilized, stained for intracellular FoxP3, and then analyzed by flow cytometry. FoxP3 expression gated on CD4+CD3+ cells is shown and is representative of at least four independent experiments.
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f6: More FoxP3+ T-cells are found in tolerant than diabetic or donor BDC.NOD mice. Lymphocytes were isolated from pancreatic (Panc LN) and mesenteric and cervical nondraining LNs (ND LN) from nod.scid mice rendered diabetic, protected from diabetes with costimulation blockade (both 6 weeks after adoptive transfer), from BDC.NOD mice, and from NOD mice. Cells were stained for surface molecules, fixed, permeabilized, stained for intracellular FoxP3, and then analyzed by flow cytometry. FoxP3 expression gated on CD4+CD3+ cells is shown and is representative of at least four independent experiments.

Mentions: Our data indicate that combined CD154/CD28-blockade arrests diabetogenesis before the peri-insulitis stage. Tregs are involved in the induction and maintenance of immune tolerance in many models of allo- and autoimmunity. In NOD and BDC.NOD mice, Tregs contribute to natural peripheral self-tolerance by interfering with the progression from peri-insulitis to destructive insulitis (checkpoint 2). To further elucidate the role of Tregs in this model, BDC.NOD donors and diabetic and tolerant recipients were evaluated for Tregs (vβ4+CD4+FoxP3+) (Fig. 6). Protected mice contain a greater percentage of Tregs than diabetic recipients, and interestingly both recipient groups have higher Treg percentages than donor BDC.NOD mice (Fig. 6) (35). Although Tregs (regulatory) and Teffs (nonregulatory) expand in nod.scid mice treated with CD154/CD28 blockade, expanded Teffs do not cause β-cell destruction concurrent with an apparent preferential expansion of Tregs.


CD28/CD154 blockade prevents autoimmune diabetes by inducing nondeletional tolerance after effector t-cell inhibition and regulatory T-cell expansion.

Rigby MR, Trexler AM, Pearson TC, Larsen CP - Diabetes (2008)

More FoxP3+ T-cells are found in tolerant than diabetic or donor BDC.NOD mice. Lymphocytes were isolated from pancreatic (Panc LN) and mesenteric and cervical nondraining LNs (ND LN) from nod.scid mice rendered diabetic, protected from diabetes with costimulation blockade (both 6 weeks after adoptive transfer), from BDC.NOD mice, and from NOD mice. Cells were stained for surface molecules, fixed, permeabilized, stained for intracellular FoxP3, and then analyzed by flow cytometry. FoxP3 expression gated on CD4+CD3+ cells is shown and is representative of at least four independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2551677&req=5

f6: More FoxP3+ T-cells are found in tolerant than diabetic or donor BDC.NOD mice. Lymphocytes were isolated from pancreatic (Panc LN) and mesenteric and cervical nondraining LNs (ND LN) from nod.scid mice rendered diabetic, protected from diabetes with costimulation blockade (both 6 weeks after adoptive transfer), from BDC.NOD mice, and from NOD mice. Cells were stained for surface molecules, fixed, permeabilized, stained for intracellular FoxP3, and then analyzed by flow cytometry. FoxP3 expression gated on CD4+CD3+ cells is shown and is representative of at least four independent experiments.
Mentions: Our data indicate that combined CD154/CD28-blockade arrests diabetogenesis before the peri-insulitis stage. Tregs are involved in the induction and maintenance of immune tolerance in many models of allo- and autoimmunity. In NOD and BDC.NOD mice, Tregs contribute to natural peripheral self-tolerance by interfering with the progression from peri-insulitis to destructive insulitis (checkpoint 2). To further elucidate the role of Tregs in this model, BDC.NOD donors and diabetic and tolerant recipients were evaluated for Tregs (vβ4+CD4+FoxP3+) (Fig. 6). Protected mice contain a greater percentage of Tregs than diabetic recipients, and interestingly both recipient groups have higher Treg percentages than donor BDC.NOD mice (Fig. 6) (35). Although Tregs (regulatory) and Teffs (nonregulatory) expand in nod.scid mice treated with CD154/CD28 blockade, expanded Teffs do not cause β-cell destruction concurrent with an apparent preferential expansion of Tregs.

Bottom Line: Blocking T-cell signaling is an effective means to prevent autoimmunity and allograft rejection in many animal models, yet the clinical translation of many of these approaches has not resulted in the success witnessed in experimental systems.Improved understanding of these approaches may assist in developing safe and effective means to treat disorders such as autoimmune diabetes.Immunotherapies that selectively suppress effector T-cells while permitting the development of natural regulatory mechanisms may have a unique role in establishing targeted long-standing immune protection and peripheral tolerance.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA. mrigby@emory.edu

ABSTRACT

Objective: Blocking T-cell signaling is an effective means to prevent autoimmunity and allograft rejection in many animal models, yet the clinical translation of many of these approaches has not resulted in the success witnessed in experimental systems. Improved understanding of these approaches may assist in developing safe and effective means to treat disorders such as autoimmune diabetes.

Research design and methods: We studied the effect of anti-CD154 and CTLA4-Ig on diabetes development, and the requirements to induce tolerance in nod.scid mice after transfer of transgenic beta-cell reactive BDC2.5.NOD T-cells.

Results: Nod.scid recipients of diabetogenic BDC2.5.NOD cells were protected indefinitely from diabetes by a short course of combined costimulation blockade, despite the continued diabetogenic potential of their T-cells. The presence of pathogenic T-cells in the absence of disease indicates peripheral immune tolerance. T-cell maturation occurred in protected recipients, yet costimulation blockade temporarily blunted early T-cell proliferation in draining pancreatic nodes. Tolerance required preexisting regulatory T-cells (Tregs), and protected recipients had greater numbers of Tregs than diabetic recipients. Diabetes protection was successful in the presence of homeostatic expansion and high T-cell precursor frequency, both obstacles to tolerance induction in other models of antigen-specific immunity.

Conclusions: Immunotherapies that selectively suppress effector T-cells while permitting the development of natural regulatory mechanisms may have a unique role in establishing targeted long-standing immune protection and peripheral tolerance. Understanding the mechanism of these approaches may assist in the design and use of therapies for human conditions, such as type 1 diabetes.

Show MeSH
Related in: MedlinePlus